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+ Aging, estrogen, and progesterone
+
+
+ Aging, estrogen, and progesterone
+
+
+
+ "Estrogen" refers not just to a family of steroids but to a class of substances that can produce
+ approximately the same effects as estradiol and its metabolites.
+
+
+
+
+ Even before the pure substance was isolated in the 1930s, the effects of fluid from ovarian follicles
+ were studied. It was soon discovered that many chemicals could produce similar effects.
+
+
+ By the middle of the century, many toxic effects of the estrogens were known, and more are being
+ discovered.
+
+
+ Cancer, abnormal blood clotting, and infertility were known to be caused by estrogen before 1940, but at
+ the same time the drug companies began calling estrogen "the female hormone," and claiming that it would
+ improve fertility.
+
+
+ Since the 19th century, some people argued that aging was caused by hormonal deficiency; for example,
+ the symptoms of thyroid deficiency resembled aging. The estrogen industry exploited this idea to create
+ the "hormone replacement" business.
+
+
+ Some hormones do decrease with aging, but others increase.
+
+
+
+ All of the unpleasant consequences of estrogen excess happen to resemble some of the events of aging.
+
+
+ If aging involves the same processes that are created by estrogen, then our knowledge of how to protect
+ ourselves against estrogen can be used to protect ourselves against aging.
+
+
+ Estrogen steals oxygen from mitochondria, shifting patterns of growth and adaptation.
+
+
+
+
+
+ The balance between what a tissue needs and what it gets will govern the way that tissue functions, in both
+ the short term and the long term. When a cell emits lactic acid and free radicals and the products of lipid
+ peroxidation, it's reasonable to assume that it isn't getting everything that it needs, such as oxygen and
+ glucose. With time, the cell will either die or adapt in some way to its deprived conditions.
+
+
+ In aging, tissues generally atrophy, with loss of both substance and activity. Ordinarily, organisms react
+ to stress with increased activity of the appropriate functional system, but when the stress is inescapable,
+ organisms adopt the strategy of decreasing their demands, as in hibernation or the defensive inhibition that
+ has been called parabiosis, the state of being "not fully alive." In many
+ situations, serotonin (which is closely associated with estrogen) seems to be an important inducer of this
+ state. There are many indications that estrogen is a factor [e.g., Shvareva & Nevretdinova, 1989,
+ Saltzman, et al., 1989] in functionally suppressed states such as hibernation, social subordination, learned
+ helplessness and depression. Social subordination in animals often involves high estrogen and reduced
+ fertility.
+
+
+
+ In good health, an animal's systems are designed so that certain tissues will be intensely but briefly
+ stimulated by estrogen. This stimulation by estrogen doesn't produce the normal amount of carbon dioxide, so
+ the tissue experiences oxygen deprivation, leading to swelling and cell division. (Along with the reduced
+ carbon dioxide production, there is increased lipid peroxidation).
+ Any similar stimulaton, whether it's produced by soot, or suffocation, or irradiation, will produce
+ the broad range of estrogen's effects, beginning with inflammation but ending with atrophy or cancer
+ if it is too prolonged.
+
+
+
+ Although, as the 21st century begins, the US government hasn't decided whether to classify estrogen as a
+ carcinogen, it was identified as a carcinogen in the first half of the 20th century--and a variety of
+ carcinogens were found to be estrogenic.
+
+
+ Many people studying estrogen's biological effects observed that certain of its effects resembled the
+ changes seen in aging, such as fibrotic changes of connective tissues, accelerated accumulation of age
+ pigment, a tendency to miscarry, or the production of degenerative changes in various organs. But as far as
+ I know, I was the first one to suggest that aging itself involves increased estrogen dominance. (Taking this
+ perspective suggests many specific things to do for aging. And, if radiation injury, and stress, are
+ "estrogenic," it suggests that specific anti-estrogenic treatments could be appropriate.) I based my
+ argument on the identity of the biochemical and tissue effects produced by aging and by estrogenic excess.
+ At that time, techniques for the accurate measurement of very small amounts of estrogen hadn't been fully
+ developed. I felt that the situation should have been clear, because of the previous decades of research,
+ and I used that as the context for arguing that the reason for age-related infertility was the same as for
+ estrogen-induced infertility or stress-related infertility, namely, the inability to deliver oxygen to the
+ embryo. I thought of the developing embryo as a sensitive indicator of processes that occur throughout the
+ body during aging and stress, and that the destruction of the embryo by the excessive estrogen of the birth
+ control pill was closely analogous to the progressive loss of function that occus in so many tissues during
+ normal aging.
+
+
+ After I wrote my dissertation, Terry Parkening, who had worked in the same lab, sent me data from rats,
+ showing that his measurements confirmed the increase of estrogen with aging. Since then, many others have
+ shown that either the absolute levels of estrogen, or the ratio of estrogen to the antiestrogens, increases
+ with aging in a wide variety of organisms of both sexes, including humans.
+
+
+ In the 1970s, the claims about estrogen curing osteoporosis apparently had been debunked. At the time, that
+ appeared to be the last of the major claims for the therapeutic properties of estrogen. Studies in dogs were
+ starting to show that estrogen was an important cause of degenerative bone disease, as well as kidney
+ disease, liver disease, thyroid disease, etc. Hormones used in contraceptives were producing cancer in dogs,
+ as well as many other diseases, so dog research was widely abandoned by the drug industry/FDA, in favor of
+ animals that were less sensitive, or differently sensitive, to the hormones. The claims that the industry
+ was making were contradicted by the dog research, so they sought new animal "models" that wouldn't so
+ clearly contradict their claims.
+
+
+
+ A great advantage, for the drug industry, of using rats instead of dogs is that expensive, and often
+ embarrassing, long-term experiments aren't possible in such short-lived animals. Rats die when their tissues
+ still appear to be relatively young. Although excess prolactin (resulting from excess estrogen) in humans is
+ an important cause of osteoporosis, in rats at a certain age and on a certain diet, hyperprolactinemia can
+ stimulate bone growth. [Piyabhan, et al., 2000, Yeh, et al., 1996] This trait of rats could be very
+ advantageous to the estrogen industry.
+
+
+ All of the maladies caused by estrogen excess appear to develop in the same way that it interferes with
+ pregnancy, by driving the tissue to require more energy and oxygen than can be delivered to it. Necrosis,
+ the death of sections of tissue, was produced acutely by extreme overdoses of estrogen, or gradually by less
+ extreme overdoses, and if the estrogenic stimulation was milder but very prolonged, the result would usually
+ be tumors, sometimes developing in the midst of atrophy or necrosis. An overdose of estrogen was used to
+ shrink breasts and prevent lactation, and an even larger dose was used to kill breast tissue in treating
+ cancer.
+ A recent study (Toth, et al., 2000) shows that, at least in women, estrogen is closely associated
+ with the general loss of fat-free tissue with aging. This shows a close association
+ between the generalized atrophy of aging and the amount of estrogen in the tissues.
+
+
+ In the case of the embryo that can't implant in the aged or estrogenized uterus, it is because oxygen is
+ being consumed so fast by the uterus that very little is available for the embryo. The uterus is,
+ effectively, in an inflamed state, and the embryo is in a state that requires abundant oxygen. The general
+ loss of tissue that Toth associated with increased estrogen follows many of the same steps that occur in the
+ failure of the embryo to implant in the uterus: Glycogen is depleted in futile oxidative
+ cycles, protein synthesis is inhibited, lipid peroxides and free radicals accumulate, cellular defensive and
+ repair processes replace normal functioning.
+
+
+
+ (With aging, the loss of glycogen in the brain has serious consequences, including insomnia. Estrogen's
+ depletion of glycogen in other tissues is probably important for their functioning, and thyroid and
+ progesterone are known to help maintain the glycogen stores.)
+
+
+ In the last several years, according to the medical literature estrogen would seem to have outgrown nearly
+ all of its bad traits. It protects the brain, the heart, the blood vessels, even the fetus, and it prevents
+ many kinds of cancer, and improves memory, mood, and immunity. And it would still seem to be of great
+ promise in treating breast cancer and prostate cancer, if we took some medical journals seriously. It
+ achieves many of these nice things by functioning as an antioxidant and by increasing circulation, often
+ acting through nitric oxide and serotonin or melatonin. Even though I have read thousands of the articles
+ that said otherwise, the near unanimity of the current research literature can almost give me the feeling
+ that things might not be exactly as they had seemed.
+
+
+ In fact they aren't, but the change is in what passes for science, rather than in the way organisms respond
+ to estrogen. Many little pictures are being presented, that seem to add up to a very different big picture.
+ It is clear that this new picture is being painted by those who fund the research, and by some of those
+ whose careers depend on that funding. The people who do the odd little studies of estrogen and cytokines,
+ nitric oxide, regulatory genes, and so on, are usually getting the data they claim to get, and if they draw
+ speculative conclusions about what their study means medically, that's their privilege. But hundreds of
+ these little publications that would be harmless individually, add up to national policy endorsed by the FDA
+ and other powerful agencies--they add up to the same sort of criminal conspiracy that the tobacco industry
+ and its researchers perpretrated throughout the twentieth century.
+
+
+ Journals that are considered to be the best in their field publish many papers that simply misrepresent some
+ of the basic facts, while interpreting experimental results that would otherwise have unpleasant commercial
+ implications.
+
+
+ For example, the follicular phase is a time of low steroid production by the ovary, until near the end of
+ the phase, just before ovulation, when estrogen rises. The luteal phase is a time of high estrogen and high
+ progesterone synthesis. Many publications describe the follicular phase as a time of high estrogen, and the
+ luteal phase as a time of low estrogen, roughly the opposite of the actual situation. And an even larger
+ number of studies get the results they want by using a short exposure to estrogen to study something which
+ takes a long time to develop.
+
+
+ In the last few years, one of the most common tricks of estrogen promotion is to argue that estrogen
+ protects against heart disease and Alzheimer's disease because it relaxes blood vessels, by increasing the
+ formation of nitric oxide. It does generally increase the formation of nitric oxide, but nitric oxide is a
+ toxic free radical that plays a major role in degenerative diseases. And the inappropriate relaxation of
+ blood vessels, coupled with increased clottability of the blood, is a major cause of pulmonary embolisms and
+ venous disorders.
+
+
+
+ In studies of tendons, excess estrogen, aging, and cooking (the phenomenon of the curling pork chop) all
+ caused hardening and contraction of the collagen. When people get to be 90 or 100 years old, the opening
+ between their eyelids is sometimes contracted, presumably because of this process of collagen shrinkage. If
+ this shrinkage of connective tissue affects the large blood vessels, they become narrower and stiffer, so
+ that the blood has to travel faster if the same amount is to be delivered in the same time.
+
+
+ Ultrasound can be used to measure the velocity of the blood flow, and increased velocity will correspond to
+ constriction of the channel, if the same amount of blood is being delivered. But many people praise
+ estrogen's vascular benefits on the basis of tests showing increased
+ blood velocity in large arteries such as the aorta, without evidence that more blood is being circulated.
+ With aging, as arteries become constricted, increased blood velocity is taken as evidence of the pathology.
+ Velocity measurements have to be interpreted in the contexts of tissue perfusion, cardiac output, etc. When
+ the diameter of the artery is considered along with the velocity of the blood, the volume of flow can be
+ determined, and then it appears that progesterone increases blood flow, while estrogen can decrease it.
+ [Dickey and Hower, 1996.] This would be consistent with the known ability of an estrogen excess to cause
+ retarded growth of the fetus, as well as specific birth defects.
+
+
+ Estrogen does increase the blood flow to particular organs, but apparently less than it
+ increases their oxygen demand, as can be seen from the color change of estrogenized tissues, toward
+ purple, rather than pink.
+ Measurements of oxygen tension in the tissue show that estrogen decreases the relative availability of
+ oxygen. And when the level of estrogen is very high, metabolically demanding tissues, such as the kidney and
+ adrenal cortex, simply die, especially under conditions that restrict blood flow. [E.g., Kocsis, et al.,
+ 1988, McCaig, et al., 1998, Yang, et al., 1999.] When estrogen's effects overlap with the stimulating
+ effects of other hormones, such as pituitary hormones, particular organs undergo something similar to
+ "excitotoxicity." When estrogen overlaps with endotoxin (as it tends to do), multiple organ failure is the
+ result.
+
+
+ The simple need for more oxygen is a stimulus to increase the growth of blood vessels, and estrogen's
+ stimulation of non-mitochondrial oxygen consumption with the production of lactic acid stimulates blood
+ vessel formation. Progesterone, by increasing oxidative efficiency, opposes this "angiogenic"
+ (neovascularization) effect of estrogen.
+
+
+
+ Szent-Gyorgyi spent most of his career studying muscles--from the anal sphincter to pigeon breast to tense
+ goats. One of his most interesting experiments investigated the effects of estrogen and progesterone on the
+ heart muscle. He showed that estrogen excess prevents the increase of stroke volume as the speed increases,
+ but that progesterone increases the stroke volume as the heart accelerates, making pumping more effective
+ without unnecessary acceleration of the heart rate. These effects are parallel to Selye's observation that
+ estrogen imitates the shock reaction.
+
+
+ In shock, the blood pressure decreases, mainly because the blood volume decreases. Water is taken up by the
+ tissues, out of the blood. Much of the remaining blood volume is accumulated in the relaxed veins, and
+ little is returned to the heart, yet the increased need for circulation accelerates the heart, causing each
+ stroke to pump only a small amount. The reduced blood pressure caused many people to think that adrenaline
+ would help to improve the circulation, but actually the "resistance arteries," small arteries that provide
+ blood to the arterioles and capillaries, are constricted in shock, (Lin, et al., 1998,) and adrenaline
+ usually makes the situation worse. When tissue is poorly oxygenated (or is exposed to estrogen) it takes up
+ water, swelling and becoming more rigid, turgid. (It also takes up calcium, especially under the influence
+ of estrogen, causing muscles to contract.) This swelling effect will be much more noticeable in small
+ arteries than in major arteries with very large channels, but when the effect is prolonged, it will affect
+ even the heart, causing it to "stiffen," weakening its ability to pump. There is some evidence that estrogen
+ can make large arteries stiffen, over a span of a few months. (Giltay, et al., 1999)
+
+
+ Estrogen, by creating an oxygen deficiency, stimulates first swelling, and then collagen synthesis. Collagen
+ tends to accumulate with aging.
+
+
+ In shock, the cells are in a very low energy state, and infusions of ATP have been found to be therapeutic,
+ but simple hypertonic solutions of glucose and salt are probably safer, and are very effective. The low
+ energy of cells causes them to take up water, but it also causes the veins (which always receive blood after
+ most of its oxygen and nutrients have been extracted) to lose their tone, allowing blood to pool in them,
+ instead of returning to the heart. (Abel and Longnecker, 1978) This contributes to varicose veins
+ (Ciardullo, et al., 2000), and to orthostatic hypotension, which is seen in women who are exposed to too
+ much estrogen, and very frequently in old people.
+
+
+ The energy failure resulting from estrogen excess has been remarkably well characterized (but the meaning of
+ this for the cell hasn't been explored). The electron transfer process of the mitochondria is interrupted by
+ the futile redox cycling catalyzed by estrogens.
+
+
+ Good sleep requires fairly vigorous metabolism and a normal body temperature. In old age, the metabolic rate
+ is decreased, and sleep becomes defective. Protein synthesis declines with aging, as the metabolic rate
+ slows. At least in the brain, protein synthesis occurs most rapidly in deep sleep. [Nakanishi, et al., 1997;
+ Ramm and Smith, 1990]
+
+
+
+ In old age, the catabolic hormones such as cortisol are relatively dominant [Deuschle, et al., 1998], and
+ even in youth, cortisol rises during darkness, reaching its peak around dawn. Even in young women, bone loss
+ occurs almost entirely during the night, when cortisol is high. The hormones that are commonly said to
+ prevent bone loss, estrogen and growth hormone, are high at night, rising along with cortisol. Estrogen
+ causes growth hormone to increase, and in the morning, young women's growth hormone has been found to be 28
+ times higher than men's.[Engstrom, et al., 1999] The growth hormone response to estrogen is probably the
+ result of the changed use of glucose under estrogen's influence, making it necessary to mobilize free fatty
+ acids from tissues. While estrogen is usually highest at night, progesterone is lowest during the night.
+ These observations should suggest that progesterone, not estrogen, is the bone protective substance.
+
+
+ The disappearance of water from the blood, as it moves into the tissues during the night, makes sleep
+ resemble a state of shock or inflammation. Since rats, that are active at night, experience the same blood
+ thickening, it's actually the darkness, rather than sleep, that creates this "inflammatory" state. Estrogen
+ increases, and acts through, the inflammatory mediators, serotonin and histamine, to increase vascular
+ leakiness, at the same time that it causes cells to take up water and calcium. The formation of lactic acid,
+ in place of carbon dioxide, tends to coordinate these effects.
+
+
+ In sleep, as in shock, hyperventilation is common, and it sometimes produces extreme vasoconstriction,
+ because of the loss of carbon dioxide.
+
+
+ Since glucose and salt are used to treat shock (intravenous 7.5% salt solutions are effective), it seems
+ appropriate to use carbohydrate (preferably sugar, rather than starch) and salty foods during the night, to
+ minimize the stress reaction. They lower adrenalin and cortisol, and help to maintain the volume and
+ fluidity of blood. Thyroid, to maintain adequate carbon dioxide, is often all it takes to improve the blood
+ levels of salt, glucose, and adrenalin.
+
+
+ Temperature falls during sleep. Recent experiments show that hypothermia during surgery exacerbates the
+ edema produced by stress, and that hypertonic (hyperosmotic or hyperoncotic) solutions alleviate the
+ swelling. It is possible that light's action directly on the cells helps them to prevent swelling, and that
+ the body's infrared emissions have a similar function. Whatever the mechanism is, adequate temperature
+ improves sleep, and an excessive nocturnal temperature drop probably increases edema, with all of its
+ harmful consequences.
+
+
+ At least some of the redox cycles involving NAD/NADH and NADP/NADPH keep electrons from moving beyond
+ ubiquinone (coQ10) and energizing the mitochondria. The cycle that makes nitric oxide is one of these, but
+ some forms of estrogen participate directly as catalysts in this energy-stealing process. One of the effects
+ of blocking electron transfer in the mitochondria is to lower the energy charge of the cells, mimicking the
+ function of the age-damaged mitochondria. Glutathione and protein sulfhydryls are oxidized, because the
+ normal energy pathways that maintain them have been disrupted.
+
+
+
+ Estrogen directly lowers the temperature, while progesterone raises the temperature. Estrogen sets the
+ brain's temperature regulator lower, but, acting through serotonin and other mediators, it can actually
+ lower the metabolic rate, too.
+
+
+ Far from being just the "hormone of estrus," estrogen, in the form of estradiol and the related steroids,
+ plays a role in organisms as diverse as yeasts, worms and mollusks, and in modifying the function of
+ practically every type of animal cell--skin, nerve, muscle, bone, hair, gland, etc. But, as more and more of
+ its functions come to be understood, it turns out that many toxic chemicals and stressful physical processes
+ can activate the same functions, and that estrogen's association with the functions of stress makes it a
+ kind of window into some universal biological functions.
+
+
+ When Hans Selye brought it to our attention that "stress" was a general life process, he began a process of
+ generalization that led people to be able to see that the changes of aging were also the result of complex
+ interactions between organisms and their environment, rather than some genetic program that operates like a
+ clock running down.
+
+
+ When W. Donner Denckla demonstrated that the removal of an animal's pituitary (or, in the case of an
+ octopus, its equivalent optic gland) radically extended the animal's life span, he proposed the existence of
+ a death hormone in the pituitary gland. But the case of the octopus makes it clear that the catabolic,
+ death-inducing hormone is produced by the ovary, under the influence of the optic gland's gonadotropins.
+ This sacrifice of "the old" (the individual) for "the new" (the progeny) is analogous to the tissue wasting
+ we see under the influence of estrogen, as it stimulates cell division.
+
+
+ In Selye's classical stress, the destruction of tissues by the catabolic hormones makes sense in terms of
+ the "functional system" described by Anokhin, in which the hormones of adaptation dissolve one tissue for
+ use by the system which is adaptively functioning, with the production of carbon dioxide by the functional
+ tissue, stabilizing it and regulating the adequate delivery of blood.
+
+
+ Progesterone is both an anticatabolic hormone and an antiestrogenic hormone, and in both cases, it protects
+ the functional systems from atrophy.
+
+
+
+ The extreme generality of the phenomenon of "estrogenicity" that was built up during the twentieth century
+ has taken the concept beyond the specific functions of estrus, and reproduction, and the activation of
+ genetic programs of the female animal, to make it necessary to see it as a way that living substance
+ responds to certain kinds of stimulus. And these ways of responding turn out to be involved in the complex
+ but coherent ways that organisms respond to aging.
+
+
+ Selye gave various names to the biology of stress, but the "general adaptation syndrome" expressed the idea
+ accurately. But the biology of estrogenicity, like the biology of aging, is so central that any name is
+ likely to be misleading. The historical accident of naming a hormone for estrus shouldn't keep us from
+ thinking about the way estrogen affects our energetics and structure, and how those processes relate to
+ aging, atrophy, cancerization, etc.
+
+
+ While progesterone is probably the most perfect antiestrogenic hormone, and therefore an anti-stress and
+ anti-aging hormone, the recognition of a wide variety of estrogen's effects has made it possible to adjust
+ many things in our diet and environment to more perfectly oppose the estrogenic and age-accelerating
+ influences.
+
+ REFERENCES
+
+ Adv Shock Res 1978;1:19-27. Alterations in venous compliance in hemorrhagic shock. Abel FL,
+ Longnecker DE "Nine dogs and one primate were placed on total cardiopulmonary bypass and subjected to a
+ simulated hemorrhagic shock procedure." "These results are interpreted as indicating a different response of
+ the two vascular beds,
+ particularly an increase in IVC [inferior vena caval] arteriolar resistance with a decrease in venous
+ tone. To the extent that the splanchnic bed contributes to the IVC system changes, they are contrary to
+ the concept of a maintained venous tone and decreased arteriolar tone after hemorrhagic shock."
+
+
+
+ Acta Physiol Scand 1990 Sep;140(1):85-94. Effects of hypertonic NaCl solution on microvascular
+ haemodynamics in normo- and hypovolaemia. Bouskela E, Grampp W, Mellander S. "The aims of this
+ study were to investigate possible resuscitation effects of a single, 10-min, 350-microliters intravenous
+ infusion of 7.5% NaCl in hamsters in hemorrhagic shock and to compare the effects of such infusion with an
+ identical one of 0.9% NaCl on the hamster cheek pouch microcirculation during normovolaemia and after acute
+ bleeding to a hypotension level of about 40 mmHg. No significant differences could be detected between the
+ effects of either infusion given to normovolaemic normotensive hamsters. In the animals subjected
+ to haemorrhage, upon bleeding, arterioles larger than 40 microns constricted, arterioles
+ smaller than 40 microns dilated and venular diameter did not change, while blood flow decreased in all
+ vessels." "Central nervous and/or reflex excitation of the sympathetic nervous system could account for the
+ constriction of venules and larger arterioles, while a direct effect of hyperosmolarity could explain the
+ dilatation of the smaller arterioles. The study can therefore help to explain some of the mechanisms
+ underlying the reported resuscitation effect of 7.5% NaCl infusion in animals during severe haemorrhagic
+ hypovolaemia."
+
+
+ Medicina (B Aires) 1998;58(4):367-73. [Physiopathologic effects of nitric oxide and their
+ relationship with oxidative stress]. [Article in Spanish] Carrizo PH, Dubin M, Stoppani AO.
+ Nitric oxide (NO.) is produced from L-arginine, as result of a reaction catalyzed by the enzyme nitric oxide
+ synthase (NOS). The reaction is the sole source of NO. in animal tissues. NO. can control physiological
+ processes (or systems) such as (a) blood pressure; (b) relaxation of arterial smooth muscle; (c) platelet
+ aggregation and adhesion; (d) neurotransmission; (e) neuroendocrine secretion. NO. contributes to the
+ killing of pathogenic microorganisms and tumoral cells by phagocytes. NO. reacts with superoxide anion thus
+ producing peroxynitrite, a cytotoxic ion capable of destroying many biological targets. The
+ superoxide/peroxinitrite balance determines the ONOO- production and, accordingly, is essential for
+ the development of hypertension, atherosclerosis, neurodegenerative diseases, viral infections,
+ ischemia-reperfusion injury, and cancer.
+
+
+
+ Stress 1998 Dec;2(4):281-7. Effects of major depression, aging and gender upon calculated diurnal
+ free plasma cortisol concentrations: a re-evaluation study. Deuschle M, Weber B, Colla M,
+ Depner M, Heuser I. "Depression, aging and female gender are associated with increased diurnal
+ concentrations of total plasma cortisol." "This finding is in line with the observation that
+ in both conditions medical problems triggered and/or maintained by glucocorticoids (e.g.
+ osteoporosis) are frequently seen."
+
+
+ Adv Exp Med Biol 1975;53:359-69. The effect of nutritional regimes upon collagen concentration and
+ survival of rats. Deyl Z, Juricova M, Stuchlikova E "It has been demonstrated that food
+ restriction put upon animals at any stage of the individual's life, if chronic, produces a distinct increase
+ in the lifespan."
+ "Collagen starts to accumulate in the kidneys and liver of experimental animals roughly ten months
+ before 90 percent of the population dies out. Thus an increase in collagen concentration can be
+ indicative of involutional changes in the organ
+
+ (and perhaps organism)."
+
+
+ Early Pregnancy 1996 Jun;2(2):113-20. Relationship of estradiol and progesterone levels to uterine
+ blood flow during early pregnancy. Dickey RP, Hower JF. "After correction for gestational age,
+ estradiol was negatively related to uterine artery flow volume (p < 0.05), diameter (p < 0.05),
+ pulsatility index (p < 0.05) and resistance index (p < 0.01) for weeks 5-16 and to diameter (p <
+ 0.05) after week 9. Progesterone was positively related to volume (p < 0.05) and velocity (p <
+ 0.01) for weeks 5-16 and to volume (p < 0.05) for weeks 5 to 9. Spiral artery indices of
+ resistance were unrelated to hormone levels. These
+ results indicate that before the 10th gestational week, uterine blood flow volume is related to
+ progesterone, but not estradiol levels, and suggest that high estradiol levels during and after the 10th
+ week may be associated with decreased uterine blood flow volume."
+
+
+ Ann Surg 1998 Jun;227(6):851-60. Microvascular changes explain the "two-hit" theory of multiple
+ organ failure. Garrison RN, Spain DA, Wilson MA, Keelen PA, Harris PD "Acute bacteremia
+ alone results in persistent intestinal vasoconstriction and mucosal hypoperfusion. Little experimental
+ data exist to support the pathogenesis of vascular dysregulation during sequential physiologic
+ insults." "Acute bacteremia, with or without prior hemorrhage, caused significant large-caliber A1
+ arteriolar constriction with a concomitant decrease in blood flow. This constriction was
+ blunted at 24 hours after hemorrhage but was restored to control values by 72 hours." "These data indicate
+ that there is altered endothelial control of the intestinal microvasculature after hemorrhage in favor of
+ enhanced dilator mechanisms in premucosal vessels with enhanced constrictor forces in inflow
+ vessels."
+
+
+
+ Am J Physiol 1998 Jul;275(1 Pt 2):H292-300.
+ Estrogen reduces myogenic tone through a nitric oxide-dependent mechanism in rat cerebral
+ arteries.
+ Geary GG, Krause DN, Duckles SP. "Gender differences in the incidence of stroke and migraine appear
+ to be related to circulating levels of estrogen; however, the underlying mechanisms are not yet
+ understood.
+
+ Using resistance-sized arteries pressurized in vitro, we have found that myogenic tone of rat cerebral
+ arteries differs between males and females. This difference appears to result from estrogen enhancement of
+ endothelial nitric oxide (NO) production."
+
+
+ Free Radic Res 1999 Feb;30(2):105-17. Inactivation of myocardial dihydrolipoamide dehydrogenase by
+ myeloperoxidase systems: effect of halides, nitrite and thiol compounds. Gutierrez-Correa J,
+ Stoppani AO. "The summarized observations support the hypothesis that peroxidase-generated "reactive
+ species" oxidize essential thiol groups at LADH catalytic site."
+
+
+
+ Medicina (B Aires) 1998;58(2):171-8. [Myeloperoxidase as a factor of oxidative damage of the
+ myocardium: inactivation of dihydrolipoamide dehydrogenase].
+ Gutierrez Correa J, Stoppani AO. "Myocardial dihydrolipoamide dehydrogenase (LADH) is inactivated after
+ incubation at 30 degree C, with myeloperoxidase (MPO)-dependent systems."
+
+
+ J Natl Cancer Inst 1981 Aug;67(2):455-9. Synergism of estrogens and X-rays in mammary carcinogenesis
+ in female ACI rats. Holtzman S, Stone JP, Shellabarger CJ.
+
+
+ Br J Exp Pathol 1988 Apr;69(2):157-67. Effect of the anti-oestrogen tamoxifen on the development of
+ renal cortical necrosis induced by oestrone + vasopressin administration in rats.
+
+ Kocsis J, Karacsony G, Karcsu S, Laszlo FA. Bilateral renal cortical necrosis was observed after vasopressin
+ administration in rats pretreated with oestrone acetate. Histochemical (succinic dehydrogenase, trichrome,
+ periodic acid Schiff) and electronmicroscopic methods were used to examine how the anti-oestrogen,
+ Tamoxifen, influences the development of this renal cortical necrosis. The experiments revealed that in most
+ rats vasopressin did not induce renal tubular necrosis if the anti-oestrogen was administered
+ simultaneously, even during oestrogen pretreatment. The results suggest that oestrogen receptors in
+ the kidney are involved in the induction of renal cortical necrosis by vasopressin.
+
+
+
+ Br J Exp Pathol 1987 Feb;68(1):35-43.
+ Histochemical and ultrastructural study of renal cortical necrosis in rats treated with oestrone +
+ vasopressin, and its prevention with a vasopressin antagonist. Kocsis J, Karacsony G, Karcsu S,
+ Laszlo FA. Renal cortical necrosis was induced by the administration of vasopressin to
+ oestrogen-pretreated rats. Histochemical (succinic dehydrogenase, trichrome, perjod acid
+ Schiff) and electronmicroscopic methods were applied to examine how the vasopressin antagonist
+ d(CH2)5Tyr(Met)AVP influences the development of this renal cortical necrosis. The experiments revealed that
+ vasopressin did not induce hypoxia or necrosis in the renal tubules if the antagonist was administered
+ simultaneously, even after oestrogen pretreatment. The conclusion is drawn that this pressor antagonist may
+ be of value for the prevention of renal cortical necrosis in rats or in human beings.
+
+
+ Invest Radiol 1979 Jul-Aug;14(4):295-9. Serioangiographic study of renal cortical necrosis induced
+ by administration of estrin and vasopressin in rats. Kocsis J, Szabo E, Laszlo FA. We report a
+ serioangiographic method in rats which permits assessment of the course and dimensions of the renal
+ arteries, the durations of the arterial and venous phases, and the intensity and uniformity of the renal
+ parenchymal filling. The procedure was employed to study the mechanism by which administration of
+ vasopressin to rats pretreated with estrin leads to renal cortical necrosis. The pathogenetic significance
+ of the spasm localized on the larger renal arteries was proved directly; the possible role of the
+ arteriovenous shunt in the development of the renal ischemia was excluded.
+
+
+
+ Contrib Nephrol 1981;28:1-216.
+ Renal cortical necrosis. Experimental induction by hormones. Laszlo FA.
+
+
+ Morphol Igazsagugyi Orv Sz 1974 Jan;14(1):8-12 [The effect os estrogen, ACTH and cortisone
+ administration, as well as hypophysectomy on histological changes in unilateral renal hilus
+ ligation]. [Article in Hungarian] Laszlo F, Monus Z.
+
+
+ Eur J Neurosci 1997 Feb;9(2):271-9. Positive correlations between cerebral protein synthesis rates
+ and deep sleep in Macaca mulatta. Nakanishi H, Sun Y, Nakamura RK, Mori K, Ito M, Suda S, Namba
+ H, Storch FI, Dang TP, Mendelson W, Mishkin M, Kennedy C, Gillin JC, Smith CB, Sokoloff L.
+
+
+
+ Can J Physiol Pharmacol 2000 Oct;78(10):757-65. Changes in the regulation of calcium metabolism and
+ bone calcium content during growth in the absence of endogenous prolactin and during hyperprolactinemia:
+ a longitudinal study in male and female Wistar rats. Piyabhan P, Krishnamra N, Limlomwongse L
+ "Since endogenous prolactin has been shown to enhance food consumption, calcium absorption, and bone calcium
+ turnover in the pregnant rat, the role of endogenous prolactin in the regulation of calcium metabolism was
+ investigated in 3-day balance studies of female Wistar rats from the age of 3 to 11 weeks." "Results showed
+ that rapid growth occurred between 3 and 6 weeks with maximum fractional calcium absorption and calcium
+ retention at 5 weeks of age in both sexes. The data also showed a physiological significance of endogenous
+ prolactin in enhancing calcium absorption and retention in 5 week old rats. In an absence of prolactin, peak
+ calcium absorption was delayed in 7-week old animals, and vertebral calcium content of 11-week old animals
+ was reduced by 18%. Hyperprolactinemia in the AP group was found to enhance fractional calcium
+ absorption and calcium retention at 7, 9, and 11 weeks and increased the femoral calcium content by
+ 16%. It could be concluded that a physiological role of prolactin is the stimulation of calcium
+ absorption and maintainance of bone calcium content during growth and development."
+
+
+ Physiol Behav 1990 Nov;48(5):749-53. Rates of cerebral protein synthesis are linked to slow wave
+ sleep in the rat. Ramm P, Smith CT. Using L-[1-14C]leucine autoradiography, rates of cerebral
+ and local cerebral protein synthesis were studied during wakefulness, slow wave sleep (SWS) and REM sleep in
+ the rat. In the cerebrum as a whole, the rate at which labelled leucine was incorporated into tissues
+ was positively correlated with the occurrence of slow wave sleep. We failed to observe a significant
+ correlation of protein synthesis rate with either wakefulness or REM sleep. As in the cerebrum
+ as a whole, most discrete brain regions showed moderate positive correlations between the occurrence of SWS
+ and rates of protein synthesis. There were no brain regions in which rates of protein synthesis showed
+ striking correlations with sleep-wake states. Thus, the occurrence of SWS is associated with higher rates of
+ protein synthesis throughout the brain. These data suggest that SWS sleep favors the restoration of cerebral
+ proteins.
+
+
+
+ Surgery 1991 Oct;110(4):685-8; discussion 688-90. The effect of hypertonic saline resuscitation on
+ bacterial translocation after hemorrhagic shock in rats. Reed LL, Manglano R, Martin M, Hochman
+ M, Kocka F, Barrett J. "Recent work suggests that moderate hypovolemia causes gut arteriolar constriction,
+ which is ameliorated by hypertonic saline resuscitation. Bacterial translocation should, therefore, be
+ reduced when hypertonic saline (HS) is used as the resuscitative fluid." "Compared to autotransfusion,
+ hemodilutional resuscitation from hemorrhagic shock with
+ hypertonic saline resulted in a significant reduction in bacterial translocation (p values were 0.03 and
+ 0.04 for 3% and 7.5% hypertonic saline, respectively). The reduction in translocation after hypertonic
+ saline resuscitation may be the consequence of microcirculatory alterations preventing gut
+ hypoperfusion."
+
+
+ Am J Physiol 1999 Feb;276(2 Pt 2):H563-71. Changes in resistance vessels during hemorrhagic shock
+ and resuscitation in conscious hamster model.
+ Sakai H, Hara H, Tsai AG, Tsuchida E, Johnson PC, Intaglietta M. "The unanesthetized hamster dorsal skinfold
+ preparation was used to monitor
+ diameters and blood flow rates in resistance arteries (small arteries, A0: diameter, 156 +/- 23
+ micrometers) and capacitance vessels (small veins, V0: 365 +/- 64 micrometers), during 45 min of hemorrhagic
+ shock at 40 mmHg mean arterial pressure (MAP) and resuscitation. A0 and V0 vessels constricted
+ significantly to 52 and 70% of the basal values,
+
+
+ respectively, whereas precapillary arterioles (A1-A4, 8-60 micrometers) and collecting venules (VC-VL, 26-80
+ micrometers) did not change or tended to dilate. Blood flow rates in the microvessels declined to
+ <20% of the basal values."
+
+
+ Horm Behav 1998 Feb;33(1):58-74. Suppression of cortisol levels in subordinate female marmosets:
+ reproductive and social contributions. Saltzman W, Schultz-Darken NJ, Wegner FH, Wittwer DJ,
+ Abbott DH "Cortisol levels of cycling females were significantly higher than those of subordinates at all
+ parts of the cycle, but were significantly higher than those of ovariectomized females only during the
+ midcycle elevation. Unexpectedly, subordinates had significantly lower cortisol levels than ovariectomized
+ females,
+ as well as higher estradiol and estrone levels and lower progesterone and luteinizing hormone (LH)
+ levels."
+
+
+ Zh Evol Biokhim Fiziol 1989 Jan-Feb;25(1):52-9. [Seasonal characteristics of the functioning of the
+ hypophysis-gonad system in the suslik Citellus parryi]. Shvareva NV, Nevretdinova ZG "In
+ experiments on the arctic ground squirrel C. parryi, studies have been made on seasonal changes in the
+ weight of testes, follicular diameter in the ovaries and the content of sex and gonadotropic hormones in the
+ peripheral blood. Testicular involution and arrest of follicular development were observed in prehibernation
+ period. During hibernation, follicular growth and the increase in the weight of testes take place." "Estradiol secretion was noted in hibernating females, whereas progesterone was found in the blood
+ only in May."
+
+
+
+ Maturitas 1984 Nov;6(3):269-78. Spontaneous skin flushing episodes in the aging female rat.
+ Simpkins JW. It is well known that with the loss of gonadal function most women experience hot flushes,
+ characterized by a rapid regional increase in cutaneous blood flow. Animal models for this vasomotor
+ syndrome have been elusive, thus hampering efforts to evaluate the endocrine and neuronal substrates of the
+ hot flush. In this report, evidence is reported for the occurrence in aging female rats of spontaneous tail
+ skin temperature (TST) fluctuations which are similar in amplitude, duration and frequency to hot flushes
+ reported for peri-menopausal women. Paradoxically, these TST pulses occur in animals with senescent
+ reproductive states in which serum estrogen levels are moderately elevated and ovariectomy eliminates
+ these rat flushing episodes. This demonstration of steroid-dependent, spontaneous flushing
+ episodes indicates that the aging female rat can be used to evaluate the neuronal and hormonal basis of
+ vasomotor instability.
+
+
+ Carcinogenesis 1994 Nov;15(11):2637-43. The metabolism of 17 beta-estradiol by lactoperoxidase: a
+ possible source of oxidative stress in breast cancer. Sipe HJ Jr, Jordan SJ, Hanna PM, Mason
+ RP. Electron spin resonance (ESR) spectroscopy and oxygen consumption measurements using a
+ Clark-type oxygen electrode have been used to study the metabolism of the estrogen 17 beta-estradiol by
+ lactoperoxidase. Evidence for a one-electron oxidation of estradiol to its reactive phenoxyl
+ radical intermediate is presented. The phenoxyl radical metabolite abstracts hydrogen from reduced
+ glutathione generating the glutathione thiyl radical, which is spin trapped by 5,5-dimethyl-1-pyrroline
+ N-oxide (DMPO) and subsequently detected by ESR spectroscopy. In the absence of DMPO,
+ molecular oxygen is consumed by a sequence of reactions initiated by the glutathione thiyl radical.
+ Similarly, the estradiol phenoxyl radical abstracts hydrogen from reduced beta-nicotinamide-adenine
+ dinucleotide (NADH) to generate the NAD. radical.
+ The NAD. radical is not spin trapped by DMPO, but instead reduces molecular oxygen to the superoxide
+ radical, which is then spin-trapped by DMPO. The superoxide generated may either spontaneously
+ dismutate to form hydrogen peroxide or react with another NADH to form NAD., thus propagating a
+ chain reaction leading to oxygen consumption and hydrogen peroxide accumulation. Ascorbate
+ inhibits oxygen consumption when estradiol is metabolized in the presence of either glutathione or NADH by
+ reducing radical intermediates back to their parent molecules and forming the relatively stable ascorbate
+ radical. These results demonstrate that the futile metabolism of micromolar quantities of estradiol
+ catalyzes the oxidation of much greater concentrations of biochemical reducing cofactors, such as
+ glutathione and NADH, with hydrogen peroxide produced as a consequence. The accumulation of
+ intracellular hydrogen peroxide could explain the hydroxyl radical-induced DNA base lesions recently
+ reported for female breast cancer tissue.
+
+
+
+ Endocrinol Metab Clin North Am 1995 Sep;24(3):531-47. Idiopathic edema. Pathogenesis, clinical
+ features, and treatment.
+
+ Streeten DH. "Idiopathic edema is usually orthostatic." "It occurs almost exclusively in post-pubertal
+ women. . . ."
+
+
+ Carcinogenesis 1995 Apr;16(4):891-5. Mitochondrial enzyme-catalyzed oxidation and reduction
+ reactions of stilbene estrogen. Thomas RD, Roy D. "We have demonstrated for the first time that
+ mitoplasts (i.e. mitochondria without outer membrane) were able to convert stilbene estrogen
+ (diethylstilbestrol, DES) to reactive metabolites, which covalently bind to mitochondrial (mt)DNA. Depending
+ on the cofactor used, mitochondrial enzymes catalyzed the oxidation and/or reduction of DES. DES was
+ oxidized to DES quinone by peroxide-supported mitochondrial enzyme." "DES quinone was reduced to DES by
+ mitoplasts in the presence of NADH." "DES quinone was also reduced to DES by pure diaphorase, a
+ mitochondrial reducing enzyme, in the presence of NADH." "These data provide direct evidence of
+ mitochondrial enzyme-catalyzed oxidation and reduction reactions of DES. In the cell, activation of DES in
+ the mitochondria (the organelle in which mtDNA synthesis, mtDNA repair and transcription systems are
+ localized) is of utmost importance, because an analogous in vivo mitochondrial metabolism of DES through
+ covalent modifications in mitochondrial genome may produce instability in the mitochondrial genome of the
+ cells. These modifications may in turn play a role in the development of DES-induced hepatocarcinogenicity."
+
+
+ J Clin Endocrinol Metab 2000 Apr;85(4):1382-7. Regulation of protein metabolism in middle-aged,
+ premenopausal women: roles of adiposity and estradiol. Toth MJ, Tchernof A, Rosen CJ, Matthews
+ DE, Poehlman ET. The age-related loss of fat-free mass (FFM) is accelerated in women during the
+ middle-age years and continues at an increased rate throughout the postmenopausal period. Because
+ protein is the primary structural component of fat-free tissue, changes in FFM are largely due to
+ alterations in protein metabolism. Knowledge of the hormonal and physiological correlates of
+ protein
+
+
+
+
+ J Korean Med Sci 1999 Jun;14(3):277-85. The metabolic effects of estriol in female rat
+ liver. Yang JM, Kim SS, Kim JI, Ahn BM, Choi SW, Kim JK, Lee CD, Chung KW, Sun HS, Park DH,
+ Thurman RG. "Basal oxygen consumption of perfused liver increased significantly in estriol or
+ ethanol-treated rats."
+ "These findings suggest that the metabolic effects of estriol (two mg per 100 mg body wt) can be
+ summarized to be highly toxic in rat liver, and these findings suggest that oral administration of
+ estrogens may induce hepatic dysfunctions and play a role in the development of liver disease."
+
+
+ Bone 1996 May;18(5):443-50.
+ Ovariectomy-induced high turnover in cortical bone is dependent on pituitary hormone in rats.
+
+ Yeh JK, Chen MM, Aloia JF.. "Our results confirmed that OV increased and HX suppressed systemic and
+ periosteal bone formation parameters in both bone sites, OV increased and HX suppressed the gain in bone
+ size and bone mass. When OV rats were HX, the serum levels of osteocalcin and periosteal bone formation
+ parameters of the tibial shaft and the fifth lumbar vertebrae were, however, depressed and did not differ
+ from that of the HX alone. DXA results show that the effect of OV on bone size and bone mass is also
+ abolished by HX. In conclusion, we have demonstrated that OV increases tibial and lumbar vertebral bone
+ formation and bone growth and this effect is pituitary hormone dependent."
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Aging Eyes, Infant Eyes, and Excitable Tissues
+
+
+ Aging Eyes, Infant Eyes, and Excitable Tissues
+
+
+
+
+ The eyes and the lungs are sensitive tissues that are easily harmed by inappropriate environmental
+ exposure. They are especially sensitive in infancy and old age.
+
+
+ For 60 years there have been controversies about the cause of retinopathy of prematurity, which has
+ blinded tens of thousands of people.
+
+
+ Degeneration of the retina is the main cause of blindness in old people. Retinal injury is caused by
+ ordinary light, when the eyes are sensitized by melatonin, prolactin, and polyunsaturated fats. Bright
+ light isn't harmful to the retina, even when it is continuous, if the retina isn't sensitized.
+
+
+
+ Melatonin and prolactin are induced by stress, and darkness is a stress because it impairs mitochondrial
+ energy production.
+
+
+ The polyunsaturated fats which accumulate in the brain and retina damage mitochondria.
+
+
+ Iron, which accumulates prenatally, and then again with aging, reacts with unsaturated fats during
+ stress to destroy cells.
+
+
+ The popular supplements melatonin, tryptophan, fish oils, St. John's wort, and the various omega -3
+ oils, all increase the risk of retinal light damage and macular degeneration. Serotonin uptake
+ inhibiting antidepressants are suspected to be able to cause it.
+
+
+ Processes similar to those that damage the over-sensitized retina can occur in other cells, as a result
+ of stress. The substances that sensitize the retina to light-damage, can also increase the incidence of
+ new or metastatic cancers.
+
+
+
+ Iron supplements and the use of supplemental oxygen, especially with a vitamin E deficiency exacerbated
+ by excessive unsaturated fats in the diet, are still commonly used exactly when they can do the most
+ damage.
+
+
+
+
+ One of the recognized achievements of biology has been the demonstration of life"s universality, in the
+ sense that organisms of all sorts use the same fundamental genetic code, and that yeasts, lizards, apes, and
+ people have remarkably similar cellular systems, as well as a great amount of genetic similarity.
+
+
+
+ There has been another, less well recognized, sort of convergence going on in physiology and
+ pathophysiology. Hans Selye"s concept of stress, "the syndrome of being sick," Otto Warburg"s argument that
+ a "respiratory defect" was behind all kinds of cancer, and the idea of free radical damage as a common
+ factor in disease and aging, helped to create a more general way of looking at the nature of disease that
+ superceded medicine"s theories of disease pathogens and genetic mutations, which created thousands of
+ "disease entities," none of which had much to do with the individuality of the patient or his environment.
+
+
+ The understanding that plants and animals have much biochemistry in common has gradually changed the
+ assumptions of the science establishment, which until recently insisted that only "ionizing radiation" could
+ affect animals or other organisms that lacked chlorophyll--and insisted that ionizing rays acted only on the
+ DNA. Visible light, the textbooks said, was not "chemically active," and so couldn"t possibly affect
+ animals" cells. In animals, coloration was seen mainly as decoration and disguise, rather than as a
+ functional part of their biochemistry.
+
+
+ (Chemically, the meaning of "a pigment" is that it"s a chemical which selectively absorbs radiation. Old observations such as Warburg"s, that visible light can restore the activity of the "respiratory
+ pigments," showed without doubt that visible light is biochemically active.
+ By the 1960s, several studies had been published showing the inhibition of respiratory enzymes by
+ blue light, and their activation by red light. The problem to be explained is why the science culture simply
+ couldn"t accept crucial facts of that sort.)
+
+
+ The retina, of course, was allowed (in the views of mainline science) to respond to ordinary light, but the
+ few people who studied the biological effects of seasonal or daily cycles of light have until recently
+ stayed very close to the nerve pathways leading from the retina to the pineal gland, because those pathways
+ could be described in terms of an evolutionarily specialized "third eye." Even with a doctrine of a
+ genetically specialized link between the retina and a little of the animal"s physiological chemistry, the
+ great, slow-witted science establishment has done its best to avoid thoughts of any deep interaction between
+ an organism and its environment, by insisting that the organism runs according to a genetically determined
+ "clock" which is located in a few cells in a certain area of the brain, and that nervous impulses from the
+ retina have only the small privilege of "setting the clock."
+
+
+ It didn"t matter to the academic and medical worlds that a professor, Frank A. Brown, had long ago disproved
+ the idea of an innate genetic "clock," because philosophy is much stronger than evidence. Leibniz had said
+ that everything in the world runs on its own inner clock, without needing to perceive its surroundings, and
+ this idea that everything in the world is a "windowless monad" resonated through the world of science,
+ because it justified the pompous authoritarian attitudes of the experts who knew that anything that wasn"t
+ already in their heads couldn"t be considered knowledge. If an organism"s "essence is contained in
+ its genes," then it clearly doesn"t interact in any meaningful way with most of its environment. This is the sort of culture that imbued research on the biology of light cycles.
+
+
+
+ When I moved from Mexico, first to Montana and then to Oregon in 1966, I became very conscious of how light
+ affects the hormones and the health. (For example, in Montana I experienced an interesting springtime
+ shedding of body hair.) Many people who came to cloudy Eugene to study, and who often lived in cheap
+ basement apartments, would develop chronic health problems within a few months. Women who had been healthy
+ when they arrived would often develop premenstrual syndrome or arthritis or colitis during their first
+ winter in Eugene.
+
+
+ The absence of bright light would create a progesterone deficiency, and would leave estrogen and prolactin
+ unopposed. Beginning in 1966, I started calling the syndrome "winter sickness," but over the next few years,
+ because of the prominence of the premenstrual syndrome and fertility problems in these seasonally
+ exacerbated disorders, I began calling it the pathology of estrogen dominance. In the endocrinology classes
+ I taught at the National College of Naturopathic Medicine, I emphasized the importance of light, and
+ suggested that medicine could be reorganized around these estrogen-related processes. If the sparrows of
+ Times Square mated in the winter because of the bright lights, it seemed clear that bright artificial light
+ would be helpful in regulating human hormones.
+
+
+ In our lab at the University of Oregon, our hamsters would try to hibernate, even though they were in
+ temperature-controlled laboratories with regular cycles of artificial light. (The ceiling lights provided
+ only dim illumination inside their cage boxes, so they were probably in a chronic state of light
+ deprivation, which probably increased their sensitivity to the weak environmental cues that Frank Brown had
+ investigated, possibly microwaves that easily penetrated the lab walls.) During the winter, when they were
+ infertile, I found that their thymus glands practically disappeared. The mechanism seemed to include the
+ increase of pineal gland activity (probably increasing melatonin synthesis) in the winter, under the
+ intensified activity of the "sympathetic nervous system" (with increased activity of adrenalin and other
+ catecholamines), and the melatonin was apparently a signal for suppressing fertility during the stressful
+ winter. In some animals (Shvareva and Nevretdinova, 1989), estrogen is increased during hibernation,
+ contributing to the reduction of body temperature.
+
+
+ In 1994 A.V. Sirotkin found that melatonin inhibits progesterone production but stimulates estrogen
+ production, and it"s widely recognized that melatonin generally inhibits the thyroid hormones, creating an
+ environment in which fertilization, implantation, and development of the embryo are not possible. This
+ combination of high estrogen with low progesterone and low thyroid decreases the resistance of the organism,
+ predisposing it to seizures and excitotoxic damage, and causing the thymus gland to atrophy.
+
+
+ Cyclical exposure to melatonin can have an effect on the reproductive system opposite to that of chronic
+ exposure, and the way exogenous melatonin is delivered to the animal can have unexpected effects on the
+ actual amount of melatonin circulating in the blood (Wright and Alves, 2001). The actual amount of melatonin
+ in the tissues, its relation to the normal cycling of the animal, and the influence of temperature, are
+ often disregarded in melatonin research, making it hard to interpret many of the publications.
+
+
+ There is a lot of talk about melatonin"s function as an antioxidant, but, like so many other "antioxidants,"
+ melatonin can act as a pro-oxidant at physiologically relevant concentrations; some studies
+ have found that it, like estrogen, increases the activity of the pro-oxidative free radical nitric oxide
+ (which acts like melatonin on pigment cells, causing them to lighten). The promoters of estrogen are also
+ making claims that estrogen is a protective antioxidant, though that isn"t true of physiological
+ concentrations of estrogen, which can catalyze intense oxidations. The market culture seems to guide most
+ research in these substances.
+
+
+
+ Almost any kind of stress increases the formation of melatonin.
+
+
+ In some animals, melatonin has been shown to be responsible for whitening of the hair during the winter. In
+ some species it acts directly on the pigment cells, but in other species it seems to inhibit the action of
+ the melanocyte stimulating hormone.
+
+
+ In snowy climates, it"s "ecologically" rational for animals to turn white in the winter, for camouflage. But
+ tadpoles also turn white in the dark, or under the influence of melatonin, and the biological meaning of
+ that isn"t so clear. It"s possible that being white would reduce their loss of heat through radiation, but I
+ think it is more likely that it relates to an increased ability of weak radiation to penetrate their
+ tissues, rather than being stopped near the surface by the melanin in the skin. The absence of melanin makes
+ them more sensitive to light. Bright light suppresses their melatonin, and makes them turn dark brown or
+ black, and this protects them from bright sunlight.
+
+
+ In the retina, melatonin increases the sensitivity of the cells to dim light. It, along with prolactin,
+ another nocturnal hormone, helps to produce dark adaptation of the eyes.
+
+
+ Melatonin increases the concentration of free fatty acids during the night (John, et al., 1983; John and
+ George, 1976)), so it"s interesting that one of the long-chain highly unsaturated fatty acids, DHA
+ (docosahexaenoic acid), also increases the light sensitivity of the retina.
+
+
+ Melatonin lowers body temperature, causes vasoconstriction in the brain, heart, and other organs, and slows
+ reactions. An antagonist to melatonin acts as an antidepressant, reducing "behavioral despair" resulting
+ from stress. (Dubocovich, et al., 1990.) So, in the behavioral sense, melatonin reduces sensitivity, yet it
+ increases the eyes" sensitivity to light, causing them to be injured by light that would otherwise be
+ harmless.
+
+
+
+ Since a hibernating animal under the influence of melatonin can become very cold, the light-sensitizing
+ function of melatonin is probably related to the biological need to be roused out of the torpor
+ occasionally. (Hibernators apparently have to warm up occasionally to sleep in the ordinary manner.)
+ Melatonin is said to intensify dreaming, which is part of the process of arousal from sleep.
+
+
+ All of the stress-related hormones increase during the night. One of the ways these hormones of darkness act
+ is to increase the sensitivity to light, in a process that is an important adaptation for organisms in dim
+ light. In the night, our ability to see (and respond to) dim light is increased. But dark-adapted eyes are
+ very sensitive to injury by bright light. Light that ordinarily wouldn"t harm the eyes, will do serious
+ damage when the eyes are dark adapted.
+
+
+ In thinking about the effects of stress and oxygen deprivation, I read the studies demonstrating that the
+ formation of the oxygen-wasting age pigment, lipofuscin, is increased by estrogen, by oxygen deprivation (in
+ carp living below the ice, or even in fetuses), by metals such as iron, by x-rays, and by highly unsaturated
+ fats.
+
+
+ Free fatty acids that are mobilized from storage tissues in the night and in the winter also tend to
+ increase with aging, as the ability to tolerate stress decreases. Poor circulation and lipofuscin tend to be
+ associated, in a vicious cycle. This means that the retina becomes easier to injure by light in old age, for
+ some of the same reasons that the infant"s retina is susceptible.
+
+
+ The fetus accumulates a very large amount of iron, and it absorbs melatonin from the maternal circulation.
+ Prolactin is sometimes elevated in the newborn. Premature babies are often given extra oxygen, which tends
+ to cause vasoconstriction by displacing carbon dioxide. Melatonin"s ability to cause vasoconstriction means
+ that stress makes supplemental oxygen more toxic. Synthetic glucocorticoids are often given to premature
+ babies, adding to the risk of retinal damage.
+
+
+ When the mother has been given iron supplements during pregnancy, along with unsaturated oils in the diet,
+ the baby is likely to be born with a vitamin E deficiency and suppressed thyroid function, increasing the
+ probability that it will be jaundiced, leading to treatment of the jaundice with exposure to very bright
+ light.
+
+
+
+ Although Yandell Henderson had already, in 1928, explained the need for carbon dioxide to be used with
+ oxygen for resuscitating infants or adults, medical researchers and hospital workers could never accept the
+ idea, probably because of a fundamental misunderstanding of the Henderson-Hasselbalch equation. Animal
+ experiments show that supplemental oxygen, without carbon dioxide, causes vasoconstriction, reducing the
+ tissues" supply of glucose as well as oxygen. In combination with too much light, especially blue light, it
+ damages the retina. At hyperbaric pressure, oxygen causes seizures, as well as damage to the lungs and other
+ tissues.
+
+
+ The contribution of bright light to retinal damage in babies has been denied in several recent publications,
+ and these articles undoubtedly provide useful material for defense lawyers to use when hospitals are sued
+ for causing blindness. One publication based on experiments with kittens concludes that bright light does
+ not harm the newborn"s retina, but the comparison is between continuous light and intermittent light, rather
+ than between bright light and dim light. Twelve hours of total darkness, rather than sparing the eye by
+ reducing its exposure to light, would sensitize the eye. The only reason such appalling things can be
+ published is that their conclusions protect the hospitals.
+
+
+ A few good studies of the effect of bright light on the retina, and the fact that dark-skinned people with
+ more protective pigment in their eyes have a lower incidence of retinopathy of prematurity, make it clear
+ that the ordinary laws of physics and chemistry actually do apply to the infant eye.
+
+
+ Light and stress, especially with excess iron, damage the retina when the cells contain too much PUFA, since
+ these fats react with light and free radicals. The nocturnal/stress hormones, especially prolactin and
+ melatonin, make the retina more sensitive to light, and more easily damaged. (It's too much darkness that
+ sets up the problem, since the eyes will adapt to excess light, but darkness increases their sensitivity.)
+
+
+ The use of lasers to operate on eyes produces intense inflammation of the eye, but even at low dose the
+ diffusing light causes retinal/macular damage.
+
+
+ Cytochrome oxidase is one of the enzymes damaged by stress and by blue light, and activated or restored by
+ red light, thyroid, and progesterone. It's a copper enzyme, so it's likely to be damaged by excess iron. It
+ is most active when it is associated with a mitochondrial lipid, cardiolipin, that contains saturated
+ palmitic acid; the substitution of polyunsaturated fats lowers its activity. Mitochonrial
+ function in general is poisoned by the unsaturated fats, especially arachidonic acid and DHA.
+
+
+
+ Creating a "deficiency" of DHA, even when an oil of known toxicity is used to replace the omega -3 oils,
+ prevents retinal damage from light. Despite evidence of this sort, Mead Johnson is going ahead with the
+ marketing of its baby formula containing added DHA which is industrially extracted from algae. (Although the
+ researchers who claim that DHA is beneficial haven"t answered my letters, a representative of the company
+ that manufactures it did answer my question about the actual composition of the oil, and acknowledged that
+ they don"t have any idea what the minor ingredients might be.)
+
+
+ When animals are made "deficient" in all the exogenous polyunsaturated fatty acids, linoleic and arachidonic
+ acid as well as linolenic and DHA, they become remarkably resistant to all sorts of stress and toxins.
+
+
+ The polyunsaturated fats make the lungs more sensitive to excess oxygen or hyperventilation, they make the
+ eyes more sensitive to light, and they make the brain more sensitive to fatigue.
+
+
+ The use of synthetic glucocorticoid hormone is standard in treating very premature babies, although it is
+ known to contribute to eye damage. This is because it is considered necessary to improve the lung function
+ of premature babies with respiratory distress. But there is no clear evidence that it is beneficial for lung
+ function in the long run, and very clear evidence that it damages the brain and other organs. There is
+ widespread agreement regarding the use of the glucocorticoids
+ prenatally to accelerate lung development in women who seem likely to deliver
+ prematurely. Natural cortisol is a factor that promotes lung development prenatally. But cortisol is also a
+ signal produced by a stressed fetus, that triggers the birth process. Cortisol, or the synthetic
+ glucocorticoid, inhibits progesterone production, and stimulates estrogen production, activating uterine
+ contractions and other processes that terminate the pregnancy.
+
+
+ Apparently, it doesn"t occur to many people that administering the glucocorticoid triggers premature birth,
+ creating the problem they are intending to treat.
+
+
+
+ Recognizing causal connections between premature birth and respiratory distress and retinopathy of
+ prematurity, it would be obvious that the greatest effort should be made to prevent the problems by
+ improving the health of pregnant women. Hospitals, however, are invested in high technology systems for
+ treating these problems, and even though their results are dismal, they can"t make money by getting pregnant
+ women to eat enough protein to prevent preeclampsia, which is a major cause of premature birth, or by
+ treating the problems with salt, magnesium, progesterone, thyroid, and aspirin when the women haven"t had a
+ good diet.
+
+
+ Historically, preeclampsia has been blamed on the mother"s or fetus"s "bad genes," and that cultural bias
+ was the setting in which these high technology prenatal and neonatal systems developed. High technology
+ "neonatology" derives from the same ideology that motivated Josef Mengele"s genetic research in Auschwitz.
+ The idea of genetic determination is still motivating resistance to reasonable preventive approaches.
+
+
+ Thyroid, i.e., T3, is very effective in accelerating lung development in the fetus, and it doesn"t have any
+ of the harmful effects of the synthetic glucocorticoids. It normalizes the hormones, increasing progesterone
+ and decreasing estrogen, which are needed for full-term gestation, the opposite of the glucocorticoids"
+ effects. While the cortisol-like drugs damage the brain and other organs, thyroid and progesterone protect
+ them.
+
+
+ Old organisms, like newborns, are easily injured by all sorts of inappropriate excitation. As in
+ premature babies, the aged eyes, lungs, and brain are especially sensitive to damage by stress.
+ But all organs are subject to the same kinds of damage.
+
+ Medical treatments for respiratory distress and macular degeneration in old people are often the same as
+ those used so inappropriately for babies.
+ The good health practices that can prevent the inflammatory and degenerative diseases can often make
+ it possible for damaged tissues to recover, even in old age.
+
+
+
+ The pituitary hormones, especially prolactin and TSH, are pro-inflammatory, and darkness increases TSH along
+ with prolactin, so to compensate for a light deficiency, the pituitary should be well-suppressed by adequate
+ thyroid. Armour thyroid or Thyrolar or Cynoplus, Cytomel, would probably be helpful. (Eye-drops containing
+ T3 might be a way to restore metabolic activity more quickly.) Limiting water intake (or using salt
+ generously) helps to inhibit prolactin secretion. The saturated fats protect against the body's stored PUFA,
+ and keeping the blood sugar up keeps the stored fats from being mobilized. Aspirin (or indomethacin) is
+ generally protective to the retina, analogously to its protection against sunburn. Adequate vitamin E is
+ extremely important. There are several prescription drugs that protect against serotonin excess, but thyroid
+ and gelatin (or glycine, as in magnesium glycinate) are protective against the serotonin and melatonin
+ toxicities. Copper and magnesium deficiencies predispose to retinal damage. Red light is protective, blue
+ light (or u.v.) is harmful, so wearing orange lenses would be helpful. Progesterone and pregnenolone, by
+ reducing the stress reactions, should be helpful--in the eye diseases of infancy and old age, as they are in
+ the respiratory distress syndromes.
+
+ REFERENCES
+
+ Eksp Klin Farmakol 1999 Mar-Apr; 62(2):58-60.
+ [Melatonin lowers the threshold of light sensitivity of the human retina]
+ ; Arushanian EB, Ovanesov KB. Department of Pharmacology, Stavropol State Medical Academy, Russia. After
+ chronic use of melatonin (3 mg before night-time for 14 days) campimetry showed a significant decrease of
+ the threshold of brilliance sensitiveness of the retina in the absence of authentic changes of the
+ sensorimotor response latency in individuals of the older age group. A connection between the eye light
+ sensitivity and the direct effect of the hormone on the photoreceptors is suggested.
+
+
+ Cochrane Database Syst Rev 2001;4:CD001077. Restricted versus liberal oxygen exposure for preventing
+ morbidity and mortality in preterm or low birth weight infants (Cochrane Review). Askie LM,
+ Henderson-Smart DJ.
+
+
+ Prog Clin Biol Res 1989;312:95-112. The metabolism of omega-3 polyunsaturated fatty acids in the
+ eye: the possible role of docosahexaenoic acid and docosanoids in retinal physiology and ocular
+ pathology. Bazan NG.
+
+
+ Biull Eksp Biol Med 1976 Oct;82(10):1181-3. [Role of the biological activity of serotonin in the
+ production of the "shock lung" syndrome.] ; Bazarevich GI, Deviataev AM, Likhtenshtein AO,
+ Natsvlishvili BP, Sadeko MK.
+
+
+ Invest Ophthalmol Vis Sci 1993 Sep;34(10):2878-80.
+ An elevated hematogenous photosensitizer in the preterm neonate. Bynoe LA, Gottsch JD, Sadda
+ SR, Panton RW, Haller EM, Gleason CA.
+
+
+ Eur J Endocrinol 1995 Dec;133(6):691-5. Melatonin enhances cortisol levels in aged but not young
+ women. Cagnacci A, Soldani R, Yen SS
+
+
+
+ Am J Psychiatry 1976 Oct;133(10):1181-6. Negative effects of melatonin on depression.
+ Carman JS, Post RM, Buswell R, Goodwin FK. In order to test the efficacy of the pineal neurohumor melatonin
+ on depression, the hormone was administered in varying doses to six moderately to severely depressed
+ patients and two patients with Huntington's chorea in double-blind crossover study. Melatonin
+ exacerbated symptoms of dysphoria in these patients, as well as causing a loss of sleep and weight and a
+ drop in oral temperature. Melatonin increased cerebrospinal fluid 5-hydroxyindoleacetic acid and
+ calcium in three of four patients studied. The authors discuss the implications of this
+ finding.
+
+
+ Neuroendocrinol Lett 2001 Dec;22(6):432-4. Melatonin shortens the survival rate of Ehrlich
+ ascites-inoculated mice. Catrina SB, Curca E, Catrina AI, Radu C, Coculescu M. Dept.
+ Endocrinology II, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania. sergiu-bogdan.catrina@molmed.ki.se
+
+
+
+ J Neurochem 1988 Apr;50(4):1185-93. Induction of intracellular superoxide radical formation by
+ arachidonic acid and by polyunsaturated fatty acids in primary astrocytic cultures. Chan PH,
+ Chen SF, Yu AC.
+
+
+ Graefes Arch Clin Exp Ophthalmol 1993 Jul;231(7):416-23. Inhibition of cytochrome oxidase and
+ blue-light damage in rat retina. Chen E. St. Erik's Eye Hospital, Karolinska Institute,
+ Stockholm, Sweden.
+ The activity of cytochrome oxidase, outer nuclear layer thickness, and edema were quantitatively
+ evaluated in the blue-light exposed rat retina.
+ Dark-adapted or cyclic-light reared rats were exposed to blue light with a retinal dose of 380 kJ/m2.
+ Immediately, 1, 2, and 3 day(s) after exposure, the retinas of six rats from each adaptation group were
+ examined. There was no difference between the dark-adapted and cyclic-light reared rats. Immediately after
+ light exposure, cytochrome oxidase activity decreased. The activity in the inner segments remained low at
+ day 1, while severe edema was observed in the inner and outer segments. The outer nuclear layer thickness
+ decreased 1-3 days after exposure. The blue-light exposure inhibited cytochrome oxidase activity and caused
+ retinal injury. Similarity of the injury process in the dark-adapted and cyclic-light reared retinas
+ suggests that rhodopsin was not involved. The inhibition of cytochrome oxidase could be a cause of retinal
+ damage.
+
+
+
+ Acta Ophthalmol Suppl 1993;(208):1-50. Inhibition of enzymes by short-wave optical radiation and its
+ effect on the retina. Chen E. Eye Laboratory, St. Erik's Eye Hospital, Stockholm, Sweden.
+ "Exposure to short-wave optical radiation is a potential hazard for vision. In the present study, blue-light
+ damage is studied in rat retina." "Blue light inhibited cytochrome
+
+ oxidase
+ at a retinal dose of about 110 kJ/m2. This inhibition was reversible, and is probably related to the light
+ regulation of retinal metabolism. At a retinal dose of about 380 kJ/m2, the inhibition of cytochrome oxidase
+ was followed consecutively by a probable redistribution of chlorine and potassium in the inner and outer
+ segments, damage to the mitochondria in the inner segments, edema in the inner and outer segments, and
+ progressive degeneration of photoreceptor cells. Dark adaptation did not increase the blue-light retinal
+ injury. These findings support the hypothesis that inhibition of cytochrome oxidase is one of the
+ causes of blue-light retinal damage."
+
+
+ Aust N Z J Ophthalmol 1997 May;25 Suppl 1:S73-5. Retinal control of scleral precursor
+ synthesis. Devadas M, Morgan
+
+
+
+ Eur J Pharmacol 1990 Jul 3;182(2):313-25. Antidepressant-like activity of the melatonin receptor
+ antagonist, luzindole (N-0774), in the mouse behavioral despair test. Dubocovich ML, Mogilnicka
+ E, Areso PM.
+
+
+ J Pharmacol Exp Ther 1988 Sep;246(3):902-10. Luzindole (N-0774): a novel melatonin
+
+ receptor antagonist. Dubocovich ML.
+
+
+ Exp Eye Res 1985 Oct;41(4):497-507. The diurnal susceptibility of rat retinal photoreceptors to
+ light-induced damage. Duncan TE, O'Steen WK. Exposure of albino rats to high intensity light
+ results in rapid, graded loss of photoreceptors. The hormonal status and age of an animal at the time of
+ exposure affect the severity of light-induced retinal damage. The adrenal axis and pituitary hormones
+ (prolactin) have been demonstrated previously to affect the degree of cell death in the retina. Because
+ circadian rhythms for adrenal and pituitary secretion have been demonstrated in the rat, a series of
+ experiments was undertaken to determine if a diurnal pattern of retinal susceptibility to light damage
+ exists which might be related to endogenous endocrine rhythms. Male Sprague-Dawley rats were exposed to 4 hr
+ of high intensity fluorescent light for 8 consecutive days during different phases of the 14:10 hr light:
+ dark animal room light cycle. Morphometric analysis performed at the light microscopic level 2 weeks after
+ exposure demonstrated a differential susceptibility to light-induced cell death depending upon the period
+ during the light-dark cycle when animals received their daily light exposure. Neuronal cell death was
+ confined to the outer nuclear layer as previously described. The retinas of animals exposed during
+ the middle of the dark period or during the first 5 hr of the light period were significantly more
+ damaged than the retinas of animals exposed during the last 9 hr of the light period. Control
+ groups for the relative amounts of dark-adaptation between groups suggested that the diurnal susceptibility
+ to light damage was not solely dependent upon the degree of dark adaptation. These results demonstrate a
+ diurnal susceptibility of photoreceptors to light-induced cell death.
+
+
+
+ Nature 1983 Dec 22-1984 Jan 4;306(5945):782-4. Melatonin is a potent modulator of dopamine release
+ in the retina. Dubocovich ML.
+
+
+ Semin Perinatol 2000 Aug;24(4):291-8. Environmental light and the preterm infant.
+ Fielder AR, Moseley MJ. The lighting environment of the preterm baby is quite unlike that
+ experienced at any other time of life. Physical and physiological factors control how much light reaches the
+ retina of the preterm baby. With respect to the former, although many neonatal intensive care units are
+ brightly and continuously lit, there is a trend to employ lower levels of illumination and to introduce
+ cycling regimens. Physiological determinants of the retinal light dose include: eyelid opening and
+ transmission, pupil diameter and the transmission characteristics of the ocular media. Early exposure to
+ light does not significantly hasten or retard normal visual development, and it is not a factor in the
+ development of retinopathy of prematurity. However, ambient neonatal intensive care unit illumination may be
+ implicated in some of the more subtle visual pathway sequelae that cannot be attributed to other major
+ complications of preterm birth including altered visual functions and arrested eye growth.
+
+
+ Pediatrics 1992 Apr;89(4 Pt 1):648-53.
+ Light and retinopathy of prematurity: does retinal location offer a clue? Fielder AR, Robinson
+ J, Shaw DE, Ng YK, Moseley MJ. Nursery illumination has been implicated in the pathogenesis of retinopathy
+ of prematurity (ROP), although the results of recent studies are conflicting. The data base for this article
+ is a prospective ROP study on 607 infants of birth weight less than or equal to 1700 g including 35 larger
+ siblings from multiple births when 1 infant fulfilled the birth weight criteria. Retinopathy commences
+ preferentially in the nasal retina of the most immature neonate and is less likely to develop, or its onset
+ is delayed, in the superior and inferior
+ regions. These findings cannot be fully accounted for by regional vascular and neuroanatomical
+ variations. Radiometric and physiological evidence suggests that the very immature neonate, most at risk
+ of developing severe ROP, receives the greatest retinal irradiance. Furthermore, ROP commences in the
+ areas of the retina receiving the highest light dose, and its onset is either retarded or inhibited in
+ the darker retinal regions. Further studies are required to determine whether early exposure to
+ light is a factor in the development of ROP. If a causal relationship is proven, here at least is one
+ modality that can easily and immediately be controlled.
+
+
+
+ N Engl J Med 1985 Aug 15;313(7):401-4. Effect of bright light in the hospital nursery on the
+ incidence of retinopathy of prematurity. Glass P, Avery GB, Subramanian KN, Keys MP, Sostek AM,
+ Friendly DS. The preterm infant is subjected to prolonged exposure to ambient nursery illumination at levels
+ that have been found to produce retinal damage in animals. We prospectively investigated the effect of
+ exposure to light in two intensive care nurseries by comparing the incidence of retinopathy of prematurity
+ among 74 infants from the standard bright nursery environment (median light level, 60 foot-candles [ftc])
+ with the incidence among 154 infants of similar birth weight for whom the light levels were reduced (median,
+ 25 ftc). There was a higher incidence of retinopathy of prematurity in the group of infants who had
+ been exposed to the brighter nursery lights, particularly in those with birth weights below
+ 1000 g (86 percent vs. 54 per cent, P less than 0.01 by chi-square test). We conclude that the high level of
+ ambient illumination commonly found in the hospital nursery may be one factor contributing to retinopathy of
+ prematurity and that safety standards with regard to current lighting practices should be reassessed.
+
+
+ Doc Ophthalmol 1990 Mar;74(3):195-203. Light and the developing retina.
+ Glass P. George Washington University School of Medicine & Health Sciences, Washington, DC.
+ "Retinopathy of prematurity (ROP) has increased in the United States in the past decade."
+
+
+
+ Pediatr Res 1987 Oct;22(4):414-6. Calcemic responses to photic and pharmacologic manipulation of serum
+ melatonin. Hakanson DO, Penny R, Bergstrom WH.
+
+
+ Pediatr Res 1990 Jun;27(6):571-3. Pineal and adrenal effects on calcium homeostasis in the
+ rat. Hakanson DO, Bergstrom WH.
+
+
+ Science 1981 Nov 13;214(4522):807-9. Phototherapy-induced hypocalcemia in newborn rats: prevention
+ by melatonin. Hakanson DO, Bergstrom WH.
+
+
+ Doc Ophthalmol 1992;79(2):141-50. Diurnal variations in the electroretinographic c-wave and retinal
+ melatonin content in rats with inherited retinal dystrophy. Hawlina M, Jenkins HG, Ikeda H.
+
+
+
+ J.A.M.A. 90:353 (Feb. 25) 1928. The Prevention and Treatment of Asphyxia in the New-Born, Henderson,
+ Yandell.
+
+
+ Neuroendocrinology 2001 Feb;73(2):111-22. Estrogen modulates alpha(1)/beta-adrenoceptor- induced
+ signaling and melatonin production in female rat pinealocytes. Hernandez-Diaz FJ, Sanchez JJ,
+ Abreu P, Lopez-Coviella I, Tabares L, Prieto L, Alonso R.
+
+
+ J Neurosci Res 1989 Oct;24(2):247-50. Brain mitochondrial swelling induced by arachidonic acid and
+ other long chain free fatty acids. Hillered L, Chan PH.
+
+
+ J Neurosci Res 1988;19(1):94-100. Effects of arachidonic acid on respiratory activities in isolated
+ brain mitochondria.
+
+ Hillered L, Chan PH.
+
+
+ J Neurosci Res 1988 Aug;20(4):451-6. Role of arachidonic acid and other free fatty acids in
+ mitochondrial dysfunction in brain ischemia. Hillered L, Chan PH.
+
+
+ J Neurosci Res 1989 Oct;24(2):247-50.
+ Brain mitochondrial swelling induced by arachidonic acid and other long chain free fatty acids.
+ Hillered L, Chan PH.
+
+
+ J Clin Epidemiol 1992 Nov;45(11):1265-87. Oxygen as a cause of blindness in premature infants:
+ "autopsy" of a decade of errors in clinical epidemiologic research. Jacobson RM, Feinstein AR.
+ Clinical Epidemiology Unit, Yale University School of Medicine, New Haven, CT 06510. "Several intellectual
+ "autopsies" have recently reviewed errors in clinical epidemiologic studies of causation, such as the
+ original claim that amyl nitrite "poppers" caused AIDS. The current autopsy was done to determine why it
+ took
+ more than a decade--1942 to 1954--to end an iatrogenic epidemic in which high-dose oxygen therapy led to
+ retrolental fibroplasia (RLF) in premature infants, blinding about 10,000 of them.
+ The autopsy revealed a museum of diverse intellectual pathology."
+
+
+
+ Curr Eye Res 2001 Jul;23(1):11-9. Rod outer segments mediate mitochondrial DNA damage and apoptosis
+ in human retinal pigment epithelium.
+
+ Jin GF, Hurst JS, Godley BF.
+
+
+ Endocrinol Exp 1976 Jun;10(2):131-7. Diurnal variation in the effect of melatonin on plasma and
+ muscle free fatty acid levels in the pigeon.
+ John TM, George JC. Pigeons maintained on standard diet and held under 12 h daily photo-period in a
+ controlled environmental room, were given intravenous injections of melatonin. A low dose (1.25 mg/kg body
+ weight) of melatonin when given in the middle of the
+ scotophase, produced a significant increase in plasma FFA when estimated at 20 min and 90 min
+ post-injection, whereas no significant change was seen with injections given in the middle of the
+ photophase. No significant change in muscle FFA level was obtained either during the photophase or the
+ scotophase when estimated at 90 min postinjection. With a higher dose (5 mg/kg body weight) of
+ melatonin given in the scotophase, on the other hand, a significant increase
+ in both plasma as well as muscle FFA levels was obtained at 90 min post-injection but there was
+ no effect on plasma FFA at 20 min or 90 min post-injection in the photophase and at 20 min in the
+ scotophase. It is concluded that melatonin has a lipid mobilizing action in the pigeon when administered
+ during the scotophase.
+
+
+
+ Arch Int Physiol Biochim 1983 Jul;91(2):115-20. Diurnal impact of locomotory activity and melatonin
+ and N-acetylserotonin treatment on blood metabolite levels in the rainbow trout. John TM,
+ Beamish FW, George JC. In rainbow trout forced to swim continuously at sustained speeds for six weeks,
+ selected doses of melatonin or N-acetylserotonin (1.25 and 5.0 mg/kg body weight) injections caused no
+ change in haematocrit. Melatonin did not produce any significant change in plasma glucose level either in
+ the photophase or in the scotophase. However, diurnal variations were observed in the effect of melatonin on
+ plasma free fatty acids (FFA). Melatonin was ineffective in causing
+ any change in plasma FFA level during photophase but during scotophase, the higher dose (5.0 mg/kg)
+ produced an increase in FFA while the lower dose (1.25 mg/kg) had no effect, N-acetylserotonin
+ administration produced diurnal variation in its effect on both plasma glucose and FFA. The
+ higher dose of N-acetylserotonin brought about a drop in plasma glucose level during photophase, but both
+ doses were ineffective during scotophase. N-acetylserotonin produced no change in FFA during photophase, but
+ during scotophase tended to lower FFA level. It is suggested that exercise shortens the time required to
+ cause a hypoglycemic effect of N-acetylserotonin during photophase, blocks FFA release-inhibiting action of
+ melatonin observed in photophase, and minimizes the time required for the FFA mobilizing action of melatonin
+ in scotophase.
+
+
+ J Neural Transm 1977;40(2):87-97. The adrenal medulla may mediate the increase in pineal melatonin
+ synthesis induced by stress, but not that caused by exposure to darkness. Lynch HJ, Ho M,
+ Wurtman RJ.
+
+
+ Bull Acad Natl Med 2000;184(2):415-28; discussion 428-30. [Pulmonary toxicity of oxygen]
+ [Article in French] Mantz JM, Stoeckel ME.
+
+
+
+ Br J Pharmacol 1977 Dec;61(4):607-14. The action of melatonin on single amphibian pigment cells in
+ tissue culture. Messenger EA, Warner AE.
+
+
+ Oftalmol Zh 1989;(8):469-73. [The early diagnosis, evaluation of treatment results and modelling of
+ certain aspects of the pathogenesis of retinal dystrophy]
+ ; Mironova EM, Pavlova ON, Ronkina TI. The paper analyses results after a study of the functional state of
+ pigmented epithelium and the retina in patients with a dry form of senile macular dystrophy as well as of
+ experimental simulation of retinal dystrophy with the help of melatonin and its treatment by taurine.
+ Melatonin in 10(-3) M concentration leads to development of dystrophic changes in pigmented
+ epithelium and interacting with it structures, this being testified by remarkable lowering of EOG parameters
+ and electron microscopic findings. Taurine in 10(-3) M concentration blocks the action of exogenic
+ melatonin as well as has a pronounced positive action on metabolism of dystrophic changes in the
+ pigmented epithelium and photoreceptors. Examination of patients with different stages of a dry form of
+ senile
+ macular dystrophy revealed statistically significant reduction of KA cEOG at the initial stage of the
+ disease in the presence of normal ERG parameters. In 18% of patients, supernormal values of KA were
+ recorded, that are likely to reflect the presence of "predystrophic hyperactivity" of the pigmented
+ epithelium cells. In progression of the process, the further reduction of electrophysiologic values was
+ recorded. The data obtained speaks about the important role of pigmented epithelium pathology in the
+ pathogenesis of senile macular dystrophy and about high information value of the cEOG method for detection
+ of early stages of the disease. It is believed that disturbances in melatonin metabolism can be one of
+ causes leading to development of retinal dystrophy.
+
+
+ J Clin Endocrinol Metab 1977 Oct;45(4):768-74. The effects of oral melatonin on skin color and on
+ the release of pituitary hormones.
+ Nordlund JJ, Lerner AB. "We studied the effects of prolonged ingestion of melatonin, 1 g per day, on skin
+ color and the serum levels of pituitary hormones in 5 human subjects with hyperpigmented skin. Melatonin
+ lightened hyperpigmented skin of one patient with untreated adrenogenital syndrome, but had no effect on
+ three patients' skin with idiopathic hyperpigmentation and one patient with treated Addison's disease."
+
+
+ Invest Ophthalmol 1976 Oct;15(10):869-72. Hormonal influences on photoreceptor damage: the pituitary
+ gland and ovaries. Olafson RP, O'Steen WK. To determine whether the absence of pituitary or
+ ovarian hormones would influence retinal degeneration, female albino rats were either hypophysectomized
+ (HYPEX) or ovariectomized (OVEX) before pubery. Later, they were exposed to continuous light for periods up
+ to 45 days. Retinas evaluated by light microscopic measurements showed damage to the outer nuclear layer
+ (ONL) and photoreceptor layer in both the operated and intact, control rats. However, the degree of damage
+ observed in retinas of HYPEX and OVEX rats was significantly less than that observed in retinas of intact
+ rats exposed to the same lighting conditions. Therefore, hypophysectomy and ovariectomy, which influence the
+ normal development of sexual maturation when performed on immature rats, significantly reduce photoreceptor
+ damage in adult rats exposed to continuous light.
+
+
+ Invest Ophthalmol Vis Sci 1996 Oct;37(11):2243-57. Retinal light damage in rats with altered levels
+ of rod outer segment docosahexaenoate. Organisciak DT, Darrow RM, Jiang YL, Blanks JC.
+
+ PURPOSE: To compare retinal light damage in rats with either normal or reduced levels of rod outer segment
+ (ROS) docosahexaenoic acid. METHODS: Weanling male albino rats were maintained in a weak cyclic light
+ environment and fed either a nonpurified control diet or a purified diet deficient in the linolenic acid
+ precursor of docosahexaenoic acid (DHA). Half the rats on the deficient diet were given linseed oil,
+ containing more than 50 mol% linolenic acid, once a week to maintain ROS DHA at near normal levels. Diets
+ and linseed oil supplementation were continued for 7 to 12 weeks. To replenish DHA in their ROS, some
+ 10-week-old rats on the deficient diet were given linseed oil three times a week for up to 3 additional
+ weeks. Groups of animals were killed at various times for ROS fatty acid determinations or were exposed to
+ intense green light using intermittent or hyperthermic light treatments. The extent of retinal light damage
+ was determined biochemically by rhodopsin or photoreceptor cell DNA measurements 2 weeks after exposure and
+ morphologically by light and electron microscopy at various times after light treatment. RESULTS: Rats maintained for 7 to 12 weeks on the linolenic acid-deficient diet had significantly lower levels of
+ DHA and significantly higher levels of n-6 docosapentaenoic acid (22:5n-6) in their ROS than
+ deficient-diet animals supplemented once a week with linseed oil or those fed the nonpurified control diet.
+ As determined by rhodopsin levels and photoreceptor cell DNA measurements, deficient diet rats
+ exhibited protection against retinal damage from either intermittent or hyperthermic light exposure.
+ However, the unsaturated fatty acid content of ROS from all three dietary groups was the same
+ and greater than 60 mol%. In 10 week-old deficient-diet rats given linseed oil three times a week, ROS DHA
+ was unchanged for the first 10 days, whereas 22:5n-6 levels declined by 50%. After 3 weeks of treatment with
+ linseed oil, ROS DHA and 22:5n-6 were nearly the same as in rats supplemented with linseed oil from weaning.
+ The time course of susceptibility to retinal light damage, however, was different. Hyperthermic light damage
+ in rats given linseed oil for only 2 days was the same as for rats always fed the deficient diet. Six days
+ after the start of linseed oil treatment, retinal light damage was the same as in rats given the linseed oil
+ supplement from weaning. Morphologic alterations in ROS of linseed oil-supplemented rats immediately after
+ intermittent light exposure were more extensive than in either the deficient-diet animals or those fed the
+ control diet. The deficient-diet rats also exhibited better preservation of photoreceptor cell nuclei and
+ structure 2 weeks after exposure. CONCLUSIONS: Rats fed a diet deficient in the linolenic acid precursor of
+ DHA are protected against experimental retinal light damage. The relationship between retinal light damage
+ and ROS lipids does not depend on the total unsaturated fatty acid content of ROS; the damage appears to be
+ related to the relative levels of DHA and 22:5n-6.
+
+
+ Exp Neurol 1970 May;27(2):194-205.
+ Retinal and optic nerve serotonin and retinal degeneration as influenced by photoperiod.
+ O'Steen WK.
+
+
+ Invest Ophthalmol Vis Sci 1982 Jan;22(1):1-7. Antagonistic effects of adrenalectomy and
+ ether/surgical stress on light-induced photoreceptor damage. O'Steen WK, Donnelly JE.
+ Light-induced damage to retinal photoreceptors in influenced by the endocrine status of the animal during
+ the period of exposure. Experimental manipulation of the pituitary gland and of prolactin levels has been
+ shown to affect retinal damage in rats exposed to visible light. When rats are experimentally stressed,
+ prolactin secretion from the pituitary gland occurs as does secretion of adrenocorticotropic hormone (ACTH),
+ which stimulates the release of adrenal cortical hormones. Since prolactin appears to influence retinal
+ damage and since stressed animals have increased serum levels of prolactin, a comparison of photoreceptor
+ damage in animals in which the adrenal glands were removed or which had been experimentally stressed was
+ undertaken in this study. Adrenalectomized rats had thicker outer nuclear layer (ONL) measurements than
+ those found in sham-operated animals. Stressed rats had severely damaged retinas with cystic degeneration
+ and significantly reduced ONL thickness measurements as compared to retinas of unstressed and
+ adrenalectomized rats. Therefore hormones of the pituitary-adrenal system appear to be involved in
+ the damage to the retina by light, and this response may be related to an interaction or synergism
+ between the adrenal gland, stress, and prolactin secretion.
+
+
+
+ Brain Res 1990 Nov 26;534(1-2):99-105. Water deprivation protects photoreceptors against light
+ damage. O'Steen WK, Bare DJ, Tytell M, Morris M, Gower DJ. "Photoreceptor cell death after
+ light-damage and during aging in rats is associated with the hormonal status of the animal, as well as other
+ environmental and intrinsic factors. Restricted caloric intake extends the life of rodents and is usually
+ accompanied by a reduction in water consumption. In this study, male and female rats were placed on
+ restricted water intake for either 3 or 7 days to induce dehydration." "Photoreceptor cells of 7-day,
+ dehydrated male and female rats survived light-damage significantly better than those allowed water ad
+ libitum; however, after 3 days of water restriction, only the male rats demonstrated protection from
+ photodamage." "AVP increased by 350% during the 7-day period of dehydration. Protection of photoreceptors
+ from light-damage in this study may be correlated with osmotically stimulated changes in the retinas of
+ dehydrated animals."
+
+
+ Brain Res 1985 Oct 7;344(2):231-9. Neuronal damage in the rat retina after chronic stress.
+ O'Steen WK, Brodish A. Long-term exposure to escapable foot shock has been used to determine if chronic
+ stress influences neuronal cell death in the retina of albino and pigmented rats. Histopathologic and
+ morphometric approaches analyzed changes in photoreceptors and neurons of the bipolar and ganglion cell
+ layers of the retina. Albino Fischer rats when exposed to chronic stress for 4-8 h daily for 1 week to 6
+ months, developed severe retinal damage, as compared to unstressed control retinas, with reduction in
+ photoreceptor and bipolar neurons, particularly in the superior central retina. The damage was observed in
+ male and female rats, but males appeared to be more susceptible to the influence of stress than female
+ animals. Ganglion cells were unaffected. Photoreceptor destruction did not occur in Long-Evans pigmented
+ rats under identical experimental conditions. The results suggest that: input of the sensory
+ stimulus, light, to the retina of stressed rats augmented neuronal damage and might be required for its
+ initiation; and hormones and/or neurotransmitters associated with long-term chronic stress
+ might be related to increased neuronal cell death in the mammalian retina.
+
+
+ Invest Ophthalmol Vis Sci 1977 Oct;16(10):940-6. Effects of hypophysectomy, pituitary gland
+ homogenates and transplants, and prolactin on photoreceptor destruction. O'Steen WK, Kraeer SL.
+ "Prepubertal removal of the pituitary gland, which in young animals influences sexual maturation, reduces
+ significantly the amount of retinal photoreceptor destruction when the rats are exposed to continuous
+ illumination in adulthood. When crude pituitary gland homogenate is administered to adult rats
+ hypophysectomized prior to puberty, photoreceptor destruction is more severe. Transplantation of whole
+ pituitary glands to the kidney capsule of hypophysectomized rats also reduces the effect of pituitary gland
+ removal and results in more extensive damage to receptor cells than found in hypophysectomized, adult
+ animals. Hypophysectomized rats treated with prolactin had more severe retinal damage than
+ untreated, hypophysectomized rats." "Results of these studies indicate the hormones of the
+ pituitary gland have a regulatory influence on the severity of light-induced, retinal photoreceptor damage
+ in the rat."
+
+
+ Life Sci 1985 Nov 4;37(18):1743-6. Stress-induced synthesis of melatonin: possible involvement of
+ the endogenous monoamine oxidase inhibitor (tribulin). Oxenkrug GF, McIntyre IM.
+
+
+ Mech Ageing Dev 2000 Jan 10;112(3):169-83. Double bond content of phospholipids and lipid
+ peroxidation negatively correlate with maximum longevity in the heart of mammals. Pamplona R,
+ Portero-Otin M, Ruiz C, Gredilla R, Herrero A, Barja G.
+
+
+
+ Prostaglandins Leukot Essent Fatty Acids 2001 Feb;64(2):75-80. Comparative studies on lipid
+ peroxidation of microsomes and mitochondria obtained from different rat tissues: effect of retinyl
+ palmitate. Piergiacomi VA, Palacios A, Catala A.
+
+
+ Curr Eye Res 1992 Oct;11(10):939-53. Oxygen-induced retinopathy in the rat: hemorrhages and
+ dysplasias may lead to retinal detachment. Penn JS, Tolman BL, Lowery LA, Koutz CA.
+
+
+ Vision Res 1995 May;35(9):1247-64. Studies on the role of the retinal dopamine/melatonin system in
+ experimental refractive errors in chickens.
+
+ Schaeffel F, Bartmann M, Hagel G, Zrenner E.
+
+
+ Exp Clin Endocrinol Diabetes 1997;105(2): 109-12. Melatonin
+
+ and serotonin regulate the release of insulin-like growth factor-I, oxytocin and progesterone by
+ cultured human granulosa cells. Schaeffer HJ, Sirotkin AV.
+
+
+ Zh Evol Biokhim Fiziol 1989 Jan-Feb;25(1):52-9. [Seasonal characteristics of the functioning of the
+ hypophysis-gonad system in the suslik Citellus parryi] Shvareva NV, Nevretdinova ZG. "In
+ females, FSH was found in the blood in October, being absent from November to
+ January; beginning from February, it may be found both in sleeping and active animals." "Estradiol secretion was noted in hibernating females, whereas progesterone was found in the blood only in
+ May."
+
+
+
+ J Pineal Res 1985;2(1):39-49. Melatonin and N-acetylserotonin stress responses: effects of type of
+ stimulation and housing conditions. Seggie J, Campbell L, Brown GM, Grota LJ.
+
+
+ Acta Ophthalmol Scand 2001 Aug;79(4):428-30. Presumed sertraline maculopathy. Sener EC,
+ Kiratli H.
+
+
+ Paediatr Perinat Epidemiol 1999 Apr;13(2):128-30. Effects of premature exposure to light: a
+ credibility struggle. Silverman WA.
+
+
+
+ J Pineal Res 1994 Oct;17(3):112-7. Direct influence of melatonin on steroid, nonapeptide hormones,
+ and cyclic nucleotide secretion by granulosa cells isolated from porcine ovaries. Sirotkin AV.
+
+ "It was found that melatonin is able to inhibit progesterone and stimulate estradiol secretion." "The present observations suggest a direct effect of melatonin on the steroid, nonapeptide hormone, and
+ cyclic nucleotide release from porcine ovarian cells."
+
+
+ J Pineal Res 1994 Oct;17(3):112-7. Direct influence of melatonin on steroid, nonapeptide hormones,
+ and cyclic nucleotide secretion by granulosa cells isolated from porcine ovaries. Sirotkin AV.
+
+
+ Prog Clin Biol Res 1989;312:229-49. Inhibitors of the arachidonic acid cascade in the management of
+ ocular inflammation.
+
+ Srinivasan BD, Kulkarni PS.
+
+
+ J Nutr 2000 Dec;130(12):3028-33. Polyunsaturated (n-3) fatty acids susceptible to peroxidation are
+ increased in plasma and tissue lipids of rats fed docosahexaenoic acid-containing oils. Song
+ JH, Fujimoto K, Miyazawa T.
+ "Thus, high incorporation of (n-3) fatty acids (mainly DHA) into plasma and tissue lipids due to
+ DHA-containing oil ingestion may undesirably affect tissues by enhancing
+ susceptibility of membranes to lipid peroxidation and by disrupting the antioxidant system."
+
+
+ Acta Ophthalmol (Copenh) 1992 Feb;70(1):115-22. Effects of steady electric fields on human retinal
+ pigment epithelial cell orientation and migration in culture. Sulik GL, Soong HK, Chang PC,
+ Parkinson WC, Elner SG, Elner VM
+
+
+
+ Ned Tijdschr Geneeskd 2001 Dec 29;145(52):2521-5. [Administration of glucocorticosteroids to
+ premature infants: increasing evidence of adverse effects] [Article in Dutch] van Bel F.
+ "Neonatal glucocorticosteroid therapy is increasingly being used for the prevention of chronic lung
+ disease in very premature infants. In the short term this therapy is usually successful. There is,
+ however, increasing evidence for long-term adverse effects. In particular there seems to be an increased
+ chance of abnormal brain development, which later results in locomotory dysfunction, developmental delay
+ and cerebral palsy."
+
+
+ Brain Res 1984 Feb 27;294(1):166-8. Pineal methoxyindoles depress calcium uptake by rat brain
+ synaptosomes. Vacas MI, Keller Sarmiento MI, Cardinali DP.
+
+
+ Ann N Y Acad Sci 1994 Nov 17;738:408-18. Serotonin binding proteins: an in vitro model system for
+ monoamine-related neurotoxicity. Vauquelin G, Del Rio MJ, Pardo CV.
+
+
+
+ J Hypertens Suppl 1985 Dec;3 Suppl 3:S107-9. Seasonal variation in the development of stress-induced
+ systolic hypertension in the rat.
+ Weinstock M, Blotnick S, Segal M. "Seasonal variation in blood pressure in human hypertensives prompted us
+ to investigate whether such a phenomenon also occurs in rats made hypertensive by environmental stress."
+
+ "Systolic pressure increased by 14-25 mmHg after 6-8 weeks of stress from October to January. Artificial
+ environmental light for 15 h prevented development of hypertension by stress,
+
+ which could also be reversed by acute administration of propranolol." "Hypertensive rats had significantly
+ greater relative heart and adrenal weights. This phenomenon can be explained by amplification of
+ sympathetic pressor activity by stress hormones, adrenaline, corticosterone and prolactin, under the
+ influence of melatonin."
+
+
+ Invest Ophthalmol Vis Sci 1992 May;33(6):1894-902. Melatonin increases photoreceptor susceptibility
+ to light-induced damage. Wiechmann AF, O'Steen WK. "Pinealectomy has been shown to
+ protect photoreceptors from light-induced damage, and melatonin treatment has been reported to increase
+ the degree of photoreceptor damage in albino rats." "The animals that received daily melatonin
+ injections (100 micrograms) in the late afternoon (3 hr before lights off) for 1-3 days before photodamage
+ showed an approximate 30% greater reduction compared with sham control animals in ONL thickness in the
+ superior quadrant, the area most susceptible to light damage. Melatonin injections given after the
+ photodamage did not affect ONL thickness. Although retinal susceptibility to light damage varied with time
+ of day, the degree to which melatonin increased the degree of damage appeared unaffected by the time of day.
+ These results suggest that melatonin may be involved in some aspects of photoreceptor sensitivity to light
+ damage."
+
+
+
+ J Neurochem 1986 Oct;47(4):1181-9. Effects of arachidonic acid on glutamate and gamma-aminobutyric
+ acid uptake in primary cultures of rat cerebral cortical astrocytes and neurons. Yu AC, Chan
+ PH, Fishman RA.
+
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
+
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+
+ Altitude and Mortality
+
+
+ Altitude and Mortality
+
+
+
+
+ Breathing pure oxygen lowers the oxygen content of tissues; breathing rarefied air, or air with carbon
+ dioxide, oxygenates and energizes the tissues; if this seems upside down, it's because medical
+ physiology has been taught upside down. And respiratory physiology holds the key to the special
+ functions of all the organs, and to many of their basic pathological changes.
+
+
+ Stress, shock, inflammation, aging, and organ failure are, in important ways, respiratory
+ problems.
+
+
+ Definitions
+ Haldane effect:
+ Oxygen displaces carbon dioxide from hemoglobin, in proportion to its partial (specific) pressure.
+
+ Bohr effect: Carbon dioxide (or acidity) displaces oxygen from hemoglobin.
+ Lactic acidemia:
+ The presence of lactic acid in the blood.
+ Alkalosis: A pH of the blood above 7.4.
+ Acidosis:
+ A blood pH below 7.4.
+ Lactate paradox: The reduced production of lactic acid at a given work rate at high altitude.
+ Muscle work efficiency may be 50% greater at high altitude. ATP wastage is decreased.
+
+ There are some popular medical ideas that obstruct clear thinking about respiration. One is that high
+ altitude deprives you of oxygen, and is likely to be bad for people with heart disease and cancer. Another
+ is that breathing pure oxygen helps sick people to oxygenate their tissues while exerting less effort in
+ breathing. These are both exactly wrong, and the errors have been explored in quite a few publications, but
+ the ideas persist in the culture to such a degree that our perceptions and intuitions
+ have been misled, making closely related things seem to be unrelated. In this culture, it
+ is hard to see that heart disease, cancer, and cataracts all involve a crucial respiratory defect, with the
+ production of too much lactic acid and too little carbon dioxide, which leads to a "swelling
+ pathology": A pathological retention of water. The swollen heart beats poorly, the swollen
+ lens turns milky, other cells divide rapidly as a result of swelling.
+
+
+ People who live at very high altitudes live significantly longer; they have a lower
+ incidence of cancer (Weinberg, et al., 1987) and heart disease (Mortimer, et al., 1977), and other
+ degenerative conditions, than people who live near sea level. As I have written earlier, I think the lower
+ energy transfer from cosmic radiation is likely to be a factor in their longevity, but several kinds of
+ evidence indicate that it is the lower oxygen pressure itself that makes the biggest contribution to their
+ longevity.
+
+
+
+ "Mountain sickness" is a potentially deadly condition that develops in some people when they ascend too
+ rapidly to a high altitude. Edema of the lungs and brain can develop rapidly, leading to convulsions and
+ death. The standard drug for preventing it is acetazolamide, which inhibits carbonic anhydrase and causes
+ carbon dioxide to be retained, creating a slight tendency toward acidosis. This treatment probably mimics
+ the retention of carbon dioxide that occurs naturally in altitude adapted people. The reasons for mountain
+ sickness, and the reasons for the low incidence of heart disease, cancer, cataracts, etc., at high altitude,
+ offer clues to the prevention of death and deterioration from many other causes.
+
+
+ When the weather in a particular place is cool, sunny and dry (which in itself is very good for the health)
+ the atmospheric pressure usually is higher than average. Although sunny dry weather is healthful,
+ periods of higher pressure correspond to an increased incidence of death
+ from heart disease and strokes.
+
+
+ The Haldane-Bohr effect describes the fact that oxygen and carbon dioxide destabilize each other"s binding
+ to hemoglobin. When oxygen pressure is high, the blood releases its carbon dioxide more easily. In stormy
+ weather, or at high altitude, the lower oxygen pressure allows the body to retain more carbon dioxide.
+ Carbon dioxide, produced in the cells, releases oxygen into the tissues, relaxes blood vessels, prevents
+ edema, eliminates ammonia, and increases the efficiency of oxidative metabolism.
+
+
+ Hyperventilation, breathing excessively and causing too much carbon dioxide to be lost, is similar to being
+ in the presence of too much oxygen; it"s similar to being at low altitude with high
+ atmospheric pressure, only worse. Therefore, the physiological events produced by hyperventilation can give
+ us an insight into what happens when the atmospheric pressure is low, by looking at the events in reverse.
+ Likewise, breathing 100% oxygen has known harmful consequences, which are very similar to those produced by
+ hyperventilation.
+
+
+
+ Hyperventilation is defined as breathing enough to produce respiratory alkalosis from the loss of carbon
+ dioxide. Lactic acid is produced in response to the alkalosis of hyperventilation.
+
+
+ Breathing too much oxygen displaces too much carbon dioxide, provoking an increase in lactic acid; too much lactate displaces both oxygen and carbon dioxide. Lactate itself tends to suppress
+ respiration.
+
+
+ Oxygen toxicity and hyperventilation create a systemic deficiency of carbon dioxide. It is this carbon
+ dioxide deficiency that makes breathing more difficult in pure oxygen, that impairs the heart"s ability to
+ work, and that increases the resistance of blood vessels, impairing circulation and oxygen delivery to
+ tissues. In conditions that permit greater carbon dioxide retention, circulation is improved and the heart
+ works more effectively. Carbon dioxide inhibits the production of lactic acid, and lactic acid lowers carbon
+ dioxide's concentratrion in a variety of ways..
+
+
+ When carbon dioxide production is low, because of hypothyroidism, there will usually be some lactate
+ entering the blood even at rest, because adrenalin and noradrenalin are produced in large amounts to
+ compensate for hypothyroidism, and the adrenergic stimulation, besides mobilizing glucose from the glycogen
+ stores, stimulates the production of lactate. The excess production of lactate displaces carbon dioxide from
+ the blood, partly as a compensation for acidity. The increased impulse to breath ("ventilatory drive")
+ produced by adrenalin makes the problem worse, and lactate can promote the adrenergic response, in a vicious
+ circle..
+
+
+ Since the 1920s when A. V. Hill proposed that the prolonged increase in oxygen consumption after a short
+ period of intense work, the "oxygen debt," was equivalent to the amount of lactic acid that had entered the
+ circulation from the muscles" anaerobic work, and that it had to be disposed of by oxidative processes,
+ physiology textbooks have given the impression that lactic acid accumulation was exactly the same as the
+ oxygen debt. In reality, several things are involved, especially the elevation of temperature produced by
+ the intense work. Increased temperature raises oxygen consumption independently of lactic acid, and lower
+ temperature decreases oxygen consump-tion, even when lactic acid is present.
+
+
+
+ The idea of the "oxygen debt" produced by exercise or stress as being equivalent to the accumulation of
+ lactic acid is far from accurate, but it"s true that activity increases the need for oxygen, and also
+ increases the tendency to accumulate lactic acid, which can then be disposed of over an extended time, with
+ the consumption of oxygen. This relationship between work and lactic acidemia and oxygen deficit led to the
+ term "lactate paradox" to describe the lower production of lactic acid during maximal work at high altitude
+ when people are adapted to the altiude. Carbon dioxide, retained through the Haldane effect, accounts for
+ the lactate paradox, by inhibiting cellular excitation and sustaining oxidative metabolism to consume
+ lactate efficiently.
+
+
+ The loss of carbon dioxide from the lungs in the presence of high oxygen pressure, the shift toward
+ alkalosis, by the Bohr-Haldane effect increases the blood"s affinity for oxygen, and restricts its delivery
+ to the tissues, but because of the abundance of oxygen in the lungs, the blood is almost competely saturated
+ with oxygen.
+
+
+ At high altitude, the slight tendency toward carbon dioxide-retention acidosis decreases the blood"s
+ affinity for oxygen, making it more available to the tissues. It happens that lactic acid also affects the
+ blood"s oxygen affinity, though not as strongly as carbon dioxide.
+ However, lactic acid doesn"t vaporize as the blood passes through the lungs, so its effect on the lungs"
+ ability to oxygenate the blood is the opposite of the easily exchangeable carbon dioxide"s.
+
+ Besides dissociating oxygen from hemoglobin, lactate also displaces carbon dioxide from its
+ (carbamino) binding sites on hemoglobin. If it does this in hemoglobin, it probably does it in many other
+ places in the body.
+
+
+ According to Meerson, ascending more than 200 feet per day produces measurable stress. People seldom notice
+ the effects of ascending a few thousand feet in a day, but it has been found that a large proportion of
+ people have bleeding into the retina when they ascend to 10,000 feet without adequate adaptation.
+ Presumably, similar symptomless bleeding occurs in other organs, but the retina can be easily inspected.
+
+
+
+ If hypothyroid people, with increased adrenalin and lactate, are hyperventilating even at rest and at sea
+ level, when they go to a high altitude where less oxygen is available, and their absorption of oxygen is
+ impaired by lactic acidemia, their "oxygen debt," conceived as circulating lactic acid, is easily
+ increased, intensifying their already excessive "ventilatory drive," and in proportion to the lactic
+ acid oxygen debt, oxygen absorption is further inhibited.
+
+
+ The lactic acid has to be disposed of, but their ability to extract oxygen is reduced. The poor oxygenation,
+ and the increased lactic acid and free fatty acids cause blood vessels to become leaky, producing edema in
+ the lungs and brain. This is very similar to the "multiple organ failure" that occurs in
+ inflammatory conditions, bacteremia, congestive heart failure, cancer, and trauma.
+
+
+ Otto Warburg established that lactic acid production even in the presence of oxygen is a fundamental
+ property of cancer. It is, to a great degree, the lactic acid which triggers the defensive
+ reactions of the organism, leading to tissue wasting from excessive glucocorticoid hormone. The cancer"s
+ production of lactic acid creates the same kind of internal imbalance produced by hyperventilation, and if
+ we look at the physiology of hyperventilation in the light of Warburg"s description of cancer,
+ hyperventilation imitates cancer metabolism, by producing lactic acid "even in the presence of oxygen."
+ Lactate, a supposedly benign metabolite of the cancer cells, which appears in all the other degenerative
+ conditions, including obesity, diabetes, Alzheimer"s disease, multiple sclerosis, is itself a central factor
+ in the degenerative process.
+
+
+ Working out the mechanisms involved in susceptibility to altitude sickness will clarify the issues involved
+ in the things that cause most people to die. At first, all of these changes occur in the regulatory systems,
+ and so can be corrected.
+
+
+
+ The vitality of the mitochondria, their capacity for oxidative energy production, is influenced by nutrition
+ and hormones. In healthy people, mitochondria work efficiently at almost any altitude, but people with
+ damaged or poorly regulated mitochondria are extremely susceptible to stress and hyperventilation.
+ Progesterone, testosterone, and thyroid (T3 and T2) are protective of normal mitochondrial function, by both
+ local and systemic effects.
+
+
+ The changes that occur in malnutrition and hypothyroidism affect the mitochondria in a multitude of ways,
+ besides the local effects of the thyroid and progesterone deficiency.
+
+
+ Increased estrogen, nitric oxide, excitatory amino acids, cortisol, lactate, free unsaturated fatty acids,
+ prolactin, growth hormone, histamine, serotonin, tumor necrosis factor and other pro-inflammatory cytokines
+ and kinins, and a variety of prostaglandins and eicosanoids, have been identified as anti-mitochondrial,
+ anti-respiratory agents. Edema itself can be counted among these agents.
+ (Carbon dioxide itself directly reduces tissue edema, as can be seen in studies of the cornea.)
+ Thyroid, progesterone, magnesium, glucose, and saturated fatty acids are among the central protective
+ elements.
+
+
+
+ The similarity of the changes occurring under the influence of estrogen excess, oxygen deprivation, aging,
+ and ionizing radiation are remarkable. People who think that radiation"s biological effects are mainly on
+ the DNA, and that estrogen acts through "estrogen receptors," aren"t interested in the parallels, but the
+ idea of a common respiratory defect, activating common pathways, suggests that there is something useful in
+ the perception that irradiation, hypoxia, and aging have estrogenic effects.
+
+
+ Irradiation by ultraviolet, gamma, or x-rays, and even by blue light, is damaging to mitochondrial
+ respiration. All of the ionizing radiations produce immediate and lingering edema, which continues to damage
+ metabolism in a more or less permanent way, apart from any detectable mutagenic actions. The amount of water
+ taken up following irradiation can be 20% to 30% of the normal weight, which is similar to the amount of
+ swelling that intense work produces in a muscle, and to the weight increase under hormonal imbalances. The
+ energy changes produced by irradiation in, for example, the heart, appear to accelerate the changes produced
+ by aging. Since unsaturated fats accumulate in the respiratory system with aging, and are targets for
+ radiation damage, the involvement of these fats in all sorts of antirespiratory degenerative processes
+ deserves more attention. Darkness, like irradiation, excess lactate, and unsaturated fats, has the
+ diabetes-like effect of greatly reducing the ability of muscle to absorb sugar, while light stimulates
+ respiration..
+
+
+ When the ideas of "stress," "respiratory defect," and "hyperventilation" are considered together, they seem
+ practically interchangeable.
+
+
+ The presence of lactic acid, which indicates stress or defective respiration, interferes with energy
+ metabolism in ways that tend to be self-promoting. Harry Rubin"s experiments demonstrated that cells become
+ cancerous before genetic changes appear. The mere presence of lactic acid can make cells more
+ susceptible to the transformation into cancer cells.
+ (Mothersill, et al., 1983.) The implications of this for the increased susceptibility to cancer
+ during stress, and for the increased resistance to cancer at high altitude, are obvious.
+
+
+ Blocking the production of lactic acid can make cells more resistant (Seymour and Mothersill, 1988);
+
+ if lactic acid were merely a useful fuel, it"s hard to see how poisoning its formation could improve cell
+ survival. But it happens to be an energy-disruptive fuel, interfering with carbon dioxide metabolism, among
+ other things.
+
+
+ Hyperventilation is present in hypothyroidism, and is driven by adrenalin, lactate, and free fatty acids.
+ Free fatty acids and lactate impair glucose use, and promote edema, especially in the lungs. Edema in the
+ lungs limits oxygen absorption. Swelling of the brain, resulting from increased vascular permeability and
+ the entry of free fatty acids, reduces its circulation and oxygenation; lactic acidemia
+ causes swelling of glial cells. Swelling of the endothelium increases vascular resistance by making the
+ channel narrower, eventually affecting all organs. Cells of the immune system release tumor necrosis factor
+ and other inflammatory cytokines, and the bowel becomes more permeable, allowing endotoxin and even bacteria
+ to enter the blood. Endotoxin impairs mitochondria, increases estrogen levels, causes Kupffer cells in the
+ liver to produce more tumor necrosis factor, etc.. Despite its name, tumor necrosis factor stimulates the
+ growth and metastasis of some types of cancer. Dilution of the body fluids, which occurs in hypothyroidsim,
+ hyperestrogenism, etc., stimulates tumor growth.
+
+
+ The inflammatory factors that can promote cell growth can, with just slight variation, deplete cellular
+ energy to the extent that the cells die from the energetic cost of the repair process, or mutate from
+ defective repairs. Niacinamide can have an "antiinflammatory" function, preventing death from multiple organ
+ failure, by interupting the reactions to nitric oxide and peroxynitrile (Cuzzocrea, et al., 1999). The
+ cells" type, environment, and history determine the different outcomes.
+
+
+ Cataracts, cancer, congestive heart failure, seemingly such different degenerative problems, have the same
+ sort of metabolic problem, leading to the abnormal absorption of water by cells, disrupting their normal
+ functions.
+
+
+ The same simple metabolic therapies, such as thyroid, progesterone, magnesium, and carbon dioxide, are
+ appropriate for a great range of seemingly different diseases. Other biochemicals, such as adenosine and
+ niacinamide, have more specific protective effects, farther downstream in the "cascade" effects of stress.
+
+
+
+ There are many little cliches in the medical culture that prevent serious thought about integral
+ therapy: "Progesterone is the pregnancy hormone," "thyroid makes your heart work too hard,"
+ "thyroid uncouples mitochondrial phosphorylation," "magnesium has nothing to do with thyroid or
+ progesterone," "lactate provides energy," etc. But many of these minor cliches are held in place by deep
+ theoretical errors about the nature of cells and organisms. Once those have been corrected, there should be
+ progress toward more powerful integral therapies.
+
+ REFERENCES
+
+ Cell Biol Int Rep 1983 Nov;7(11):971-80.
+ Lactate-mediated changes in growth morphology and transformation frequency of irradiated C3H 10T1/2
+ cells. Mothersill C, Seymour CB, Moriarty M. Treatment of mammalian cells with lactate or
+ inhibitors of glycolysis alters their radiation response, particularly in the low dose region of the dose
+ response curve. The occurrence of both high lactate levels and high glycolytic metabolism in
+ tumours is well known and therefore the effect of lactate on a cell line sensitive to radiation
+ induced transformation was examined using a single exposure to Cobalt 60 gamma rays as the carcinogen
+ challenge. The results indicate that cells treated with
+ 5mM lactate before irradiation exhibit changes in morphology and growth rate and that the transformation
+ frequency is increased by three to ten fold following 24 hours lactate treatment just prior to
+ irradiation.
+
+ Examination of radiation survival curves showed a positive correlation between transformation frequency and
+ size of the shoulder, but increasing transformation frequency was associated with a decrease in Do. A
+ mechanism involving altered Redox potential in lactate treated cells is suggested. The results are discussed
+ in terms of their possible significance for radiotherapy.
+
+
+ Radiat Environ Biophys 1988;27(1):49-57. The effect of glycolysis
+
+ inhibitors on the radiation response of CHO-K1 cells. Seymour CB, Mothersill C Saint Luke's Hospital,
+ Rathgar, Dublin, Ireland. Exposure of CHO-K1 cells to three different inhibitors of glycolysis, prior to
+ treatment with a single dose of ionising radiation, reduced their survival. The effects were
+ concentration-dependent but occurred under all conditions where cells were exposed to the inhibitors
+ prior to irradiation. The results are similar to those obtained by this group when glycolysis was
+ altered using analogues of D-glucose or by blocking the pyruvate----lactate reaction using added lactate
+ or oxamate. They support data from other workers suggesting a role for energy metabolism in the final
+ expression of radiation damage.
+
+
+
+ Crit Care Med 1999 Aug;27(8):1517-23. Protective effect of poly(ADP-ribose) synthetase inhibition on
+ multiple organ failure after zymosan-induced peritonitis in the rat. Cuzzocrea S, Zingarelli B,
+ Costantino G, Sottile A, Teti D, Caputi AP
+
+
+ Eur J Cancer 1975 May;11(5):365-371. Cancer and altitude. Does intracellular pH regulate cell
+ division? Burton AC.
+
+
+
+ Monaldi Arch Chest Dis 1999 Aug;54(4):365-72. The pathophysiology of hyperventilation syndrome.
+ Folgering H. Dept Pulmonology Dekkerswald, University of Nijmegen, Groesbeek, The Netherlands..
+ Hyperventilation is defined as breathing in excess of the metabolic needs of the body, eliminating
+ more carbon dioxide than is produced, and, consequently, resulting in respiratory alkalosis and an
+ elevated blood pH. The traditional definition of hyperventilation syndrome describes "a
+ syndrome, characterized by a variety of somatic symptoms induced by physiologically inappropriate
+ hyperventilation and usually reproduced by voluntary hyperventilation". The spectrum of symptoms ascribed to
+ hyperventilation syndrome is extremely broad, aspecific and varying. They stem from virtually every tract,
+ and can be caused by physiological mechanisms such as low Pa,CO2, or the
+ increased sympathetic adrenergic tone. Psychological mechanisms also contribute to the
+ symptomatology, or even generate some of the symptoms. Taking the traditional definition of hyperventilation
+ syndrome as a starting point, there should be three elements to the diagnostic criterion: 1) the patient
+ should hyperventilate and have low Pa,CO2, 2) somatic diseases causing hyperventilation should have been
+ excluded, and 3) the patient should have a number of complaints which are, or have been, related to the
+ hypocapnia. Recent studies have questioned the tight relationship between hypocapnia and complaints.
+ However, the latter can be maintained and/or elicited when situations in the absence of hypocapnia in which
+ the first hyperventilation and hypocapnia was present recur. Thus, the main approach to diagnosis is the
+ detection of signs of (possible) dysregulation of breathing leading to hypocapnia. The therapeutic approach
+ to hyperventilation syndrome has several stages and/or degrees of intervention: psychological counselling,
+ physiotherapy and relaxation, and finally drug therapy. Depending on the severity of the problem, one or
+ more therapeutic strategies can be chosen.
+
+
+ N Engl J Med 1977 Mar 17;296(11):581-585.
+ Reduction in mortality from coronary heart disease in men residing at high altitude. Mortimer
+ EA Jr, Monson RR, MacMahon B In New Mexico, where inhabited areas vary from 914 to over 2135 m above sea
+ level, we compared age-adjusted mortality rates for arteriosclerotic heart disease for white men and women
+ for the years 1957-1970 in five sets of counties, grouped by altitude in 305-m (1000-foot) increments. The
+ results show a serial decline in mortality from the lowest to the highest altitude for males but not for
+ females. Mortality rates for males residing in the county groups higher than 1220 m in order of ascending
+ altitude were 98, 90, 86 and 72 per cent of that for the county group below 1220-m altitude (P less
+ than 0.0001). The results do not appear to be explained by artifacts in ascertainment,
+ variations in ethnicity or urbanization. A possible explanation of the trend is that adjustment to residence
+ at high altitude is incomplete and daily activities therefore represent greater exercise than when
+ undertaken at lower altitudes.
+
+
+
+ Br Med J 1980 Jan 5;280(6206):5. Cardiovascular mortality and altitude.
+
+
+ Radiat Res 1987 Nov;112(2):381-390. Altitude, radiation, and mortality from cancer and heart
+ disease. Weinberg CR, Brown KG, Hoel DG. The variation in background radiation levels is an
+ important source of information for estimating human risks associated with low-level exposure to ionizing
+ radiation. Several studies conducted in the United States, correlating mortality rates for cancer with
+ estimated background radiation levels, found an unexpected inverse relationship. Such results have been
+ interpreted as suggesting that low levels of ionizing radiation may actually confer some benefit. An
+ environmental factor strongly correlated with background radiation is altitude. Since there are important
+ physiological adaptations associated with breathing thinner air, such changes may themselves influence risk.
+ We therefore fit models that simultaneously incorporated altitude and background radiation as predictors of
+ mortality. The negative correlations with background radiation seen for mortality
+ from arteriosclerotic heart disease and cancers of the lung, the intestine, and the breast
+ disappeared or became positive once altitude was included in the models. By contrast, the
+ significant negative correlations with altitude persisted with adjustment for radiation. Interpretation
+ of these results is problematic, but recent evidence implicating reactive forms of oxygen in
+ carcinogenesis and atherosclerosis may be relevant. We conclude that the cancer correlational studies
+ carried out in the United States using vital statistics data do not in themselves demonstrate a lack of
+ carcinogenic effect of low radiation levels, and that reduced oxygen pressure of inspired air may be
+ protective against certain causes of death.
+
+
+
+ Biull Eksp Biol Med 1993 Jun;115(6):576-578. [The effect of high-altitude ecological and
+ experimental stresses on the thrombocyte-vascular wall system]. [Article in Russian].
+ Bekbolotova AK, Lemeshenko VA, Aliev MA. Experiments in animals (rats) and examinations of the population of
+ high-altitude shepherds were used to study the functional system "Thrombocytes-Vessel Wall" (STVW) for
+ evaluation of the organism ecological adaptation to "pure" high-altitude stress, with and without
+ combination with experimental-adrenergic cardionecrosogenic stress (ACNS, in rats). The adaptive increase of
+ antiaggregation prostacyclin activity of the aorta in rats and PGI2 reaction of vessels in human population
+ of high-altitude in mountains (2000, 3000-3500 m) were found to be a common biologist regularity. The
+ adaptive increase of coronary reserve of the heart and vasodilatator-antiaggregation status in
+ high-altitude shepherds correlated with an increase of antiaggregation activity of the aorta and
+ decrease of spontaneous aggregation of the thrombocytes in rats under conditions of more prolonged
+ adaptation to high-altitude ecological stress.
+
+
+
+
+ Diabetologia 1982 Jun;22(6):493. Measurement of glycosylated haemoglobin at high altitudes.
+ Paisey R, Valles V, Arredondo G, Wong B, Lozano-Castaneda O.
+
+
+ [Change in the ultrastructure of rat myocardium under the influence of 12-months' adaptation to high
+ altitude] Zhaparov B; Mirrakhimov MM. Biull Eksp Biol Med, 1977 Jul, 84:7, 109-12. The right
+ and left ventricle myocardium of rats was studied in the course of a 12-month period of adaptation to high
+ altitude (3200 m above the sea level). A long-term exposure of the animals to the high altitude led the
+ development of ventricular hypertrophy mostly of the right, and partly of the left ventricle.
+ Hyperplasia and hypertrophy of individual organellae, particularly mitochondria, were found in
+ most cardiomyocytes of both ventricles. In animals adapted to the high altitude the mitochondrial succinic
+ dehydrogenase activity was more pronounced than in control ones. The results obtained testified to the
+ enhanced intracellular metabolism reflecting myocardial compensatory adaptive responses.
+
+
+ [Morphologic characteristics of the hearts of argali continuously dwelling at high mountain
+ altitudes], Zhaparov B; Kamitov SKh; Mirrakhimov MM, Biull Eksp Biol Med, 1980 Apr, 89:4, 498-501 The hearts of argali [wild sheep] living at 3800-5000 m above the sea level were
+ examined.
+ Macroscopy showed complete absence of fatty tissue under the epicardium. Increased number of
+ the capillaries surrounding cardiomyocytes, intercalated discs in many zones of the myocardium, sharp
+ thickening giving pronounced cross lines of myofibrils were revealed on semithin and ultrathin sections. The
+ data obtained demonstrate specificity of the heart structure of argali and are
+ discussed from the standpoint of increased compensatory-adaptive changes in the test organ, these
+ changes being associated with its enhanced function provoked by high altitude conditions.
+
+
+
+
+ J Dev Physiol 1990 Sep;14(3):139-46. Effect of lactate and beta-hydroxybutyrate infusions on brain
+ metabolism in the fetal sheep.
+
+ Despite large increases in fetal arterial lactate and beta-hydroxybutyrate during the respective
+ infusions, no significant uptake of either substrate was demonstrated. However during both types of
+ infusion, the brain arterio-venous difference for glucose decreased 30% (P less than 0.05). Since the
+ brain arterio-venous difference for oxygen was unchanged, and blood flow to the cerebral hemispheres
+ (measured in 11 studies) was also unchanged, the infusions appeared to cause a true decrease in brain
+ glucose uptake. This decrease paralleled the rise in lactate concentration during lactate infusions, and
+ the rise in lactate and butyrate concentrations during the butyrate infusions. Both substrates
+ have metabolic actions that may inhibit brain glucose uptake. We speculate that the deleterious
+ effects of high lactate and ketone states in the perinatal period may in part be due to inhibition of
+ brain glucose uptake.
+
+
+ Hypertens 1995 Feb;9(2):119-22.
+ Pressor effect of hyperventilation in healthy subjects. Todd GP, Chadwick IG, Yeo WW, Jackson
+ PR, Ramsay LE University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield, UK
+ Hyperventilation is an important feature of panic disorder, and an association has been reported between
+ panic disorder and hypertension. We have examined the effect of hyperventilation on the blood pressure (BP)
+ of healthy subjects. Twenty six subjects were randomised in a balanced two-period cross-over study to
+ compare the effects of hyperventilation with that of normal breathing on sitting BP, heart rate and the
+ electrocardiogram. Each study phase lasted 40 min, with 15 min of baseline observation, 5 min of
+ hyperventilation or normal breathing, and 20 min of continued
+ observation. Hyperventilation significantly increased SBP by 8.9 mm Hg (95% CI 3.8-13.8, P < 0.01),
+ diastolic blood pressure by 8.2 mm Hg (95% CI 1.7-14.7, P < 0.05), mean arterial pressure by 10.0 mm
+ Hg (95% CI 3.3-16.7, P < 0.01) and heart rate by 36 beats/min (95% CI 31-44, P < 0.01). The
+ changes in diastolic and mean arterial pressure correlated significantly with the total
+
+
+ Intravenous infusion of free fatty acid (FFA) 20 mg.kg-1.min-1 produces pulmonary edema, hypoxemia,
+ hyperventilation and increase in the alveolar surfactant content in rabbits in less than 15
+ min.
+
+
+
+ Respiration 1986;49(3):187-94. Role of hypocapnia in the alveolar surfactant increase induced by
+ free fatty acid intravenous infusion in the rabbit.
+ Oyarzun MJ, Donoso P, Quijada D. Intravenous infusion of free fatty acid (FFA) produces an increase
+ in the alveolar surfactant pool of the rabbit and pulmonary edema, hyperventilation, hypoxemia and
+ hypocapnia. Previous studies suggested that alveolar PCO2 would be a regulator of intracellular storages
+ of surfactant. In order to
+
+
+
+ Farmakol Toksikol 1977. Sep-Oct; 40(5):620-3..
+ [Effect of combinations of apressin, obsidan, diprazin, adenosine, NAD and nicotinamide on the
+ resistance of rats to hypoxia and on carbohydrate metabolic indices]. [Article in Russian]
+ Abakumov GZ As evidenced from experiments on rats, a combined application of apressin with obsidan and
+ diprazine, and also of adenozine with nicotine-amidadenine-dinucleotide (NAD), as well as of adeozine with
+ nicotine amide potentiates the protective effect of these substances in hypobaric hypoxia, increases the
+ resistance of the animals to cerebral ischemia, brings down the excess lactate level and raises the
+ redoz potential of the system lactic-acid-pyruvic acid in the brain of rats exposed to the
+ effects of rarefied atmosphere.
+
+
+
+ Schweiz Med Wochenschr 1977 Nov 5;107(44):1585-6. [Protective effect of pyridoxilate on the hypoxic
+ myocardium. Experimental studies]. [Article in French] Moret PR, Lutzen U The protective action
+ of piridoxilate on hypoxic myocardium has been studied on rats in acute hypoxia (isolated heart, perfused
+ with a non-oxygenated solution) and in prolonged hypoxia (3 days at high [3454 m] altitude). Piridoxilate
+ maintained a higher ATP level with a much lower production of lactate. The mechanisms of action of
+ piridoxilate are probably fairly similar to those of Na dichloracetate.
+
+
+ J. Appl Physiol 1991 Apr;70(4):1720-30. .Metabolic and work efficiencies during exercise in Andean
+ natives. Hochachka PW, Stanley C, Matheson GO, McKenzie DC, Allen PS, Parkhouse WS Department
+ of Zoology, University of British Columbia, Vancouver, Canada.
+ Maximum O2 and CO2 fluxes during exercise were less perturbed by hypoxia in Quechua natives
+ from the Andes than in lowlanders. In exploring how this was achieved, we found that, for a given
+ work rate, Quechua highlanders at 4,200 m accumulated substantially less lactate
+ than lowlanders at sea level normoxia (approximately 5-7 vs. 10-14 mM) despite hypobaric hypoxia.
+ This phenomenon, known as the lactate paradox, was entirely refractory to normoxia-hypoxia transitions. In
+ lowlanders, the lactate paradox is an acclimation; however, in Quechuas, the lactate paradox is an
+ expression of metabolic organization that did not deacclimate, at least over the 6-wk period of our study.
+ Thus it was concluded that this metabolic organization is a developmentally or genetically fixed
+ characteristic selected because of the efficiency advantage of aerobic metabolism (high ATP yield
+ per mol of substrate metabolized) compared with anaerobic glycolysis. Measurements of
+ respiratory quotient indicated preferential use of carbohydrate as fuel for muscle work, which is also
+ advantageous in hypoxia because it maximizes the yield of ATP per mol of O2 consumed. Finally, minimizing
+ the cost of muscle work was also reflected in energetic efficiency as classically defined (power output per
+ metabolic power input);
+ this was evident at all work rates but was most pronounced at submaximal work rates (efficiency
+ approximately 1.5 times higher than in lowlander athletes). Because plots of power output vs.
+ metabolic power input did not extrapolate to the origin, it was concluded 1) that exercise in both groups
+ sustained a significant ATP expenditure not convertible to mechanical work but 2) that this expenditure was
+ downregulated in Andean natives by thus far unexplained mechanisms.
+
+
+
+ Br J Anaesth 1975 Jun;47(6):669-78. Effect of CO2 on myocardial contractility and aortic input
+ impedance during anaesthesia. Foex P, Prys-Roberts C. The haemodynamic responses to hypocapnia
+ and hypercapnia have been studied in the dog during intermittent positive pressure ventilation under
+ halothane anaesthesia (1% halothane in oxygen) and under nitrous oxide anaesthesia (30% oxygen in nitrous
+ oxide). In the absence of significant
+ variations of either myocardial contractility or left ventricular end-diastolic pressure, the changes of
+ stroke volume and cardiac output (diminution because of hypocapnia, augmentation because of hypercapnia)
+ were determined by alterations of systemic vascular resistance (augmentation because of hypocapnia,
+ diminution because of hypercapnia).
+
+
+
+ J Appl Physiol 1991 May;70(5):1963-76.
+ Skeletal muscle metabolism and work capacity: a 31P-NMR study of Andean natives and lowlanders.
+ Matheson GO, Allen PS, Ellinger DC, Hanstock CC, Gheorghiu D, McKenzie DC, Stanley C, Parkhouse WS,
+ Hochachka PW Sports Medicine Division, University of British Columbia, Vancouver, Canada. Two metabolic
+ features of altitude-adapted humans are the maximal O2 consumption (VO2max) paradox (higher work
+ rates following acclimatization without increases in VO2max)
+ and the lactate paradox (progressive reductions in muscle and blood lactate with exercise at
+ increasing altitude). To
+
+
+
+ J Hum Hypertens 1995 Feb;9(2):119-22.
+ Pressor effect of hyperventilation in healthy subjects.Todd GP, Chadwick IG, Yeo WW, Jackson
+ PR, Ramsay LE.
+
+
+ J Infect Dis 1998 May;177(5):1418-21.The effect of lactic acid on mononuclear cell secretion of
+ proinflammatory cytokines in response to group B streptococci.
+ Steele PM, Augustine NH, Hill HR Department of Pathology, University of Utah School of Medicine, Salt Lake
+ City 84132, USA.
+
+
+ J Appl Physiol 1994 Apr;76(4):1462-7. Lactic acidosis as a facilitator of oxyhemoglobin
+ dissociation during exercise. Stringer W, Wasserman K, Casaburi R, Porszasz J, Maehara K, French W.
+
+
+
+ Involvement of nitric oxide and N-methyl- D-aspartate in acute hypoxic altitude convulsion in mice.
+ Chen CH; Chen AC; Liu HJ. Aviat Space Environ Med, 1997 Apr, 68:4, 296-9. "Altitude convulsion is a
+ rather specific form of experimental convulsion which is induced by acute exposure to a hypobaric hypoxic
+ condition. Several neurotransmitters have been shown to be involved in the mechanisms of altitude
+ convulsions." "The novel neurotransmitter nitric oxide (NO) may be involved in the mechanisms of altitude
+ convulsion through its neuronal signalling roles in relation to the NMDA receptor." "NO synthesis
+ precursor, L-arginine (20, 40, 200, 800 mg/kg), resulted in a dose-dependent decrease in the ACT in
+ mice, while the NO synthase (NOS) inhibitor, NG-nitro-L-arginine-methyl ester (L-NAME, 1.25, 2.50, 5.00
+ mg/kg, i.p.) increased the ACT."
+ "CONCLUSIONS: These findings suggest an important signalling role for nitric oxide and NMDA in the
+ development of altitude convulsion and further support the hypothesized relationship between NMDA-receptor
+ mediated neurotoxicity and nitric oxide."
+
+
+ Excitotoxicity in the lung: N-methyl-D-aspartate- induced, nitric oxide-dependent, pulmonary edema
+ is attenuated by vasoactive intestinal peptide and by inhibitors of poly(ADP-ribose) polymerase.
+
+ Said SI; Berisha HI; Pakbaz H. Proc Natl Acad Sci U S A, 1996 May 14, 93:10, 4688-92. "Excitatory
+ amino acid toxicity, resulting from overactivation of N-methyl-D-aspartate (NMDA) glutamate receptors,
+ is a major mechanism of neuronal cell death in acute and chronic neurological diseases. We have
+ investigated whether excitotoxicity may occur in peripheral organs, causing tissue injury, and report
+ that NMDA receptor activation in perfused, ventilated rat lungs triggered acute injury, marked by
+ increased pressures needed to ventilate and perfuse the lung, and by high-permeability edema."
+ The injury was prevented by competitive NMDA receptor antagonists or by channel-blocker MK-801, and was reduced in the presence of Mg2+. As with NMDA toxicity to central neurons, the lung injury was
+ nitric oxide (NO) dependent: it required L-arginine, was associated with increased production of
+ NO, and was attenuated by either of two NO synthase inhibitors. The neuropeptide
+ vasoactive intestinal peptide and
+ inhibitors of poly(ADP-ribose) polymerase also prevented this injury, but without inhibiting NO
+ synthesis, both acting by inhibiting a toxic action of NO that is critical to tissue injury.
+
+
+ The findings indicate that: (i) NMDA receptors exist in the lung (and probably elsewhere outside the central
+ nervous system), (ii) excessive activation of these receptors may provoke acute edematous lung injury as
+ seen in the "adult respiratory distress syndrome," and (iii) this injury can be modulated by blockade of one
+ of three critical steps: NMDA receptor binding, inhibition of NO synthesis, or activation of
+ poly(ADP-ribose) polymerase.
+
+
+ Adenosine modulates N-methyl-D- aspartate- stimulated hippocampal nitric oxide production in vivo.
+ Bhardwaj A; Northington FJ; Koehler RC; Stiefel T; Hanley DF; Traystman RJ. Stroke, 1995 Sep, 26:9,
+ 1627-33. "Adenosine acts presynaptically to inhibit release of excitatory amino acids (EAAs) and is thus
+ considered to be neuroprotective. Because EAA-stimulated synthesis of nitric oxide (NO) may play an
+ important role in long-term potentiation and excitotoxic-mediated injury, we tested the hypotheses that
+ adenosine agonists attenuate basal and EAA-induced NO production in the hippocampus in vivo and that
+ adenosine A1 receptors mediate this response." "...these data are consistent with in vitro results showing
+ that NMDA receptor stimulation enhances NO production. Furthermore, we conclude that stimulation of A1
+ receptors can attenuate the basal as well as NMDA-induced production of NO. Because NMDA receptor
+ stimulation amplifies glutamate release, our data are consistent with presynaptic A1 receptor-mediated
+ inhibition of EAA release and consequent downregulation of NO production."
+
+
+ Anesthesiology 1993 Jan;78(1):91-9.
+ Hypocapnia worsens arterial blood oxygenation and increases VA/Q heterogeneity in canine pulmonary
+ edema. Domino KB, Lu Y, Eisenstein BL, Hlastala MP. University of Washington Medical School,
+ Seattle. "Hyperventilation frequently is employed to reduce carbon dioxide partial pressure in patients in
+ the operating room and intensive care unit. However the effect of hypocapnia on oxygenation is complex and
+ may result in worsening in patients with preexisting intrapulmonary shunt." "Both hypocapnia and hypercapnia
+ were associated with an increased VA/Q inequality. However, PaO2 decreased and P[A-a]O2 increased with only
+ hypocapnia. These results suggest that hyperventilation to reduce PaCO2 may be detrimental to arterial PO2
+ in some patients with lung disease."
+
+
+
+ Acta Anaesthesiol Scand 1996 Jan;40(1):133-4 Hyperlactatemia associated with hypocarbic
+ hyperventilation. Cheung PY
+
+
+ Am J Physiol 1999 May;276(5 Pt 1):E922-9 Hyperlactatemia reduces muscle glucose uptake and GLUT-4 mRNA while
+ increasing (E1alpha)PDH gene expression in rat. Lombardi AM, Fabris R, Bassetto F, Serra R, Leturque A,
+ Federspil G, Girard J, Vettor R Endocrine Metabolic Laboratory, Department of Medical and Surgical Sciences,
+ University of Padova, 35100 Padova, Italy.
+ An increased basal plasma lactate concentration is present in many physiological and pathological
+ conditions, including obesity and diabetes. We previously demonstrated that acute lactate infusion in
+ rats produced a decrease in overall glucose uptake.
+ The present study was carried out to further investigate the effect of lactate on glucose transport and
+ utilization in skeletal muscle. In chronically catheterized rats, a 24-h sodium lactate or bicarbonate
+ infusion was performed. To study glucose uptake in muscle, a bolus of 2-deoxy-[3H]glucose was injected in
+ basal condition and during euglycemic-hyperinsulinemic clamp. Our results show that hyperlactatemia
+ decreased glucose uptake in muscles (i.e., red quadriceps; P < 0.05). Moreover in red muscles, both
+ GLUT-4 mRNA (-30% in red quadriceps and -60% in soleus; P < 0.025) and protein (-40% in red quadriceps; P
+ < 0.05) were decreased, whereas the (E1alpha)pyruvate dehydrogenase (PDH) mRNA was increased (+40% in red
+ quadriceps; P < 0.001) in lactate-infused animals. PDH protein was also increased (4-fold in red
+ gastrocnemius and 2-fold in red quadriceps). These results indicate that chronic
+ hyperlactatemia reduces glucose uptake by affecting the expression of genes involved in glucose
+ metabolism in muscle, suggesting a role for lactate in the development of insulin
+ resistance.
+
+
+
+ Radiat Res 1993 Apr;134(1):79-85 Effects of in vivo heart irradiation on myocardial energy
+ metabolism in rats.
+ Franken NA, Hollaar L, Bosker FJ, van Ravels FJ, van der Laarse A, Wondergem J Department of Clinical
+ Oncology, University Hospital, Leiden, The Netherlands. To investigate the effect of in vivo heart
+ irradiation on myocardial energy metabolism, we measured myocardial adenosine nucleotide concentrations and
+ mitochondrial oxygen consumption in left ventricular tissue of rats 0-16 months after local heart
+ irradiation (20 Gy). At 24 h and 2 months no difference in myocardial adenosine nucleotide concentration was
+ apparent between irradiated and control hearts. The total myocardial adenosine nucleotide concentrations in
+ irradiated hearts compared to those of nonirradiated controls tended to be lower from 4 months onward. The
+ rate of
+ oxidative energy production (state 3 respiration) in irradiated hearts was significantly reduced ompared
+ with that of age-matched controls from 2 months onward. Moreover, as a result of aging, time-dependent
+ decrease in the rate of oxidative energy production was observed in both rradiated and control hearts
+
+
+ changes in energy supplies provide a mechanism to explain impaired contractility after local heart
+ irradiation.
+
+
+
+ J Radiat Res (Tokyo) 1993 Sep;34(3):195-203.
+ Radiosensitization of human lung fibroblasts by chemical that decrease ATP levels.
+ Kumar A, Kimura H, Aoyama T.
+ "Radiosensitization by lactate, pyruvate, nalidixic acid and novobiocin was studied in exponentially
+ growing SH-18L human lung fibroblasts. All the chemicals had a slight radiosensitizing effect at a low
+ concentration and a definite effect at a higher one." "Fibroblasts incubated with the low concentration
+ of each chemical for 24 hrs after X irradiation showed no reduction in intracellular ATP content,
+ whereas, the higher concentration produced a significant decrease.
+ These observations suggest that the decrease in the ATP content may be involved in the
+ radiosensitization of human fibroblasts at high concentrations of these chemicals.
+ In contrast, radiosensitization at a low concentration is not explained by a relationship to ATP
+ content. Different mechanisms may be involved in radiosensitization at low and high concentrations of
+ these chemicals."
+
+
+ J Exp Med 1993 May 1;177(5):1391-8. Enhancement of experimental metastasis by tumor necrosis
+ factor. Orosz P, Echtenacher B, Falk W, Ruschoff J, Weber D, Mannel D.N. Institute for
+ Immunology and Genetics, German Cancer Research Center, Heidelberg. "The influence of endogenous and
+ exogenous tumor necrosis factor (TNF) on metastasis was investigated in an experimental fibrosarcoma
+ metastasis model." "This effect was time dependent, as administration of rmTNF 5 h before or 1 h but not 24
+ h after tumor cell inoculation caused an increase of tumor cell colony formation on the lung surface,
+ suggesting an influence of TNF on the vascular adhesion and diapedesis of tumor cells. Since tumor-bearing
+ mice showed an enhanced ability to produce TNF after endotoxin injection compared to control mice,
+ tumor-bearing mice were treated with anti-mTNF antibodies. Neutralization of endogenous tumor-induced TNF
+ led to a significant decrease of the number of pulmonary metastases. Histological analysis of
+ micrometastases in the lung on day 5 by silver staining of proteins associated with nucleolar organizer
+ regions revealed
+ more metastatic foci and augmented proliferative activity of the tumor cells after
+
+ rmTNF pretreatment of mice. However, no direct effect of rmTNF on the proliferation rate of
+ tumor cells was seen in vitro."
+
+
+ Nippon Geka Gakkai Zasshi 1996 Sep;97(9):726-32.
+ [Energy substrate metabolism during stress].
+ Sugimoto H. Department of Traumatology and Critical Care Medicine, Osaka University School of
+ Medicine, Suita, Japan.
+ "Energy substrate metabolism during stress is characterized by increased REE (resting energy
+ expenditure), hyperglycemia, hyperlactatemia and protein catabolism. This stress-induced hypermetabolic
+ responses are closely related to increased secretion of neurohormonal and cytokine mediators. The
+ insulin resistance hyperglycemia has been called "stress diabetes" or 'surgical diabetes.' Glucose
+ disposal has been thought to be impaired in this condition." "This hyperglycemia in stress diabetes
+ results from a postreceptor mechanism. Stress hyperlactatemia is thought to be caused by decreased
+ pyruvate dehydrogenase activity rather than tissue hypoperfusion."
+
+
+ Clin Physiol 1995 Nov;15(6):581-95.
+
+ Effects of lactate infusion on hepatic gluconeogenesis and glycogenolysis.
+
+ Haesler E, Schneiter P, Temler E, Jequier E, Tappy L.
+
+
+ Cancer Res 1993 Apr. 15;53(8):1939-44..
+
+ Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer:
+ monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression.
+
+ Wu S, Boyer CM, Whitaker RS, Berchuck A, Wiener JR, Weinberg JB, Bast RC Jr.
+
+
+ Klin Med (Mosk) 1989 May;67(5):38-41. ["Dry" carbon dioxide baths in treating patients with
+ myocardial infarction at the sanatorium stage of rehabilitation].
+
+
+ [Article in Russian] Barashkova NL, Kartamysheva NL, Krasnova VP, Kriuchkova LN, Miasoedova E.S. A group of
+ 75 patients with a history of myocardial infarction and repeated myocardial infarction were subjected to
+ treatment involving dry carbon dioxide baths. Its results demonstrated normalization of IHD manifestations,
+ such as coronary and heart failure, functional state of the cardiovascular system, its reserve
+ potentialities and adaptation to physical effort. Under the influence of a course treatment with dry carbon
+ dioxide baths hemodynamic parameters of cardiac output (cardiac and stroke volume) underwent favourable
+ changes, rhythm slowed down, diastole became longer and systolic and diastolic arterial pressure decreased.
+ The data obtained substantiate application of dry carbon dioxide baths in the recovery period to I-III
+ functional classes patients with a history of myocardial infarction.
+
+
+ J Dev Physiol 1989 Nov;12(5):283-6. Haemodynamic effects of respiratory alkalosis independent of
+ changes in airway pressure in anaesthetized newborn dogs. Reuter JH, Donovan EF, Kotagal U.R.
+ "We have recently reported a decrease in cardiac output in newborn dogs during respiratory alkalosis
+ which is independent of changes in airway pressure."
+
+
+ Undersea Hyperb Med 1994 Jun;21(2):169-83. Influence of hyperbaric oxygen on left ventricular
+ contractility, total coronary blood flow, and myocardial oxygen consumption in the conscious dog.
+
+ Savitt MA, Rankin JS, Elberry JR, Owen CH, Camporesi E.M. "It is known that hyperbaric oxygenation
+ (HBO) decreases total coronary blood flow (TCBF) and cardiac output (CO)."
+
+
+ Heart rhythm disturbances in the inhabitants of mountainous regions.
+
+ Mirrakhimov MM; Meimanaliev TS Cor Vasa, 1981, 23:5, 359-65.
+
+ "During exercise heart arrhythmias
+
+ appeared conspicuously less frequently in the high mountain than in the low altitude inhabitants."
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
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+
+ The problem of Alzheimer's disease as a clue to immortality - Part 1
+
+
+ The problem of Alzheimer's disease as a clue to immortality - Part 1
+
+
+
+ I. INTRODUCTION
+
+
+ II. COMMON FACTORS IN INJURY DURING GROWTH AND AGING
+
+
+ III. A VIEW OF ENTROPY--RENEWAL OF THE BRAIN
+
+
+ IV. FALSE SIGNALS FROM THE ENVIRONMENT
+
+
+ A. EDUCATION, DIET AND MEDICINE INTERACT
+
+
+
+ B. SIGNALS IN THE ABSTRACT
+
+
+ V. HORMONE IMBALANCE, LEADING TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S DISEASE
+
+
+ A. THE FUNCTION OF ENERGY
+
+
+ B. EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS
+
+
+ C. VITAMIN A AND STEROIDS
+
+
+
+ D. THE NATURE OF ALZHEIMER'S DISEASE
+
+
+ E. AN EXAMPLE; DIET AFFECTS HORMONES WHICH AFFECT STRUCTURE AND LEAD TO APPARENT SELF- DESTRUCTION
+
+
+ VI. STRUCTURE AS A REGULATORY SYSTEM--AN EMERGING VISION OF PERVASIVE EPIGENESIS
+
+
+ I. INTRODUCTION
+
+
+ The toxicity of estrogen and of the unsaturated fats has been known for most of the twentieth century, and
+ much has been learned about their interactions in the aging process. The body, during this time, has been
+ understood as a dynamic interaction of cellular trophic influences which govern both form and function. My
+ argument here will be that some of our adaptive, protective regulatory processes are overridden by the
+ excessive supply of unsaturated fats--supported by a few other toxins--in our diet, acting as a false-signal
+ system, and that cholesterol, pregnenolone, and progesterone which are our main long-range defenses, are
+ overcome by the effects of the unsaturated fats, and that the resulting cascade of ineffective and defective
+ reactions (including various estrogen-stimulated processes) leads to lower and lower energy production,
+ reduced function, and death. At certain times, especially childhood and old age, iron (which also has
+ important regulatory roles) accumulates to the point that its signal functions may be inappropriate.
+
+
+
+ It interacts with estrogen and unsaturated fats in ways that can change restraint and adaptation into sudden
+ self-destruction, apoptotic cell death. If we look at the human organism from one perspective, it seems
+ coherent and intelligible, but from the perspective of established academic biological doctrine, it seems
+ appallingly complex, lacking any visible integrating principle, and as a result simplistic mechanical,
+ pharmaceutical, or religious ideas are increasingly offered to fill the gap. But experimental data can be
+ taken out of the muddle, and put to coherent human use. In what follows, I am acting as though the doctrines
+ of genetic determination and regulation by membranes were mere historical relics. The emerging control
+ systems are now clear enough that we can begin to use them to reverse the degenerative diseases: Alzheimer's
+ dementia, epileptic dementia, arthritis, osteoporosis, depression, hypertension, hardening of the heart and
+ blood vessels, diabetes, and some types of tumor, immunodeficiencies, reflex problems, and special atrophic
+ problems, including clearing of amyloid and mucoid deposits. I think many people experience regenerative
+ age-regressing when many circumstances are just right; for example, taking a trip to the mountains in the
+ spring with friends can optimize several basic regulatory systems.
+
+
+ II. COMMON FACTORS IN BRAIN INJURY DURING GROWTH AND AGING
+
+
+
+ Most people are surprised by the number of cells in the prenatal brain, and in the very old brain: In the
+ human fetus at 6 months of development, there are about twice as many brain cells as there are at the time
+ of birth, and in old age the number of cells in the brain keeps increasing with age, so that at the age of
+ 90 the amount of DNA in the brain (36.94 grams) is about 50%.greater than at the age of 16-20 (23.04 grams).
+ In the aged brain, glial cells multiply while neurons die. In the fetus, the cells that die are apparently
+ nerve cells that haven't yet matured. The factors that are known to reduce the brain size at birth are also
+ factors that are involved in the degenerating brain in old age or Alzheimer's disease: lack of oxygen,
+ excess unsaturated fats or deficiency of saturated fats, estrogen excess, progesterone deficiency, and lack
+ of glucose. A lack of carbon dioxide is probably harmful in both. Inflammation and blood clots may be
+ factors in the aging brain, and bleeding with vascular spasm is sometimes a contributing factor to brain
+ damage in both the old and the fetal brain. Endotoxemia may be a factor in nerve degeneration only during
+ adult life, but it is sometimes present during pregnancy.
+
+
+ M. C. Diamond, Enriching Heredity: The Importance of the Environment on the Anatomy of the Brain. Free
+ Press, N.Y., 1988. C. Finch and L. Hayflick, Handbook of the Biology of Aging. Van Nostrand Reinhold, N.Y.,
+ 1977.
+
+
+ III. A VIEW OF ENTROPY: RENEWAL OF THE BRAIN
+
+
+
+
+ When a fertilized egg is developing into a person, each cell division creates a new environment for the
+ daughter cells, to which they adapt. They may run into limits and resistances (sometimes a certain gene
+ doesn't meet the need of the situation, or toxins are present, or nutrients and hormones are imperfectly
+ supplied), but the process is flexible, and a way is normally found to get around the limitation. The
+ embryo's brain development is my favorite example of the ways genes interact with the environment. We might
+ think of the "optimal brain development" of a person, or a rat, or a chicken, as something which is clearly
+ limited by "the genes." But if rats are given a stimulating environment, each generation gets a slightly
+ bigger, slightly more intelligent brain. If rats are treated during pregnancy to increase the amount of
+ progesterone, the offspring have bigger brains and learn more efficiently. Still, that might just be
+ restoring a condition that was natural for rats in some perfect environment. Chickens develop inside an egg
+ shell, and so the nutrients needed for their development are all present when the egg is laid.
+
+
+ The brain, like the other organs, stops growing when the food supply is used up. But an experimenter
+ (Zamenhof) opened the egg shells at the stage of development when the brain normally stops growing, and
+ added glucose, and found that the brain continued growing, producing chickens with bigger brains. The
+ "genes" of a chicken, as part of a system, have something to do with the development of that system, but the
+ environment existing in and around the organism is able to guide and support the way the system develops.
+ The size, complexity, and intelligence of the brain represents a very large part of the "information"
+ contained in the organism, and Zamenhof's experiment showed that the ability to realize this potential, to
+ create this complexity, comes from the support of the environment, and that the "genetic nature of the
+ chicken" didn't constitute a limit to the development of its brain.
+
+
+ I am going to argue that Alzheimer's disease is analogous to the situation confronted by the developing
+ chicken embryo or the rat or human fetus, when the environment is unable to meet the needs of the highly
+ energetic, demanding and sensitive brain cells, and the brain cells begin to die, instead of developing into
+ a more complex state, passing beyond various barriers and limitations. There are two stereotypes that are in
+ conflict with this view: (1) That the structure of the brain is determined at an early point in life,
+ sometimes explicitly stated as the age of 12 or 16, and (2) that the structure of the brain goes into an
+ "entropic" deterioration during the process of aging. My position is that the brain cells are in a vital
+ developmental process at all times, and that the same things that injure the brain of a fetus also injure
+ the brain of an aging person.
+
+
+ If novelty is really appearing during development, then it is hard to maintain that "entropy increases"
+ during the development of an individual. Isn't a child a richer organization than a fertilized egg? Isn't an
+ adult more individualized or realized than an infant? Seen from the inside, our known world gets richer with
+ experience. Learning is certainly anti-entropic. Where does the idea of "increasing entropy with living"
+ come from? Many things contribute, including a doctrine of genetic determinism, the old Platonic idea of the
+ imperfection of the concrete, the unreality of the existent, and the medieval idea of the "corruption of the
+ body." These philosophies still motivate some people in aging research. The astrophysicist, N. A. Kozyrev,
+ showed that the idea of an "entropic cosmos" derived simply from the assumptions of 19th century deism, "God
+ set the clockwork universe in motion, and left it to run down." Early in this century, Raymond Pearl argued
+ that the "rate of living" governed the life-span, so that "fast living" meant a short life. He based his
+ argument on cantaloupe seeds: the faster they grew, the sooner they died. This was because he didn't give
+ them anything but water, so they had to live on their stored energy; if they grew quickly, obviously they
+ ran out of stored energy sooner. I have never heard that described as a stupid idea, but I think politeness
+ is sometimes carried too far. In the clock analogy, or the seed analogy, the available energy is used up.
+
+
+ The clock with its wound-up spring and the seed in a dish of water may be considered as closed systems, and
+ we can understand their fate. But if it is foolish to argue from a confined seed to free-living organisms,
+ then it is just as foolish to argue from a clock to a cosmos. Unfortunately, these inferences about closed
+ systems are often applied to real situations that aren't energetically closed.
+
+
+ The "rate of living" theory of aging picked up the idea of aging as a natural physical property of time, and
+ gave it expression in mathematical form, arguing (Hershey, "Entropy, basal metabolism and life expectancy,"
+ Gerontologia 7, 245-250, 1963) that "the total lifetime entropy production" could be calculated, to give
+ insight into "life expectancy and evolutional development." Unfortunately, the equation Hershey used assumed
+ that the flow of heat out of the body into the surroundings is reversible. This suggests an image of Dr.
+ Frankenstein vivifying his monster with lightning, putting the heat back into the body. If heat is to be
+ "put back into the body," it is necessary to make sure that it is appropriate for the structure as it
+ exists.
+
+
+ Actually, it is just the directed flow of energy which generates the structures. If any biological argument
+ can be made from the idea of entropy, it is that it would be extremely difficult to regenerate food, by
+ putting heat into a person. In a few situations, it is possible to show that living structures can directly
+ absorb heat from their environment (causing the temperature to fall)--"negative heat production"--but the
+ exact meaning of this isn't clear. (B. C. Abbott, et al., "The positive and negative heat production
+ associated with a nerve impulse," Proc. R. Soc. B 148, 149, 1958; R. D. Keynes and J. M. Ritchie, "The
+ initial heat production of amphibian myelinated nerve fibres," Proc. Physiol. Soc., June 1970, page 29P-30P:
+ "It is now clear that in both crustacean...and mammalian (Howarth, et al., 1968) non-myelinated fibres there
+ is an initial production of heat during (or soon after) the action potential, 80% of which is rapidly
+ reabsorbed.") A. I. Zotin ("Aging and rejuvenation from the standpoint of the thermodynamics of irreversible
+ processes," Priroda, No. 9, 49-55, 1970), citing the theory of Prigogine-Wiame, argued that the aging
+ process involves both a decrease in entropy and a decrease in the rate of heat production.
+
+
+ Regeneration involves a production of entropy, as when an egg is formed. (The temperature fluctuation at the
+ time of ovulation might make a contribution to the construction of the entropic egg.) The argument that
+ aging of the animal (like aging of the cosmos) is governed by "the tendency of entropy to increase" has led
+ people to say that rejuvenation would be like unscrambling an egg. Zotin's argument is interesting, because
+ he says that an egg is a "scrambled animal." This view is very much like Warburg's and Szent-Gyorgyi's
+ theory of cancer, that it is like a reversion to a simpler state of life. To sketch out what I have argued
+ in different contexts, water is the part of the living substance that we can most meaningfully discuss in
+ terms of entropy. In fact, much of the concept of entropy has derived from the study of water, as it changed
+ state in steam engines, etc. Cancer cells, like egg cells, have a higher water content than the
+ differentiated, functioning cells of an adult, and the water is less rigidly ordered by the cellular
+ molecules. This different, more mobile state of the water, can be measured by the NMR (nuclear magnetic
+ resonance) machines which are used for MRI (magnetic resonance imaging).
+
+
+ Estrogen has a special place in relation to the water in an organism. It is intimately involved with the
+ formation of the egg cell, and wherever it operates, it increases both the quantity of water and,
+ apparently, the disorder of the water. Its function, I believe, is to promote regeneration, as in Zotin's
+ scheme, by increasing entropy, or "scrambling the animal." The way it promotes regeneration is by promoting
+ water uptake, stimulating cell division, and erasing the differentiated state to one degree or another,
+ providing a new supply of "stem cells," or cells at the beginning of a certain sequence of differentiation.
+ These more numerous cells then must find a hospitable environment in which to develop and adapt. If the
+ proper support can't be found, then they will be recycled, like the unfed cells in the brain of a fetus. If
+ we imagine the course of development as a summary of evolution ("ontogeny recapitulating phylogeny"), then
+ the egg, as it "unscrambles" itself in embryonic development, passing through stages resembling jelly fish,
+ worm, fish, reptile, bird, baboon, keeps finding that the available energy allows it to, in effect, say "I
+ want this, I don't want that," until it emerges as a human baby, saying "I want," and begins eating and
+ learning, and with luck continues the unscrambling, or self-actualization.. Degenerative aging, rather than
+ being "physically derived from the properties of time," seems to be produced situationally, by various types
+ of contamination of our energy supply. Unsaturated fats, interacting with an excess of iron and a deficiency
+ of oxygen or usable energy, redirect our developmental path.
+
+
+ The saturated fats, in themselves, seem to have no "signalling" functions, and when they are naturally
+ modified by our desaturating enzymes, the substances produced behave very differently from the plant-derived
+ "eicosanoids." As far as their effects have been observed, it seems that they are adaptive, rather than
+ dysadaptive. All of the factors that affect the brain of a fetus should be examined in relation to the aging
+ brain. Besides estrogen and fats, I am thinking of oxygen and carbon dioxide, glucose, iron and calcium,
+ cholesterol, progesterone, pregnenolone, DHEA, the endorphins, GABA, thyroid, and vitamin A. An additional
+ factor, endotoxin poisoning, eventually tends to intervene during stress and aging, exacerbating the trend
+ begun under the influence of the other factors.
+
+
+ IV. FALSE SIGNALS FROM THE ENVIRONMENT
+
+ The environment can be supportive, but it can also divert development from an optimal course.
+
+
+ Passively taking whatever you are given, by history and nature, is entropic; choosing intelligently from
+ possible diets, selecting courses of action, will create pattern and reduce entropy. If education contains
+ an element of choice and self-actualization, then the results seen in several Alzheimer's studies could have
+ a significance larger than what has been suggested by the investigators. A diagnostic bias has been reported
+ to result from the use of standardized tests based on vocabulary, because education increases vocabulary,
+ and tends to cover up the loss of vocabulary that occurs in dementia. In the Framingham study, it was
+ concluded that there was a real association of lower educational level with dementia, but the suggestion was
+ made that self-destructive practices such as smoking were more common among the less educated.
+
+
+ The Seattle study of the patients in a health maintenance organization showed a very distinct difference in
+ educational level between the demented and the non-demented, both of whom had roughly similar frequency of
+ prescriptions for estrogen. The features that seemed important to me, that weren't discussed by the authors,
+ were that the demented women had a much lower rate of progestogen use, and a much higher incidence of
+ hysterectomy, which interferes with natural progesterone production. Although Brenner, et al., in the
+ Seattle study concluded that "this study provides no evidence that estrogen replacement therapy has an
+ effect on the risk of Alzheimer's disease in postmenopausal women," they reported that "Current estrogen use
+ of both the oral and the vaginal routes had odds ratios below 1, while former use of both types yielded odds
+ ratios above 1...." (They seem to neglect the fact that Alzheimer's-type disease in old people has a long
+ developmental history, so it is precisely the "former" use that is relevent. 31% of the demented women had
+ formerly used estrogen, and only 20% of the control group. Since estrogen is a brain excitant, present use
+ creates exactly the same sort of effect on verbal fluency and other signs of awareness of the environment
+ that a little cocaine does. Anyone who neglects this effect is probably deliberately constructing a
+ propaganda study.)
+
+
+
+ This observation, that the demented had 155% as much former estrogen use as the normal group, as well as the
+ difference in rates of progestogen use (normal patients had 50% more progestogen use than demented) and
+ hysterectomy (demented had 44.1% vs. 17% in the normals, i.e., 259% as many; the incidence of hysterectomies
+ after the age of 55, which is a strong indication of a natural excess of estrogen, in the demented was 374%
+ of the incidence in the non-demented), should call for a larger study to clarify these observatons, which
+ tend to indicate that exposure to estrogen in middle-age increases the risk of Alzheimer's disease in old
+ age, and that even medical progestogens offer some protection against it..
+
+
+ (Although this study might have been bigger and better, it is far better than the junk-studies that have
+ been promoted by the pharmaceutical publicity machine. I have seen or heard roughly 100 mentions of the
+ pro-estrogen anti-scientific "studies," and none mentioning this one.)
+
+
+ D. E. Brenner, et al., Postmenopausal estrogen replacement therapy and the risk of Alzheimer's disease: A
+ population-based case-control study," Am. J. Epidemiol. 140, 262-267, 1994. "Women tend to have higher
+ age-specific prevalence and incidence rates of Alzheimer's disease than do men." A.F. Jorm, The Epidemiology
+ of Alzheimer's disease and related disorders, Chapman and Hall, London, 1990, and W. A. Rocca, et al., Ann.
+ Neurol. 30, 381-190, 1991.
+
+
+
+ H. C. Liu, et al., "Performance on a dementia screening test in relation to demographic variables--study of
+ 5297 community residents in Taiwan," Arch. Neurol. 51(9), 910-915, 1994. "Commonly used dementia screening
+ tests may be unfair to poorly educated individuals, especially women and rural residents."
+
+
+ SIGNALS IN THE ABSTRACT
+
+
+ When I taught endocrinology, I annoyed my tidy-minded students by urging them to consider the potential
+ hormone-like action of everything in the body, and to think of layers of control, ranging from sugar, salt,
+ and carbon dioxide, through the "official hormones," to complex nervous system actions such as expectancy,
+ and biorhythms. Certain things that are active in very important processes deserve special attention as
+ "signals," but they still have to be understood in context. In this sense, we can think of Ca2+ as a signal
+ substance, in its many contexts; it is strongly regulated by the cell's energy charge. Magnesium and sodium
+ antagonize it in certain situations. Linoleic acid, linolenic acid, arachidonic acid: Their toxicity is
+ potentially prevented by the Mead acids, and their eicosanoid derivatives, which behave very differently
+ from the familiar prostaglandins, as far as they have been compared; can be drastically reduced by dietary
+ changes. Prostaglandins, prostacyclin, thromboxane: Formation is blocked by aspirin and other
+ antiinflammatory drugs.
+
+
+
+ Adenosine: Sleep inducing protective effect. Adenosine is structurally very similar to inosine, another
+ natural substance (found in meat, for example) which is a component of "inosiplex," an antiviral drug (Brown
+ and Gordon, Fed. Proc. 29, 684, 1970, and Can. J. Microbiol. 18, 1463, 1972) or immunostimulant which has
+ also been found to have an anti-senility effect (Doty and Gordon, Fed. Proc. 29). Adenosine is a free
+ radical scavenger, and protects against calcium and glutamate excitotoxicity. (I. Yokoi, et al., "Adenosines
+ scavenged hydroxyl radicals and prevented posttraumatic epilepsy," Free Radical Biol. Med. 19(4), 473-479,
+ 1995; M. P. Abbracchio, et al., "Adenosine A(1) receptors in rat brain synaptosomes: Transductional
+ mechanisms, efects on glutamate release, and preservation after metabolic inhibition," Drug Develop. Res.
+ 35(3), 119-129, 1995.) It also appears to protect against the relative hyperventilation that wastes carbon
+ dioxide, and endotoxin can interfere with its protective action. Guanosine, in this same group of
+ substances, might have some similar properties. Thymidine and cytidine, which are pyrimidine-based, are
+ endogenous analogs of the barbiturates, and like them, they might be regulators of the cytochrome P450
+ enzymes. Uridine, in this group, promotes glycogen synthesis, and is released from bacteria in the presence
+ of penicillin.
+
+
+ Iron: Regulator of mRNA stability, heme synthesis; reacts with reductants and unsaturated oils, to produce
+ free radicals and lipid peroxides; its absorption is increased by estrogen, hypothyroidism, anemia or lack
+ of oxygen. Glutamate and aspartate, excitotoxins, and GABA, an inhibitory transmitter.
+
+
+
+ These have metabolic links with each other, with ammonia, and with stress and energy metabolism.
+
+
+ Estrogen and acetylcholine, excitotoxins; see Savolainen, et al., 1994. The information on this is
+ overwhelmingly clear, and the publicity to the contrary is a horrifying example of the corruption of the
+ mass media by the drug industry.
+
+
+ Endorphins: Stress induced, laterally specific, involved in estrogen action, antagonized by naloxone and
+ similar anti-opiate drugs. I have proposed that the endorphins can cause or sustain some of the symptoms of
+ aging. Naloxone appears to be a useful treatment for senility. E. Roberts, Ann. N. Y. Acad. Sci. 396, 165,
+ 1982; B. Reisberg, et al., N. Engl. J. Med. 308, 721, 1983.
+
+
+ Endotoxin: Antimitochondrial action, causes elevation of estrogen. It synergizes with unsaturated fats, and
+ naloxone opposes some of its toxic effects.
+
+
+
+ Urea, cholesterol: Structural stability of proteins and lipid-protein complexes.
+
+
+ Things that act directly on the water structure: I think all of the natural regulators have an effect on the
+ structure of water, but some unusual substances seem to act primarily on the water. Noble gases, for
+ example, have no chemical effects, but they tend to form "cages" of water molecules around themselves.
+ Camphor, adamantane, and the antiviral drug amantadine, probably have a similar water-structuring effect,
+ and amantadine, which is widely used as a therapy in Parkinson's disease, has an anti-excitotoxic action.
+
+
+
+ Article continued in Part 2 - click
+ here
+
+
+
+ Raymond Peat, Ph.D.
+
+
+ Copyright 1997
+
+
+
+ SELECTED REFERENCES
+
+
+ S. Rose, "Genuine genetics or conceited convenience?" Trends in Neuro. Sci. 17(3), 105, 1994.
+
+
+
+ F. P. Monnet, et al., "Neurosteroids, via sigma receptors, modulate the [H3]norepinephrine release evoked by
+ N-methyl-D-aspartate in the rat hippocampus," P.N.A.S. (USA) 92(9), 3773-3778, 1995. "...progesterone may
+ act as a sigma antagonist."
+
+
+ J. L. Sanne and K. E. Krueger, "Expression of cytochrome P450 side-chain cleavage enzyme and 3
+ beta-hydroxysteroid dehydrogenase in the rat central nervous system: A study by polymerase chain reaction
+ and in situ hybridization," J. of Neurochemistry 65(2), 528-536, 1995.
+
+
+ V. V. Zakusov and R. U. Ostrovskaya, "Increased resistance of mice to hypoxia under the influence of
+ tranquilizers of the benzodiazepine series," Byulletan Eksperimentalnoy Biologii i Meditsiny 71(2), 45-47,
+ 1971. [The protection was not from the sedative effects, "Rather, the protective effect of these compounds
+ is attributed to some specific intervention in the metabolism whereby the sensitivity of the tissues to
+ oxygen insufficiency is reduced. ...the cortical structures of the brain especially appear to derive
+ enhanced resistance to oxygen deficiency."]
+
+
+ A. I. Zotin, "Aging and rejuvenation from the standpoint of the thermodynamics of irreversible processes,"
+ Priroda 9, 49-55, 1970. [The process of aging "...is manifested by a decrease in entropy and...also by a
+ continuous decrease in the rate of heat production.. The organism exhibits two types of approaches to a
+ steady state: (i) constitutive movement of the system to the final steady state and (ii) inducible return of
+ the system to the current steady state after deviating under the influence of internal or external factors.
+ Oogenesis represents a constitutive deviation from the steady state; entropy reaches a level sufficient for
+ the start of development and passage of the living system into the state of constitutive approach to the
+ final steady state. From the standpoint of the thermodynamic theory of development, oogenesis reflects the
+ process of regeneration of the system. In all other stages of life there is only the aging process
+ accompanied by a decrease in entropy."
+
+
+ M. M. Tikhomirova, et al., "Mechanisms underlying the resistance of genetic material of the animal cell to
+ stress treatment," Genetika 30(8), 1092-1104, 1994. "...these studies prove that the formation of a mutation
+ is a multistage process involving many cell and organism systems...which are affected by environmental
+ factors.... They can hinder or accelerate the mutational process, in this way providing both a superadditive
+ effect and adaptive response. Recent studies deal with a universal system of heat shock proteins, which is
+ involved in the maintenance of resistance of genetic material and genetic processes in the cell." Gross,
+ "Reproductive cycle biochemistry," Fertility & Sterility 12(3), 245-260, 1961. "The maintenance of an
+ environment conducive to anaerobic metabolism--which may involve the maintenance of an adequate supply of
+ the substances that permit anaerobiosis...seems to depend primarily upon the action of estrogen."
+ "Glycolytic metabolism gradually increases throughout the proliferative phases of the cycle, reaching a
+ maximum coincident with the ovulation phase, when estrogen is at a peak. Following this, glycolysis
+ decreases, the respiratory mechanisms being more active during the secretory phase. Eschbach and Negelein
+ showed the metabolism of the infantile mouse uterus to be less anaerobic than that of the adult. If estrogen
+ is administered, however, there is a 98 per cent increase in glycolytic mechanisms.""The effect of the
+ progestational steroids may be such as to interfere with the biochemical pattern required for support of
+ this anaerobic environment."
+
+
+ M. A. G. Sissan, et al., "Effects of low-dose oral contraceptive oestrogen and progestin on lipid
+ peroxidation in rats," J. of International Med. Res. 23(4), 272-278, 1995. "The levels of lipid peroxides,
+ free fatty acids and glutathione in the liver, and of serum ceruloplasmin increased significantly with
+ oestrogen treatment. Lipid peroxides (in the liver only), and serum ceruloplasmin decreased significantly
+ when progestin was administered. The activities of superoxide dismutase and catalase decreased significantly
+ in the oestrogen group...but increased in the progestin group."
+
+
+
+ A. Jendryczko, et al., "Effects of two low-dose oral contraceptives on erythrocyte superoxide dismutase,
+ catalase and glutathione peroxidase activities," Zentralbl. Gynakol. (Germany) 115(11), 469-472, 1993.
+ "These data suggest that low-dose oral contraceptives, by decreasing the activities of antioxidant enzymes
+ and by enhancing the lipid peroxidation, increase the risk of cardiovascular disease."
+
+
+ J. W. Olney, "Excitotoxins in foods," Neurotoxicology 15(3), 535-544, 1994. "The most frequently encountered
+ food excitotoxin is glutamate which is commercially added to many foods despite evidence that it can freely
+ penetrate certain brain regions and rapidly destroy neurons by hyperactivating the NMDA subtype of glutamate
+ receptor."
+
+
+ K. Savolainen, et al., "Phosphoinositide second messengers in cholinergic excitotoxicity," Neurotoxicology
+ 15(3), 493-502, 1994. "Acetylcholine is a powerful excitotoxic neurotransmitter in the brain. By stimulating
+ calcium-mobilizing receptors, acetylcholine, through G-proteins, stimulates phospholipase C and cause the
+ hydrolysis of a membrane phospholipid...." "Inositol-1,4,5-triphosphate is important in cholinergic neuronal
+ stimulation, and injury. Cholinergic agonists cause tonic-clonic convulsions which may be either transient
+ or persistent. Even short-term cholinergic convusions may be associated with neuronal injury, especially in
+ the basal forebrain and the hippocampus. Cholinergic-induced convulsions also elevate levels of brain
+ calcium which precede neuronal injury. Female sex and senescence increase the sensitivity of rats to
+ cholinergic excitotoxicity." "Furthermore, glutamate increases neuronal oxidative stress...."
+
+
+ L. N. Simanovskiy and Zh. A. Chotoyev, "The effect of hypoxia on glycogenolysis and glycolysis rates in the
+ rat brain," Zhurnal Evolyutsionnoy Biokhimii i Fiziologii 6(5), 577-579, 1970. "Glycogenolysis and
+ glycolysis in the whole brain of young and old rats were studied at sea level and under hypoxic conditions
+ in a low-pressure chamber or at an altitude of 3,200 meters. The rate of carbohydrate metabolism increaased
+ during postnatal development. In the absence of hypoxia, the rate of accumulation of lactate from either
+ glycogen or glucose increases with maturation of the animals. The brain of young rats consumes primarily
+ glycogen, particularly under anaerobic conditions." "Adaptation of mature rats to intermittent hypoxia is
+ related to an increase in glycolysis, whereas adaptation of rats to high altitudes results in an increase in
+ glycogenolysis. The type of carbohydrate metabolism is thus similar to the metabolism characteristic of the
+ early stages of ontogenesis."
+
+
+
+ Ye. Sadovskiy, "For the prolongation of human life," Sovetskaya Belorussiya 23, page 4, Dec. 1970. "...the
+ accumulation of metals in the organism with age is one of the most important factors in the development of
+ the aging process."
+
+
+ Cerebral ischemia (and several other imbalances, relating to steroid regulation, shock) might be relieved by
+ naloxone: D. S. Baskin and Y. Hosobuchi, Lancet ii, 272-275, 1981.
+
+
+ V. Reynolds, et al., "Heart rate variation, age, and behavior in subjects with senile dementia of Alzheimer
+ type," Chronobiol. Int. 12(1), 37-45, 1995. "...circadian rhythm of SDAT may be more often unimodal than
+ that of normal subjects of similar age, and that phase shift of the endogenous, clock-mediated component of
+ the rhythm (with higher heart rate at night) is to be expected in a proportion of individuals with SDAT."
+
+
+
+ M. Martinez, et al., "Glucose deprivation increases aspartic acid release from synaptosomes of aged mice,"
+ Brain Res. 673(1), 149-152, 1995. "...in the absence of glucose in the medium of incubation aspartate and
+ glutamate release was higher in old than in young animals." "...there is an age-dependent dysfunction in
+ this process linked to energy metabolism disturbance."
+
+
+ J. M. Pasquini and A. M. Adamo, "Thyroid hormones and the central nervous system," Dev. Neurosci. 12(1-2),
+ 1-8, 1994. "Among their actions, T3 and T4 have effects on the differentiation of various cell types in the
+ rat brain and cerebellum as well as on the process of myelination. Recently, several investigators have
+ shown effects of thyroid hormones on myelin protein gene expression."
+
+
+ G. C. Ness and Z. H. Zhao, "Thyroid hormone rapidly induces hepatic LDL receptor mRNA levels in
+ hypophysectomized rats," Arch. Biochem. Biophys. 315(1), 199-202, 1994.
+
+
+ E. M. Mutisya, et al., "Cortical cytochrome oxidase activity is reduced in Alzheimer's disease," J.
+ Neurochem. 63(6), 2170-2184, 1994. "These results provide further evidence of a cytochrome oxidase defect in
+ Alzheimer's disease postmortem brain tissue. A deficiency in this key energy-metabolizing enzyme could lead
+ to a reduction in energy stores and thereby contribute to the neurodegenerative process."
+
+
+ G. J. Bu, et al., "Subcellular localization and endocytic function of low density lipoprotein
+ receptor-related protein in human glioblastoma cells," J. Biol. Chem. 269(47), 29874-29882, 1994. "Our
+ results thus strongly suggest several potential roles for LRP in brain protein and lipoprotein metabolism,
+ as well as control of extracellular protease activity."
+
+
+ V. Vandenbrouck, et al., "The modulation of apolipoprotein E gene expression by 3,3'-5-triiodothyronine in
+ HepG(2) cells occurs at transcriptional and post-transcriptional levels," Eur. J. Biochem. 224(2), 463-471,
+ 1994. "...thyroid hormone stimulated apoE gene transcription threefold in 24 hours."
+
+
+
+ T. Yamada, et al., "Apolipoprotein E mRNA in the brains of patients with Alzheimer's disease," J. Neurol.
+ Sci. 129(1), 56-61, 1995. In A.D. Apo E "was decreased in relation to the apoE-epsilon 4 gene dosage." "AD
+ patients who had long survival times showed high expression of apoE and low expression of GFAP [glial
+ fibrillary acidic protein]. These results suggest that apoE suppresses the progression of AD, including
+ gliosis, in the brain."
+
+
+ G. P. Jarvik, et al., "Genetic influences on age-related change in total cholesterol, low density
+ lipoprotein-cholesterol, and triglyceride levels: Longitudinal apolipoprotein E genotype effects," Genet.
+ Epidemiol. 11(4), 375-384, 1994. "Apo E is a component of LDL, is a ligand for the LDL receptor, and apo E
+ genotype has been consistently associated with variation in mean levels of total cholesterol and LDL-C...."
+ With aging, total cholesterol and LDL-C became significantly lower in the "epsilon 4 genotype" group; this
+ is the group at risk for AD.
+
+
+ S. Miller and J. M. Wehner, "Cholesterol treatment facilitates spatial learning performance in DBA/2Ibg
+ mice," Pharmacology Biochemistry and Behavior 49(1) 257-261, 1994. "Our results suggest that subchronic
+ treatment with the steroid hormone precursor, cholesterol, enhances spatial learning performance in DBA
+ mice."
+
+
+ A. D. Roses, "Apolipoprotein E affects the rate of Alzheimer disease expression: beta-amyloid burden is a
+ secondary consequence dependent on ApoE genotype and duration of disease," J. Neuropathol. Exp. Neurol.
+ 53(5), 429-437, 1994.
+
+
+
+ T. Gunther and V. Hollriegl, "Increased protein oxidation by magnesium deficiency and vitamin E depletion,"
+ Magnesium-Bull. 16(3), 101-103, 1994.
+
+
+ F. Oyama, et al., "Apolipoprotein E genotype, Alzheimer's pathologies and related gene expression in the
+ aged population," Mol. Brain Res. 29(1), 92-98, 1995. "...ApoE4/4 accelerates and ApoE2/3 decelerates the
+ development of the AD pathologies in the aged brain...."
+
+
+
+ M. L. C. Maatschieman, et al., "Microglia in diffuse plaques in hereditary cerebral hemorrhage with
+ amyloidosis (Dutch). An immunohistochemical study," J. Neuropathol. Exp. Neurol. 53(5), 483-491, 1994.
+ "Microglia are intimately associated with congophilic plaques in Alzheimer's disease...." "Intensely
+ immunoreactive microglia with enlarged cell bodies and short, thick processes clustered in congophilic
+ plaques."
+
+
+ J. Poirier, "Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease," Trends Neurosci.
+ 17(12), 525-530, 1994. "The coordinated expression of ApoE and its receptor...[low density lipoprotein
+ (LDL)] receptor, appears to regulate the transport of cholesterol and phospholipids during the early and
+ intermediate phases of the reinnervation process." "...a dysfunction of the lipid-transport system
+ associated with compensatory sprouting and synaptic remodeling could be central to the AD process."
+
+
+
+ P. H. Chan and R. A. Fishman, "Brain edema: Induction in cortical slices by polyunsaturated fatty acids,"
+ Science 201, 358-369, 1978. "This cellular edema was specific, since neither saturated fatty acids nor a
+ fatty acid containing a single double bond had such effect." R. Nogues, et al., "Influence of nutrition,
+ thyroid hormones, and rectal temperature on in-hospital mortality of elderly patients with acut illness," Am
+ J Clin Nutr 61(3), 597-602, 1995. "Serum albumin, body weight, and total T3 concentration were higher in
+ survivors than in nonsurvivors." "Mild hypothermia was a good predictor of death. Hypoalbuminemia and
+ hypothermia were associated with low T3 and high rT3 values."
+
+
+ R. C. Vannucci, et al., "Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: An
+ experimental study in the immature rat," Pediatrics 95(6), 868-874, 1995.
+
+
+
+ H. M. Wisniewski and P. B. Kozlowski, "Evidence for blood-brain barrier changes in senile dementia of the
+ Alzheimer type (SDAT)", Ann. N. Y. Acad. Sci. 396, 119-129, 1982. "...one would expect that the chronic
+ "flooding" of the neuronal elements with serum proteins would affect their performance." "The cause of the
+ increased BBB permeability in SDAT is unknown."
+
+
+ J. S. Jensen, et al., "Microalbuminuria reflects a generalized transvascular albumin leakiness in clinically
+ healthy subjects," Clin. Sci. 88(6), 629-633, 1995. "It is suggested that the observed transvascular
+ leakiness, in addition,may cause increased lipid insudation to the arterial walls."
+
+
+
+ C. Nilsson, et al., "The nocturnal increase in human cerebrospinal fluid production is inhibited by a
+ beta(1)-receptor antagonist," Amer. J. Physiol.-Regul. Integr. C 36(6), R1445-R1448, 1994.
+
+
+ D. L. Williams, et al., "Cell surface 'blanket' of apolipoprotein E on rat adrenocortical cells," J. Lipid
+ Res. 36(4), 745-758, 1995. "...the zona fasciculata cell is encircled or covered with apoE on all faces of
+ the cell. ...this cell surface 'blanket' of apoE participates in the uptake of lipoprotein cholesterol by
+ either the endocytic or selective uptake pathways." C. A. Frye and J. D. Sturgis, "Neurosteroids affect
+ spatial reference, working, and long-term memory of female rats," Neurobiol. Learn. Memory 64(1), 83-96,
+ 1995. [Female rats take longer to acquire a spatial task during behavioral estrus.)]
+
+
+ M. Warner and J. A. Gustafsson, "Cytochrome P450 in the brain: Neuroendocrine functions," Front
+ Neuroendocrinol 16(3), 224-236, 1995. [Discusses the GABA(A) receptor active steroids, and the accumulation
+ of pregnenolone in the brain.]
+
+
+ P. Robel, et al., "Biosynthesis and assay of neurosteroids in rats and mice: Functional correlates," J.
+ Steroid Biochem. Mol. Biol. 53(1-6), 355-360, 1995. [Discusses the effects of pregnenolone and progesterone
+ on aggression and learning. The animals which learned most easily had the highest levels of pregnenolone
+ sulfate.] K. W. Lange and P. Riederer, "Glutamatergic drugs in Parkinson's disease," Life Sci. 55(25-26,
+ 2067-2075, 1994. "...excitatory amino acids such as glutamate are involved in the pathophysiological cascade
+ of MPTP...-induced neuronal cell death." "The 1-amino-adamantanes amantadine and memantine have recently
+ been shown to be non-competitive NMDA antagonists and are widely used in Europe as antiparkinsonian agents."
+
+
+ R. A. Wallis, et al., "Glycine-induced CA1 excitotoxicity in the rat hippocampal slice," Brain Res. 664(1-2)
+ 115-125, 1994. K. Ossawska, "The role of excitatory amino acids in experimental models of Parkinson's
+ disease," J. Neural Transm.-Parkinsons 8(1-2_, 39-71, 1994.
+
+
+ G. S. Roth, et al., "Membrane alterations as causes of impaired signal transduction in Alzheimer's disease
+ and aging," Trends Neurosci. 18, 203-206, 1995. "Reconstituted lipid membranes from cortical gray matter of
+ AD brain samples were significantly thinner (that is, had less microviscosity) than corresponding
+ age-matched controls." "This change in membrane width correlated with a 30% decrease in the moles of
+ cholesterol:phospholipid." "Addition of cholesterol restored the membrane width to that of the age-matched
+ control samples."
+
+
+ T. Reed, et al., "Lower cognitive performance in normal older adult male twins carrying the apolipoprotein E
+ epsilon 4 allele," Arch. Neurol. 51(12), 1189-1182, 1994.
+
+
+ S.Y. Tan and M. B. Pepys, "Amyloidosis," Histopathology 25(5), 403-414, 1994. "...abnormal protein fibrils
+ which are derived from different proteins in different forms of the disease. Asymptomatic amyloid deposition
+ in a variety of tissues is a universal accompaniment of ageing, and clinical amyloidosis is not rare.
+ Intracerebral and cerebrovascular beta-protein amyloid deposits are a hallmark of the pathology of ...
+ Alzheimer's disease...." "Amyloid deposits are in a state of dynamic turnover and can regress if new fibril
+ formation is halted." A. V. Sirotkin, "Direct influence of melatonin on steroid, nonapeptide hormones, and
+ cyclic nucleotide secretion by granulosa cells isolated from porcine ovaries," J. Pineal Res. 17(3),
+ 112-117, 1994. "It was found that melatonin is able to inhibit progesterone and stimulate estradiol
+ secretion." "Some inhibition of vasopressin and cAMP and significant stimulation of cGMP also resulted from
+ melatonin treatment." R. M. Sapolsky, "Glucocorticoid toxicity in the hippocampus: Reversal with
+ supplementation with brain fuels," J. Neurosci. 6, 2240-2245, 1986. R. M. Sapolsky, "Glucocorticoids,
+ hippocampal damage and the glutaminergic synapse," Prog. Brain Res. 86, 13-23, 1990. M. Schwartz, et al.,
+ "Growth-associated triggering factors and central nervous system regeneration," p. 47 in Trophic Factors and
+ the Nervous System, edited by L. A. Horrocks, et al., Raven Press, NY, 1990. R. W. Ordway, et al., "Direct
+ regulation of ion channels by fatty acids," Trends Neurosci. 14, 96-100, 1991.
+
+
+ H. G. P. Swarts, et al., "Binding of unsaturated fatty acids to Na+,K+-ATPase leading to inhibition and
+ inactivation," Biochim. Biophys. Acta 1024, 32-40, 1990.
+
+
+ G. Autore, et al., "Essential fatty acid-deficient diet modifies PAF levels in stomach and duodenum of
+ endotoxin-treated rats," J. Lipid Mediators Cell Signalling 9, 145-153, 1994. J. Rafael, et al., "The effect
+ of essential fatty acid deficiency on basal respiration and function of liver mitochondria in rats," J.
+ Nutr. 114, 255-262, 1984.
+
+
+ A. M. Weiner, et al., "Nonviral retroposons, genes, pseudogenes, and transposable elements generated by the
+ reverse flow of genetic information," Ann. Rev. Biochem. 55, 631-661, 1986. I. Zs.-Nagy, "Semiconduction of
+ proteins as an attribute of the living state: The ideas of Albert Szent-Gyorgyi revisited in light of the
+ recent knowledge regarding oxygen free radicals," Exp. Gerontology 30(3-4), 327-335, 1995. "In this
+ assumption, the continuous radical flux is as important for the maintenance of the living state, as the
+ voltage power supply is essential for the functioning of the computer."
+
+
+
+ Article continued in Part 2 - click
+ here
+
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
+
+
+
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+
+ The problem of Alzheimer's disease as a clue to immortality - Part 2
+
+
+ The problem of Alzheimer's disease as a clue to immortality - Part 2
+
+
+
+ V. HORMONE IMBALANCE, LEADING TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S DISEASE
+
+
+
+ "All cell death is characterized by an increase of intracellular calcium...." "Increase of cytoplasmic
+ free calcium may therefore be called 'the final common path' of cell disease and cell death. Aging as a
+ background of diseases is also characterized by an increase of intracellular calcium. Diseases typically
+ associated with aging include hypertension, arteriosclerosis, diabetes mellitus and dementia."
+
+
+ T. Fujita, "Calcium, parathyroids and aging," in Calcium-Regulating Hormones. 1. Role in Disease and
+ Aging, H. Morii, editor, Contrib. Nephrol. Basel, Karger, 1991, vol. 90, pp. 206-211.
+
+
+ THE FUNCTION OF ENERGY
+
+ Most people are slightly demented now and then, when they are very sleepy or tired, or sick, or drunk, or
+ having a hormone imbalance or extreme anxiety state. Sometimes physicians have described people as demented,
+ implying that the condition would never improve, when the person was depressed or hypothyroid. If the person
+ has a history of epilepsy, or is very old, the physician is more likely to diagnose dementia than if the
+ same loss of mental function occurs in a younger person without a history of a nervous disorder. Even people
+ with less education are at increased risk of being diagnosed as "demented."
+
+
+ In 1976, I saw a 52 year-old woman who had the diagnosis of epileptic dementia. After 3 or 4 days of taking
+ progesterone, her mental function returned to the extent that she could find her way around town by herself,
+ and could work. A few months later, she returned to graduate school, got straight As and a master's degree.
+ A few years later, a man in his 80s showed the classical signs of senile dementia, with childishness,
+ confusion, self-centeredness, and unstable emotions. A few days after getting a mixture of thyroid,
+ pregnenolone, and progesterone, his mind was again clear, and he was able to work on a research project he
+ had set aside years before.
+
+
+ When the body temperature is very much below normal, mental functioning is seriously limited. I think the
+ first question that should be asked about a demented person is "is this the cold brain syndrome, or is
+ something else involved?" When it is known that the brain has shrunken drastically, and filled up with
+ plaques and developed gliosis, we know that something more than a "cold brain" is involved, but we don't
+ know how much function could be regained if the hormones were normalized. Every moment of malfunction
+ probably leaves its structural mark. Early or late, it is good to prevent the functional errors that lead to
+ further damage, and to give the regenerative systems an opportunity to work. Before the final "calcium
+ death" described (above) by Fujita, there are many opportunities for intervening to stop or reverse the
+ process. The older the person is, the more emphasis should be put on protective inhibition, rather than
+ immediately increasing energy production. Magnesium, carbon dioxide, sleep, red light, and naloxone might be
+ appropriate at the beginning of therapy.
+
+
+ The resting state of a cell is a highly energized state. To the old Pavlovians, the resting state existed at
+ two energy levels, and they applied the term "protective inhibition" generally to the depleted state
+ (parabiosis) that occurs in exhaustion or coma, but I am using the phrase in a more general sense, that
+ seems reasonable now that the concept of "excitotoxic" injury has become current. I mean it to include
+ everything which protects against excitotoxic injury. This definition therefore has the virtue of being
+ biochemically and physiologically very specific, while retaining the functional and therapeutic significance
+ that it had for the Pavlovians. (My book, Mind and Tissue, and the chapter "A unifying principle"
+ in
+ Generative Energy, discussed the idea of the resting state and protective inhibition.)
+
+
+ Ordinary healthy sleep is an example of restorative, protective inhibition. The energy charge, including
+ levels of ATP, creatine phosphate, and glycogen storage, regulates many restorative enzyme systems. I have
+ suggested (1975, J. Orthomol. Psychiatry) how the entropy-sensitivity or cold-inactivation of an enzyme
+ could be involved in shifting the brain toward a state of inhibition. A recent publication (J. H. Benington
+ and H. C. Heller, "Restoration of brain energy metabolism as the function of sleep," Progress in Neurobiol.
+ 45, 347-360, 1995) has proposed that reduction of energy charge and depolarization of cells act through
+ adenosine secretion to restore glycogen stores. Since glycogen stores decrease with aging, this work
+ supports the idea that protective inhibition is weakened with aging. (L. N. Simanovskiy and Zh. A. Chotoyev,
+ "The effect of hypoxia on glycogenolysis and glycolysis rates in the rat brain," Zhurnal Evolyutsionnoy
+ Biokhimii i Fiziologii 6(5), 577-579, 1970.)
+
+
+ J. H. Benington and H. C. Heller, "Restoration of brain energy metabolism as the function of sleep," Prog.
+ in Neurobiology 45, 347-360, 1995. "...the conditions that have been demonstrated to stimulate adenosine
+ release from neural tissue represent either increases in metabolic demand (...activation of excitatory
+ receptors) or decreases in metabolic supply (hypoxia, ischaemia, hypoglycemia)...." "In the brain,
+ adenosine-stimulated increases in potassium conductance produce hyperpolarization, thereby reducing neuronal
+ responsiveness...." "Adenosine release is triggered globally in response to changes in cerebral energy
+ homeostasis." "A number of findings provide indirect support for the hypothesis that glycogen stores are
+ depleted during waking and restored during sleep." "Reduced availability of glycogen to astrocytes
+ must...increase adenosine release...." "Because ATP concentration is 100-fold greater than AMP
+ concentration, a minute decrease in cellular energy charge...is translated into a large proportional
+ increase in extracellular adenosine cencentration...."
+
+
+ The terms "functional quiescence" and "G0 quiescence" are similar in meaning to the resting state; I think
+ of cells in the state of "G0 quiescence" as being stem cells, waiting for use in regeneration, but I don't
+ subscribe to the idea that they can't be reconstituted from functioning, differentiated cells. In plants,
+ dedifferentiation is achieved fairly easily, and in the study of animal cells the trend in that direction
+ seems very obvious, though many people keep saying that it just isn't possible. In general, the things such
+ as lipid peroxidation or calcium influx which cause cell replication at one level, cause cell death at a
+ higher level.
+
+
+ Energy to resist stress makes quiescence possible, and prevents the deterioration of cells, of the sort that
+ occurs in aging. O. Toussaint, et al., "Cellular aging and energetic factors," Exp. Gerontology 30(1), 1-22,
+ 1995. "Experiments performed with endothelial cells in the context of the ischemia-reperfusion toxicity of
+ free radicals, also offer good examples of the impact of cell energy on cell resistance to these toxic
+ molecules." "...if a supplement of energy is given...the toxic effect of the free radicals is much
+ reduced...."
+
+
+ The specific approaches of this orientation --to energize but quiet the brain--are diametrically opposed to
+ some of the "therapies" for Alzheimer's disease that have been promoted recently by the drug industries:
+ Things to increase stimulation, especially to increase cholinergic excitation; even the excitotoxic amino
+ acids themselves and their analogs; and estrogen, which is a multiple brain excitant, proconvulsant,
+ excitotoxic promoter, and anti-memory agent. Those product-centered publications stand out distinctly from
+ the actual research.
+
+
+ There are many energy-related vicious circles associated with aging, but the central one seems to be the
+ fat-thyroid-estrogen-free-radical-calcium sequence, in which the ability to produce stabilizing substances
+ including carbon dioxide and progesterone is progressively lost, increasing susceptibility to the unstable
+ unsaturated fats.
+
+ EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS
+
+ Estrogen production is facilitated when tissue is cooler, and it lowers body temperature. Estrogen and the
+ endorphins act together in many ways (including the behavior of estrus), and naloxone (the antagonist of
+ morphine and the endorphins) raises body temperature and in other ways opposes estrogen. Naloxone has been
+ found to improve the symptoms of demented people, and I have seen it quickly, and dramatically, improve the
+ mental clarity of a 60 year old woman who had used estrogen. It, like clonidine (the anti-adrenaline drug),
+ is a good candidate for controlling the hot flashes and other symptoms of menopause.
+
+
+ In various degenerative brain conditions, blood clotting has been implicated either as a cause or a
+ complication. Many people are promoting unsaturated oils for their "anti-clotting" value, in spite of the
+ older literature showing that they inhibit proteolytic enzymes and slow clot removal. Several newer
+ publications have revealed other aspects of their involvement in thrombus formation. A. J. Honour, et al.,
+ "The effects of changes in diet on lipid levels and platelet thrombus formation in living blood vessels,"
+ Br. J. Expt. Pathol. 59(4), 390-394, 1978--corn oil caused platelets to be more sensitive to ADP.
+
+
+
+ Although there is a lot of talk about "membrane fluidity," as a desirable thing, and the loss of unsaturated
+ lipids in the aged brain, there are some interesting observations related to "viscosity" in Alzheimer's
+ disease. The platelets of Alzheimer's patients are less viscous, and lipids extracted from the brain are
+ more fluid, and contain 30% less cholesterol than normal (on a molar basis, in relation to phospholipids).
+ (G. S. Roth, et al., 1995.) In general, lipid peroxidation causes cellular viscosity to increase, apparently
+ by causing cross-linking of proteins, but I think the significance of the decreased cholesterol relates to
+ its significance as precursor to pregnenolone and progesterone, and to the known association with
+ Alzheimer's disease of a variant form of the cholesterol transporter protein, ApoE, which I suppose is a
+ slightly less stable molecular form that is more susceptible to malfunction in stress.
+
+
+ The extracellular matrix is a major factor in the function and stability of brain cells. (L. F. Agnati, et
+ al., "The concept of trophic units in the central nervous system," Prog. in Neurobiol. 46, 561-574, 1995.
+ Any factor producing edema tends to disrupt the extracellular matrix (Chan and Fishman, 1978, 1980, and L.
+ Loeb, 1948.)
+
+
+ Seizures are known to be promoted by estrogen, by unsaturated fats, and by lipid peroxidation, and to cause
+ an increase in the size of the free fatty acid pool in the brain. Prolonged seizures cause nerve damage in
+ certain areas, especially the hippocampus, thalamus, and neocortex (Siesjo, et al., 1989). Dementia is known
+ to be produced by prolonged seizures.
+
+
+
+ Prenatal exposure to estrogen, to oxygen deficiency, or to unsaturated fats decreases the size of the brain
+ at birth. There is apparently a requirement for saturated fats during development (J. M. Bourre, N.
+ Gozlan-Devillierre, O. Morand, and N. Baumann, "Importance of exogenous saturated fatty acids during brain
+ development and myelination in mice," Ann. Biol. Anim., Biochim., Biophys. 19(1B), 172-180, 1979.
+
+
+ Under the influence of estrogen, or unsaturated fats, brain cells swell, and their shape and interactions
+ are altered. Memory is impaired by an excess of estrogen. Estrogen and unsaturated fat and excess iron kill
+ cells by lipid peroxidation, and this process is promoted by oxygen deficiency. The fetus and the very old
+ have high levels of iron in the cells. Estrogen increases iron uptake. Estrogen treatment produces elevation
+ of free fatty acids in the blood, and lipid peroxidation in tissues. This tends to accelerate the
+ accumulation of lipofuscin, age-pigment. Lactic acid, the production of which is promoted by estrogen,
+ lowers the availability of carbon dioxide, leading to impairment of blood supply to the brain.
+
+
+ Estrogen stimulates cell division, but can also increase the rate of cell death. Unsaturated fatty acids can
+ also stimulate or kill.
+
+
+ Both estrogen and unsaturated fats promote the formation of age-pigment. Besides increasing the free fatty
+ acid concentration, estrogen possibly depresses the level of cholesterol, both of which are changes seen in
+ the senile brain.
+
+
+ Estrogen causes massive alterations of extracellular matrix, and seems to promote dissolution of
+ microtubules (Nemetschek-Gannsler), as calcium does. Unsaturated fats increase calcium uptake by at least
+ some brain cells (H. Katsuki and S. Okuda, 1995.) Unsaturated fats, like estrogen, increase the permeability
+ of blood vessels. The unsaturated fat causes edema of the brain, inhibits choline uptake, blocking
+ acetylcholine production.
+
+
+
+ Progesterone is a nerve growth factor, produced by glial cells (oligodendrocytes). It promotes the
+ production of myelin, protects against seizures, and protects cells against free radicals. It protects
+ before conception, during gestation, during growth and puberty, and during aging. It promotes regeneration.
+ Its production is blocked by stress, lipid peroxidation, and an excess of estrogen and iron.
+
+
+ Aspirin protects against iron toxicity, clot formation, and reduces lipid peroxidation while blocking
+ prostaglandin formation. Aspirin and other antiinflammatory drugs, taken for arthritis, have been clearly
+ associated with a reduced incidence of Alzheimer's disease. Aspirin reduces the formation of prostaglandins
+ from arachidonic acid.
+
+
+ Unsaturated fatty acids, but not saturated fatty acids, are signals which activate cell systems.
+
+
+ Many different stimuli can induce cell activity, cell death, or change to another cell type. (J. Niquet, et
+ al., "Glial reaction after seizure induced hippocampal lesion: Immunohistochemical characterization of
+ proliferating glial cells," J. Neurocytol. 23(10), 641-656, 1994: "...hippocampal astrocytes from
+ kainate-treated rats experess A2B5 immunoreactivity, a marker of type-2 astrocytes." "This suggests that in
+ the CNS, normal resident astrocytes acquire the phenotypic properties of type-2 astrocytes.")
+
+
+
+ A "deficiency" of polyunsaturated fatty acids leads to altered rates of cellular regeneration and
+ differentiation, a larger brain at birth, improved function of the immune system, decreased inflammation,
+ decreased mortality from endotoxin poisoining, lower susceptibility to lipid peroxidation, increased basal
+ metabolic rate and respiration, increased thyroid function, later puberty and decreases other signs of
+ estrogen dominance. When dietary PUFA are not available, the body produces a small amount of unsaturated
+ fatty acid (Mead acids), but these do not activate cell systems in the same way that plant-derived PUFAs do,
+ and they are the precursors for an entirely different group of prostaglandins.
+
+ VITAMIN A AND THE STEROIDS
+
+ In a variety of cell types, vitamin A functions as an estrogen antagonist, inhibiting cell division and
+ promoting or maintaining the functioning state. It promotes protein synthesis, regulates lysosomes, and
+ protects against lipid peroxidation. Just as stress and estrogen-toxicity resemble aging, so does a vitamin
+ A deficiency. While its known functions are varied, I think the largest use of vitamin A is for the
+ production of pregnenolone, progesterone, and the other youth-associated steroids. One of vitamin E's
+ important functions is protecting vitamin A from destructive oxidation. Although little attention has been
+ given to the effects of unsaturated fats on vitamin A, their destruction of vitamin E will necessarily lead
+ to the destruction of vitamin A. The increased lipid peroxidation of old age represents a vicious circle, in
+ which the loss of the antioxidants and vitamin A leads to their further destruction.
+
+
+ To produce pregnenolone, thyroid, vitamin A, and cholesterol have to be delivered to the mitochondria in the
+ right proportion and sufficient quantity. Normally, stress is balanced by increased synthesis of
+ pregnenolone, which improves the ability to cope with stress. Lipid peroxidation, resulting from the
+ accumulation of unsaturated fatty acids, iron, and energy deficiency, damages the mitochondrias' ability to
+ produce pregnenolone. When pregnenolone is inadequate, cortisol is over-produced. When progesterone is
+ deficient, estrogen's effect is largely unopposed. When both thyroid and progesterone are deficient, even
+ fat cells synthesize estrogen.
+
+
+ THE NATURE OF ALZHEIMER'S DISEASE
+
+ Although Alzheimer's disease until recently referred to a certain type of organic dementia occuring in
+ people in their thirties, forties and fifties (presenile dementia), structural similarities seen in senile
+ dementia have caused the term to lose its original meaning. Alzheimer's sclerosis of blood vessels, and even
+ the death of nerve cells, are sometimes neglected in favor of the more stylish ideas, emphasizing certain
+ proteins that cause the tangles and plaques. Until recently, the "tangles" were commonly interpreted as the
+ debris left after the death of a cell, rather than as one of the processes causing the death of the cell.
+
+
+ Alzheimer-type dementia is different from other dementias, but it overlaps with them, and with age-related
+ and stress-related changes in other organs.
+
+
+ Physical signs (seen at autopsy) of AD:
+
+
+ 1) Death of neurons (increase of glial cells),
+
+
+
+ 2) Amyloid plaques (extracellular), associated with a particular variant of apolipoprotein E, the epsilon 4
+ allele,
+
+
+ 3) Fibrillary tangles (intracellular, or remaining after the rest of the cell has disappeared),
+
+
+ 4) Amyloid in blood vessels.
+
+
+ Functional and biochemical observations:
+
+
+ 1) The mitochondrial energy problem, cytochrome oxidase and its regulation; body temperature/pulse-rate
+ cycle disturbance; lipid peroxidation; respiratory defect; altered amino acid uptake; memory impairment;
+ dominance of the excitatory systems vs. the inhibitory adenosine/GABA/progesterone/pregnenolone system.
+ Increased calcium uptake, which is associated with lipid peroxidation and cell death. Increased cortisol and
+ DHEA.
+
+
+ 2) Deposit of abnormal proteins, such as transthyretin-amyloid; albumin binding of PUFA, vs. transport of
+ thyroid and retinol.
+
+ Beta-glucuronidase increases, depositing estrogen in cells. (A. J. Cross, et al., "Cortical
+ neurochemistry in Alzheimer-type dementia," Chapter 10, pages 153-170 in
+ Aging of the Brain and Alzheimer's Disease, Prog. in Brain Res. 70, edited by D. F. Swaab, et al.,
+ Elsevier, N.Y., 1986.)
+
+
+ 3)
+ Abnormally phosphorylated (tau) proteins; association with the variant form of Apo E; tau microtubule
+ organizing proteins, microtubules are involved in transporting cholesterol; phosphorylation, by the kinase
+ systems, regulated by PUFA; the intermediate filaments are generally stress-associated.
+
+
+ 4) ApoE, in cytoplasm, involved in cholesterol delivery for pregnenolone synthesis, as in the adrenal; its
+ expression regulated by thyroid. Regulation of the side-chain cleaving enzymes; regulation of the
+ cholesterol intake and conversion to pregnenolone by the endozepine receptor/GABA receptor, modified by
+ progesterone.
+
+
+ AN EXAMPLE OF A REGULATORY PROBLEM
+
+ Vegetable oil suppresses the thyroid, increasing estrogen. Estrogen and calcium depolymerize microtubules.
+ Microtubule transport for Apo E, transthyretin, thyroid, and cholesterol for pregnenolone synthesis is
+ disrupted. Transthyretin and Apo E accumulate unused, and deposit in blood vessels, around nerves, and in
+ cytoplasm. Pregnenolone and progesterone deficiency (aggravating thyroid deficiency) causes memory loss,
+ destabilization of nerve cells, failure of myelin formation, and excess cortisol synthesis. Free radicals
+ and calcium cause multiple cell injuries including nerve-death. Estrogen is released by elevated
+ beta-glucuronidase. Imbalances of other steroids, including cortisol and DHEA, develop as cells compensate
+ for pregnenolone deficiency, causing shifts in balance of glial cells. Hypothyroidism, estrogen excess, free
+ unsaturated fats cause increased vascular permeability and brain edema, protein leakage, and alteration of
+ the matrix..
+
+
+ VIII: STRUCTURE AS A REGULATORY SYSTEM--AN EMERGING VISION OF PERVASIVE EPIGENESIS
+
+
+ In the introduction I mentioned that membranous regulation and genetic determination should be considered as
+ defunct theories. What I have been saying about self-actualizing systems and the factors that disrupt them
+ derives from a view of cell function that has been developing since the 1920s.
+
+
+ Around 1940, a Russian biochemist (Oparin, I think) proposed that the enzymes of glycolysis were bound to
+ the structure of the cell when they were not in use, and that they were "desorbed" under the conditions that
+ required abundant glycolysis. Knowing that concept, in 1970 I proposed that the cell water itself underwent
+ a transition under such conditions (which could include increased temperature, reduced oxygen, or nervous or
+ hormonal stimulation). Activation of glycolysis is usually explained by the availability of regulatory
+ substances such as ammonia, phosphate, and NAD, and many biochemists were content to understand cells in
+ terms of test-tube models. But in the last few years, it has become clear that some of these basic
+ regulatory molecules do bind to structural components of the cell. (T. Henics, "Thoughts over cell biology:
+ A commentary," Physiol. Chem. Phys. & Med. NMR 27, 139-140, 1995.) Although the details aren't clear, it
+ is known that hormones and other factors stabilize or destabilize RNA, and that during some of these events
+ relevant enzymes bind to the RNA. When these facts are combined with the information that is accumulating on
+ splicing and modification of RNA, and the copying of RNA back into DNA, the hereditary system is seen to be
+ much more flexible than it was believed to be.
+
+
+ A global change of state is able to steer each part of the process, continuously. In this way, the cell
+ resembles an analog, rather than a digital, control system: each part is momentarily guided, rather than
+ waiting for "feedback."
+
+
+ Where before, cellular "regulatory mechanisms" referred to certain feedback mechanisms based on interactions
+ of randomly diffusing molecules, the new understanding of the cell sees a highly structured system in which
+ very little is random, and the cell's adaptive possibilities, instead of being limited to a certain number
+ of genetic switches, are shaped by every imaginable environmental influence. The cell's structure, far from
+ being "read out of the genome," is sensitively reshaped constantly by processes that incorporate some of the
+ environment in establishing each new stability. The old-model-geneticists have been forced to admit that the
+ genes can't specify everything in the organism's structure, and it was the brain's complexity that forced
+ this recognition that certain things are developed "epigenetically." But the new fact that most biologists
+ are reluctant to accept is that the structure of the cell itself is developed very largely on the basis of
+ information received from the environment--that is, "epigenetically."
+
+
+
+ Traditionally, epigenesis has meant that the form of an embryo or organism didn't preexist, or wasn't
+ completely specified by the genes. That is, it has had to do with the relationships between cells. It
+ involved a recognition that "cells are clever enough to design an organism." It is a significant step beyond
+ that to the recognition that "cells are clever enough to redesign themselves to meet situations never seen
+ before."
+
+
+ Biologists working with bacteria and yeasts have seen them adapt in non-random ways to novel conditions.
+ "Directed mutations" are impossible, according to the "central dogma" that has the support of textbooks and
+ most biology professors, but they do occur in those single-celled organisms. Barbara McClintock showed that
+ in corn her mobile genes were mobilized by stress. Although this isn't exactly "directed mutation," it is an
+ example of a mechanism for increasing adaptation when adaptation is need. There is a certain type of enzyme
+ which makes specific cuts in the DNA chain. Biotechnologists find them convenient for their purposes, but
+ their presence serves physiological purposes, presumably in all organisms, like those described by
+ McClintock in corn. During the terminal stress that produces the special kind of cell death known as
+ apoptosis, these enzymes make confetti of the genome.
+
+
+
+ Poisons, such as estrogen, unsaturated fatty acids, or even radiation, produce different effects at
+ different doses. Low doses typically stimulate cell division, larger doses produce changes of cell type and
+ altered states of differentiation, and finally, adequate doses produce apoptotic cell death. There is a
+ special ideology around apoptosis, which holds that it is "genetically programmed," implying that whenever
+ it occurs in the brain, it was destined to happen sooner or later. But in fact, "growth factors" of various
+ sorts can prevent it. It is increasingly clear that it represents excessive stress and deficient resources.
+ The involvement of the genetic apparatus in differentiation and radical adaptation suggests that the
+ (epigenetic) resources of cells are unlimited.
+
+
+ The changes that are known to be produced by the poisons that we are habitually exposed to are exactly the
+ changes that occur in the aging brain. As I scan over hundreds of studies that define the effects of
+ estrogen, unsaturated fats, excess iron, and lipid peroxidation, my argument seems commonplace, even
+ trivial, except that I know that it clearly relates to therapies for most of the degenerative diseases, and
+ that the great culture-machine is propagating a different view at several points that are essential for my
+ argument.
+
+
+ They are advancing a myth about human nature, so I will advance a counter-myth. At the time people were
+ growing their large brains they lived in the tropics. I suggest that in this time before the development of
+ grain-based agriculture, they ate a diet that was relatively free of unsaturated fats and low in iron--based
+ on tropical fruits. I suggest that the Boskop skull from Mt. Kilimanjaro was representative of people under
+ those conditions, and that just by our present knowledge of the association of brain size with longevity,
+ they--as various "Golden Age" myths claim--must have had a very long life-span. As people moved north and
+ developed new ways of living, their consumption of unsaturated fats increased, their brain size decreased,
+ and they aged rapidly. Neanderthal relics show that flaxseed was a staple of their diet.
+
+
+
+ Even living in the tropics, there are many possibilities for diets rich in signal-disrupting substances,
+ including iron, and in high latitudes there are opportunities for reducing our exposure to them. As a source
+ of protein, milk is uniquely low in its iron content. Potatoes, because of the high quality of their
+ protein, are probably relatively free of toxic signal-substances. Many tropical fruits, besides having
+ relatively saturated fats, are also low in iron, and often contain important quantities of amino acids and
+ proteins. In this context, Jeanne Calment's life-long, daily consumption of chocolate comes to mind: As she
+ approaches her 121st birthday, she is still eating chocolate, though she has stopped smoking and drinking
+ wine. The saturated fats in chocolate have been found to block the toxicity of oils rich in linoleic acid,
+ and its odd proteins seem to have an anabolic action.
+
+
+ If we really take seriously even the traditional sort of epigenesis, and especially if we accept the deeper
+ idea of epigenesis on the level of cellular structure and function, we have to see the organism as a sort of
+ "whirlwind of cells," made up of whirlwinds of atoms (in Vernadsky's phrase) in which our way of life sets
+ the boundaries within which our cells will restructure themselves.
+
+
+ The random production of free radicals, rather than acting only by way of genetic damage or protein
+ cross-linking, is also able to act as a signalling process, that is, on a strictly physiological level. An
+ excess of unsaturated fatty acids itself constitutes a massive distortion of the regulatory systems, but it
+ also leads to distortions in the "eicosanoid" system and the increasingly uncontrolled production of free
+ radicals, and to changes in energy, thyroid activity, and steroid balance. The aging body, rather than being
+ like a car that needs more and more repairs until it collapses from simple wear, is more like a car
+ traveling a road that becomes increasingly rough and muddy, until the road becomes an impassable swamp.
+
+
+ The suggested therapy is a correction of the signalling process, rather than "genetic surgery,"
+ transplantation, etc., which is the pessimistic implication of the doctrine that oxidative damage is simply
+ a matter of "wear and tear," "somatic mutations," and "cross-linking." Those problems are reparable, and our
+ emphasis should be on the production of energy and the avoidance of the conditions that allow the
+ undesirable signals to accumulate.
+
+
+ The absence of cancer on a diet lacking unsaturated fats, the increased rate of metabolism, decreased free
+ radical production, resistance to stress and poisoning by iron, alcohol, endotoxin, alloxan and
+ streptozotocin, etc., improvement of brain structure and function, decreased susceptibility to blood clots,
+ and lack of obesity and age pigment on a diet using coconut oil rather than unsaturated fats, indicates that
+ something very simple can be done to reduce the suffering from the major degenerative diseases, and that it
+ is very likely acting by reducing the aging process itself at its physiological core.
+
+
+ Copyright: Raymond Peat, PhD 1997
+
+
+ PO Box 5764 Eugene, OR 97405
+
+
+
SELECTED REFERENCES
+
+
+
+ Winfried G. Rossmanith, "Gonadotropin secretion during aging in women: Review article," Exp. Gerontology
+ 30(3/4) 369-381, 1995. "...major functional derangements, primarily at a hypothalamic rather than a
+ pituitary site, have been determined as concomitants of aging in women." "...aging may impair the negative
+ feedback sensitivity to ovarian sex steroids...." Hormonal changes at menopause "may represent the sum of
+ functional aberrations that were initiated much earlier in life...." "...prolonged estrogen exposure
+ facilitates the loss of hypothalamic neurons...."
+
+
+ J. R. Brawer, et al., "Ovary-dependent degeneration in the hypothalamic arcuate nucleus," Endocrinology 107,
+ 274-279, 1980.
+
+
+
+ G. C. Desjardins, "Estrogen-induced hypothalamic beta-endorphin neuron loss: A possible model of
+ hypothalamic aging," Exp. Gerontology 30(3/4), 253-267, 1995. "This loss of opioid neurons is prevented by
+ treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals."
+ "...this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the
+ vicinity of LHRH cell bodies." Resulting supersensitivity of the cells results "in chronic opioid
+ suppression of the pattern of LHRH release, and subsequently that of LH." The neurotoxic effects of
+ estradiol cause a "cascade of neuroendocrine aberrations resulting in anovulatory acyclicity." Treatment
+ with an opiod antagonist "reversed the cystic morphology of ovaries and restored normal ovarian cycles" in
+ estrogen-treated rats.
+
+
+
+ G. B. Melis, et al., "Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women
+ using naloxone," Neuroendocrinology 39, 60-63, 1984.
+
+
+ H. J. Sipe, et al., "The metabolism of 17 beta-estradiol by lactoperoxidase: A possible source of oxidative
+ stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994. "...molecular oxygen is consumed by a
+ sequence of reactions initiated by the glutathione thiyl radical. ...the estradiol phenoxyl radical
+ abstracts hydrogen from...NADH to generate the NAD radical." "...the futile metabolism of micromolar
+ quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing
+ cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence."
+
+
+ S. Santagati, et al., "Estrogen receptor is expressed in different types of glial cells in culture," J.
+ Neurochem. 63(6), 2058-2064, 1994. "...in all three types of glial cell analyzed in almost equal amounts..."
+
+
+
+ D. X. Liu and L. P. Li, "Prostaglandin F-2 alpha rises in response to hydroxyl radical generated in vivo,"
+ Free Radical Biol. Med. 18(3), 571-576, 1995. "Free radicals and some free fatty acids, such as arachidonic
+ acid metabolites...may form a feedback loop in which generation of one type leads to formation of the
+ other." "Prostaglandin F-2 alpha dramatically increased in response to hydroxyl radical generation...."
+
+
+ J. Owens and P. A. Schwartzkroin, "Suppression of evoked IPSPs by arachidonic acid and prostaglandin F-2
+ alpha," Brain Res. 691(1-2), 223-228, 1995. "These findings suggest that high levels of AA and its
+ metabolites may bias neurons towards excitation."
+
+
+ E. A. Quail and G. C. T. Yeoh, "The effect of iron status on glyceraldehyde 3-phosphate dehydrogenase
+ expression in rat liver," FEBS Lett. 359(2-3), 126-128, 1995. "...the overexpression of GAPDH mRNA in iron
+ deficiency is probably due to increased message stability." [This is one of the points discussed by Henics.
+ Estrogen, which increases iron retention, also modifies mRNA stability.]
+
+
+
+ J. G. Liehr, et al., "4-hydroxylation of estradiol by human uterine myometrium and myoma microsomes:
+ Implications for the mechanism of uterine tumorigenesis," Proc Natl Acad Sci USA 92(20), 9220-9224, 1995.
+ "... elicits biological activities distinct from estradiol, most notably an oxidant stress response induced
+ by free radicals generated by metabolic redox cycling reactions."
+
+
+ J. G. Liehr and D. Roy, "Free radical generation by redox cycling of estrogens," Free Rad. Biol. Med. 8,
+ 415-423, 1990.
+
+
+ P. Aschheim, "Resultats fournis par la greffe heterochrone des ovaires dan l'etude de la regulation
+ hypothalamo-hypophyso-ovarienne de la ratte senile," Gerontologia 10, 65-75, 1964/65. "Our last experiment,
+ grafting ovaries...into senile rats which had been castrated (ovariectomized) when young, and its result,
+ the appearance of estrous cycles, seems explicable by this hypothesis. Everything happens as if the long
+ absence of ovarian hormones... had kept the cells of the hypothalamus in the state of youth. It's as if the
+ messages of the circulating steroids fatigued the hypothalamic memory." "What are the factors that cause
+ this diminution of the hypothalamic sensitivity...? Kennedy incriminates a decrease in the cellular
+ metabolism in general...."
+
+
+ P. Ascheim, "Aging in the hypothalamic-hypophyseal ovarian axis in the rat," pp. 376-418 in: A. V. Everitt
+ and J. A. Burgess, editors, Hypothalamus, Pituitary and Aging, C>C> Thomas, Springfield, 1976.
+
+
+ Gross, "Reproductive cycle biochemistry," Fertility & Sterility 12(3), 245-260, 1961. "The maintenance
+ of an environment conducive to anaerobic metabolism--which may involve the maintenance of an adequate supply
+ of the substances that permit anaerobiosis...seems to depend primarily upon the action of estrogen."
+ "Glycolytic metabolism gradually increases throughout the proliferative phases of the cycle, reaching a
+ maximum coincident with the ovulation phase, when estrogen is at a peak. Following this, glycolysis
+ decreases, the respiratory mechanisms being more active during the secretory phase. Eschbach and Negelein
+ showed the metabolism of the infantile mouse uterus to be less anaerobic than that of the adult. If estrogen
+ is administered, however, there is a 98 per cent increase in glycolytic mechanisms.""The effect of the
+ progestational steroids may be such as to interfere with the biochemical pattern required for support of
+ this anaerobic environment."
+
+
+ C. S. Bangur, J. L. Howland, S. S. Katyare, "Thyroid hormone treatment alters phospholipid composition and
+ membrane fluidity of rat brain mitochondria," Biochem. J. 305(1), 29-32, 1995. (Increases fluidity.)
+
+
+ R. S. Sohal, et al., "Mitochondrial superoxide and hydrogen peroxide generation, protein oxidative damage,
+ and longevity in different species of flies," Free Rad. Biol. & Med. 19(4), 499-504, 1995. Cytochrome C
+ oxidase protects against free radical damage. This enzyme depends on thyroid and light.
+
+
+
+ D. L. Williams, et al., "Cell surface 'blanket' of apolipoprotein E on rat adrenocortical cells," J. Lipid
+ Res. 36(4), 745-758, 1995. "...the zona fasciculata cell is encircled or covered with apoE on all faces of
+ the cell. ...this cell surface 'blanket' of apoE participates in the uptake of lipoprotein cholesterol by
+ either the endocytic or selective uptake pathways."
+
+
+ C. A. Frye and J. D. Sturgis, "Neurosteroids affect spatial reference, working, and long-term memory of
+ female rats," Neurobiol. Learn. Memory 64(1), 83-96, 1995. [Female rats take longer to acquire a spatial
+ task during behavioral estrus.] M. Warner and J. A. Gustafsson, "Cytochrome P450 in the brain:
+ Neuroendocrine functions," Front Neuroendocrinol 16(3), 224-236, 1995. [Discusses the GABA(A) receptor
+ active steroids, and the accumulation of pregnenolone in the brain.]
+
+
+ P. Robel, et al., "Biosynthesis and assay of neurosteroids in rats and mice: Functional correlates," J.
+ Steroid Biochem. Mol. Biol. 53(1-6), 355-360, 1995. [Discusses the effects of pregnenolone and progesterone
+ on aggression and learning. The animals which learned most easily had the highest levels of pregnenolone
+ sulfate.]
+
+
+
+ J. R. Pasqualini, et al., "Effect of the progestagen promegestone (R-5020) on mRNA of the oestrone
+ sulphatase in the MCF-7 human mammary cancer cells," Anticancer Res. 14(4A), 1589-1593, 1994. Progestagen
+ decreases estrogen sulfatase in mammary cancers. [Sulfatase, like beta-glucuronidase, causes active estrogen
+ to be released.]
+
+
+ W. J. Trooster, et al., "Treatment of acute experimental allergic encephalomyelitis in the Lewis rat with
+ the sex hormone progesterone," Int. J. Immunopathol. Pharmacol. 7(3), 183-192, 1994. "...we suggest that
+ treatment with progesterone protected against the histological signs of EAE through a peripheral immune
+ mechanism."
+
+
+ H. L. Koenig, et al., "Progesterone synthesis and myelin formation by Schwann cells," Science (268),
+ 1500-1503, 1995. "The high concentrations of progesterone in intact adult nerves also indicate a role for
+ this neurosteroid in the slow but continuous renewal of peripheral myelin."
+
+
+
+ N. C. Lan and K. W. Gee, "Neuroactive steroid actions at the GABA(A) receptor," Horm. Behav. 28(4), 537-544,
+ 1994. Neuroactive steroids "...do not interact with any of the classical cytosolic hormonal steroid
+ receptors." "The interaction of neuroactive steroids with GABA(A) receptor is specific to a site on the
+ receptor complex distinct from the benzodiazepine and barbiturate modulatory sites."
+
+
+ J. F. FierroRenoy, et al., "Three different thyroid hormone receptor isoforms are detected in a pure culture
+ of ovine oligodendrocytes," Glia 14(4), 322-328, 1995. "Our results demonstrate that differentiated
+ oligodendrocytes express alpha-1 and alpha-2 variant and beta-1 isoforms of TH at the protein level and
+ support the notion of a direct impact of thyroid hormones on oligodendrocytes in their regulation of myelin
+ synthesis."
+
+
+ J. Masse, "Nutrition, thyroid hormones, body temperature, and mortality of elderly patients with acute
+ illnesses," Am. J. Clin. Nutr. 62(3), 647-648, 1995.
+
+
+
+ E. J. Masoro, "Dietary restriction," Exp. Gerontology 30(3/4), 291-298, 1995. "These antiaging actions
+ result from a reduction of energy intake by the animal but are not due to a decrease in metabolic rate per
+ unit of lean body mass." [The slowed rate of aging is associated with increased metabolic rate--as if
+ metabolic inhibitors accumulate at a slower rate.]
+
+
+ D. L. Cheney, et al., "Pregnenolone sulfate antagonizes dizocilpine amnesia: Role for allopregnanolone,"
+ Neuroreport 6(12), 1697-1700, 1995. "We and others have shown that allopregnanolone potently modulate
+ GABA(A) receptor function whereas 5 alpha-dihydroprogesterone fails to induce rapid changes...."
+
+
+ B. S. McEwen and E. Gould, "Adrenal steroid influences on the survival of hippocampal neurons," Biochem.
+ Pharmacol 40, 2393-2402, 1990.
+
+
+
+ P. W. Landfield, et al., "Hippocampal aging and adrenocorticoids: Quantitative correlations," Science
+ 202(8), 1098-1101, 1978.
+
+
+ A. M. Dudchenko, et al., "Effect of corticosterone on the macroergic pool and membrane permeability in
+ sections of rat hippocampus," Bull. Exp. Biol. & Med. 116(12), 1505-1508, 1993. "...the hippocampus is
+ one of the most vulnerable brain structures...." "...a reduction of the oxygen content...causes a sharp
+ increase of membrane permeability, which is...in line with the trend toward a decrease of the macroergic
+ [energy] content (especially creatine phosphate and ATP content) in the hippocampal cells." "The death of
+ hippocampal neurons, triggered...by hyperactivation of the glutamate receptors, is accelerated in the
+ presence of" glucocorticoids, while these hormones may be protective against oxygen deficit, by increasing
+ the availability of glucose, and possibly of amino acids.
+
+
+
+ M. J. Meaney, et al., "Individual differences in hypothalamic-pituitary-adrenal activity in later life and
+ hippocampal aging," Exp. Gerontology 30(3/4), 229-251, 1995. "...glucocorticoids...both increase the toxic
+ glutamate signal and decrease the metabolic capacity of neurons to survive." (Glucose is protective.) "Our
+ current foxus is on the potential role of progesterone as a modulator of glucocorticoid action."
+
+
+ P. Sheng, et al., "Methamphetamine causes reactive gliosis in vitro: Attenuation by the ADP-ribosylation
+ inhibitor, benzamide," Life Sciences 55(3), 51-54, 1994
+
+
+ N. S. Verkhratsky, "Limbic control of endocrine glands in aged rats," Exp. Gerontology 30(3/4, 415-421,
+ 1995. Aging causes "degeneration of pyramidal cells in the hippocampus of humans..., accumulation of
+ lipofuscin...,a decrease in the excitability of amygdala medial nuclei and an increased excitability of its
+ central nuclei..., and a deterioration of their vascularization." "...stimulation of hippocampus inhibits
+ ACTH secretion...and causes a decrease of plasma corticosteroids...."
+
+
+ R. M. Sapolsky, et al., "Prolonged glucocorticoid exposure reduces hippocampal neuron number: Implications
+ for aging," J. Neurosci. 5 1221, 1985.
+
+
+ J. L. W. Yau, Mol. Brain Res. 27(1), 174-178, 1994. "Glucocorticoid excess is associated with hippocampal
+ neuronal dysfunction and loss, mainly affecting CA1."
+
+
+ B. Nasman, et al., "A subtle disturbance in the feedback regulation of the hypothalamic-pituitary-adrenal
+ axis in the early phase of Alzheimer's disease," Psychoneuroendocrinology 20(20, 211-220, 1995. "After 0.5
+ mg dexamethasone, serum cortisol levels were significantly less suppressed...."
+
+
+ C. Mondadori, "In search of the mechanism of action of the nootropics: New insights and potential clinical
+ implications," Life Sci. 55(25-26), 2171-2178, 1994. "...the fact that high levels of corticosteroids
+ suppress the effects of the nootropics could also have clinical implications: in the light of the
+ observation that the majority of Alzheimer patients have elevated steroid levels it could explain why there
+ is always only a small proportion of patients...that respond to treatment with nootropics."
+
+
+ J. M. Pasquini and A. M. Adamo, "Thyroid hormones and the central nervous system," Dev. Neurosci. 12(1-2),
+ 1-8, 1994. "Among their actions, T3 and T4 have effects on the differentiation of various cell types in the
+ rat brain and cerebellum as well as on the process of myelination. Recently, several investigators have
+ shown effects of thyroid hormones on myelin protein gene expression."
+
+
+ M. Martinez, et al., "Glucose deprivation increases aspartic acid release from synaptosomes of aged mice,"
+ Brain Res. 673(1), 149-152, 1995. "...in the absence of glucose in the medium of incubation aspartate and
+ glutamate release was higher in old than in young animals." "...there is an age-dependent dysfunction in
+ this process linked to energy metabolism disturbance."
+
+
+ P. Corbisier, et al., "Bioenergetics of mitochondria determine cell survival in stressful conditions," Prog.
+ in Cell Res. (5), 237-241, 1995. "...the growth rate of young or old cells injected with coupled
+ mitochondria...was not statistically different."
+
+
+ G. Paradies, et al., "Molecular basis of the age-dependent decrease in the cytochrome oxidase activity in
+ rat heart mitochondria," Prog. in Cell Res. 5, 243-247, 1995. The activity of cytochrome oxidase "was
+ markedly decreased with aging. This decrease was associated with a parallel decrease in the mitochondrial
+ respiratory activity." "Cardiolipin content was significantly reduced in mitochondrial membrane from aged
+ rats."
+
+
+
+ G. C. Ness and Z. H. Zhao, "Thyroid hormone rapidly induces hepatic LDL receptor mRNA levels in
+ hypophysectomized rats," Arch. Biochem. Biophys. 315(1), 199-202, 1994.
+
+
+ E. M. Mutisya, et al., "Cortical cytochrome oxidase activity is reduced in Alzheimer's disease," J.
+ Neurochem. 63(6), 2170-2184, 1994. "These results provide further evidence of a cytochrome oxidase defect in
+ Alzheimer's disease postmortem brain tissue. A deficiency in this key energy-metabolizing enzyme could lead
+ to a reduction in energy stores and thereby contribute to the neurodegenerative process."
+
+
+ G. J. Bu, et al., "Subcellular localization and endocytic function of low density lipoprotein
+ receptor-related protein in human glioblastoma cells," J. Biol. Chem. 269(47), 29874-29882, 1994. "Our
+ results thus strongly suggest several potential roles for LRP in brain protein and lipoprotein metabolism,
+ as well as control of extracellular protease activity."
+
+
+
+ V. Vandenbrouck, et al., "The modulation of apolipoprotein E gene expression by 3,3'-5-triiodothyronine in
+ HepG(2) cells occurs at transcriptional and post-transcriptional levels," Eur. J. Biochem. 224(2), 463-471,
+ 1994. "...thyroid hormone stimulated apoE gene transcription threefold in 24 hours."
+
+
+ M. J. Ignatius, et al. "Expression of apolipoprotein-E during nerve degeneration and regeneration," Proc.
+ Natl. Acad. Sci. (USA) 83, 1125-1129, 1986.
+
+
+ B. T. Stokes, et al., "Energy depletion, calcium and the cytoskeleton: A model for trophic intervention,"
+ pp. 279-292, in Trophic Factors and the Nervous System, L. A. Horrocks, et al., editors, Raven Press, NY,
+ 1990. "Injury to neuronal cells is associated with a decline in high energy phosphates, a loss of cation
+ homeostasis, and possibly, an increase in reactive oxygen radicals." "Virtually all components of the
+ cytoskeleton are either directly or indirectly affected by alterations in calcium metabolism."
+ "...calcium-activated proteases may also specifically modulate components of the cytoskeleton." "...ATP
+ depletion itself may directly alter the structural components of the neuronal cytoskeleton." "...major
+ neurodegenerative diseases such as Alzheimer's, Parkinsonian syndrome, amyotrophic lateral sclerosis...are
+ also characterized by changes in the neuronal cytoskeleton."
+
+
+ T. Gunther, et al., "Effects of magnesium and iron on lipid peroxidation in cultured hepatocytes," Mol. Cell
+ Biochem. 144(2), 141-145, 1995. (Magnesium protects against iron.)
+
+
+ K. D. Croft, et al., "Oxidation of low-density lipoproteins: Effect of antioxidant content, fatty acid
+ composition and intrinsic phospholipase activity on susceptibility to metal ion-induced oxidation,"
+ BBA-Lipid Lipid Metab. 1254(3), 250-256, 1995.
+
+
+ J. H. Choi and B. P. Yu, "Brain synaptosomal aging: Free radicals and membrane fluidity," Free Radical Biol.
+ Med. 18(2), 133-139, 1995 ("...fluidity loss may be influenced by factors other than cholesterol. We suggest
+ that lipid peroxidation may be a major factor in the change in fluidity during the aging process.")
+
+
+
+ J. H. Choi and B. P. Yu, "Modification of age-related alterations of iron, ferritin, and lipid peroxidation
+ in rat serum," Age 17(3), 93-97, 1994.
+
+
+ E. Chiarpotto, et al., "Metabolism of 4-hydroxy-2-nonenal and aging," Biochem. Biophys. Res. Commun. 297(2),
+ 477-484, 1995. (Accumulation of unsaturated fat breakdown product in old animals.)
+
+
+ H. J. Sipe, et al., "The metabolism of beta-estradiol by lactoperoxidase: A possible source of oxidative
+ stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994.
+
+
+
+ M. J. Endresen, et al., "Effects of free fatty acids found increased in women who develop pre-eclampsia on
+ the ability of endothelial cells to produce prostacyclin, cGMP and inhibit platelet aggregation," Scan. J.
+ Clin. Lab. Invest. 54(7), 549-557, 1994. "...levels of circulating free fatty acids are increased
+ in women who later develop pre-eclampsia long before the clinical onset of the disease." "...linoleic acid
+ reduced the thrombin-stimulated prostacyclin release by 30-60%, oleic acid by 10-30%, wheras palmitic acid
+ had no effect." "Linoleic acid reduced the endothelial cells" ability to inhibit platelet aggregation by
+ 10-45%...."
+
+
+ L. A. Norris and J. Bonnar, "Effect of oestrogen dose on whole blood platelet activation in women taking new
+ low dose oral contraceptives," Thromb. Haemost. 72(6), 926-930, 1994: "Increased levels of ADP and
+ arachidonic acid-induced aggregation were observed in women taking the 30 microgram ethinyloestradiol
+ combination. Platelet release of beta-thromboglobulin (beta TG) was also significantly increased. Increased
+ collagen-induced aggregation was observed but this failed to reach statistical significance for the
+ individual treatment groups.") Estrogen dominance is an essential factor in preeclampsia. Women who have
+ died of (eclamptic) convulsions have been found to have massive clots in their brain blood vessels. Much of
+ this work had its origin in the 1930s (Shute and others), and was buried by the power of the estrogen
+ industry.
+
+
+ H. Darmani, et al., "Interferon-gamma and polyunsaturated fatty acids increase the binding of
+ lipopolysaccharide to macrophages," Int. J. Exp. Pathol. 75(5), 363-368, 1994.
+
+
+ G. Autore, et al., "Essential fatty acid-deficient diet modifies PAF levels in stomach and duodenum of
+ endotoxin-treated rats," J. Lipid Mediators Cell Signalling 9, 145-153, 1994. Deficiency of "essential" fats
+ decreases damage from endotoxin.
+
+
+ N. Auge, et al., "Proliferative and cytotoxic effects of mildly oxidized low-density lipoproteins on
+ vascular smooth-muscle cells," Biochem. J. 309(Part 3), 1015-1020, 1995. "The proliferative effect on
+ smooth-muscle cells is counterbalanced at high concentrations of mildly oxidized LDLs (or at high oxidation
+ levels) by their cytotoxic effect."
+
+
+ S. K. Clinton, et al., "The combined effects of dietary fat and estrogen on survival, 7,12-dimethyl-
+ benz(a)-anthracene-induced breast cancer and prolactin metabolism in rats," J. Nutr. 125(5), 1192-1204,
+ 1995. "Mortality in controls was doubled by feeding a high fat diet...." "...the presence of estrogen may be
+ a prerequisite for significant dietary modulation."
+
+
+
+ R. Sanchez Olea, et al., "Inhibition by polyunsaturated fatty acids of cell volume regulation and osmolyte
+ fluxes in astrocytes," Amer. J. of Physiology--cell physiology 38(1), C96-C102, 1995. "...potent blockers of
+ regulatory volume decrease and of the swelling-activated efflux of taurine, D-aspartate, inositol, and I-125
+ (used as marker of Cl). ...oleic and ricinoleic acids and saturated fatty acids were ineffective."
+ "...polyunsaturated fatty acids directly inhibit the permeability pathways correcting cell volume after
+ swelling in cultured astrocytes."
+
+
+ M. E. Miller, et al., "Influence of hormones on platelet intracellular calcium," Thrombosis Research 77(6),
+ 515-530, 1995. "Platelet intracellular calcium concentration and release was significantly decreased in
+ women ingesting tamoxifen compared to controls and significantly increased, as was platelet adhesion, in
+ oral contraceptive users." "Only oral contraceptive users had increased sensitivity to aggregating agents.
+ (...platelet calcium levels are closely related to the degree of platelet adhesion and aggregation in vivo."
+
+
+
+ F. Mercure and G. Vanderkraak, "Inhibition of gonadotropin-stimulated ovarian steroid production by PUFA in
+ teleost fish," Lipids 30(6), 547-554, 1995. "EPA and DHA inhibited gonadotropin-stimulated testosterone
+ production in a dose-related manner...."
+
+
+ A A Farooqui, K Wells, L A Horrocks, "Breakdown of membrane phospholipids in Alzheimer disease--involvement
+ of excitatory amino acid receptors," Mol Chem Neuropathol 25(2-3) 155-173, 1995. "The release of
+ arachidonate from the sn-2 position of glycerophospholipids is catalyzed by phospholipases and lipases.
+ These enzymes are coupled to EAA receptors. Overstimulation of these receptors may be involved in abnormal
+ calcium homeostasis, degradation of membrane phospholipids, and the accumulation of free fatty acids,
+ prostaglandins, and lipid peroxides. Accumulation of the mentioned metabolites, as well as abnormalities in
+ signal transduction owing to stimulation of lipases and phospholipases, may be involved in the pathogenesis
+ of the neurodegeneration in AD."
+
+
+ Leo Loeb, V. Suntzeff, and E. L. Burns, "Changes in the nature of the stroma in vagina, cervix and uterus of
+ the mouse produced by long-continued injections of estrogen and by advancing age," The American Journal of
+ Cancer 35(2), 159-174, 1939. Loeb, et al., speak of collagenous deposits as fibrous-hyaline tissue, varying
+ from a fibrillar to a homogeneous appearance, and varying in consistency from very dense and glassy in
+ appearance, to the softer gelatinous substance between cells and around arteries and glands. This material
+ increases with aging and eventually appears between cells in the muscular part of the uterus. With the
+ injection of moderate amounts of estrogen, the quantity of the material is increased. When large amounts of
+ estrogen are injected, "The connective tissue and muscle appear rarefied, almost as though they were
+ perforated by a large number of small holes." "...this condition is presumably due to a deposit of a mixture
+ of hyaline material and edematous fluid...." "This process of hyalinization...is counteracted by invasion by
+ connective tissue." In this way there may take place in many areas a substitution and organization of the
+ hyaline material by connective tissue, in which dilated capillaries may also be visible." "There is a second
+ process which in many cases accompanies the invasion and organization of hyaline substance by connective
+ tissue, namely a formation, at the margin of the hyaline material, of epithelioid and of small giant cells
+ possessing more than one nucleus." "As a rule, the epithelioid cells are seen alone; giant cells are more
+ rare." "...the connective-tissue fibrils may in places appear somewhat separated, perhaps by edematous
+ fluid." "The first changes consist very likely in the transudation of fluid from the vessels into the
+ connective tissue." "It seems, then, that at a very early stage after the beginning of the injections of
+ effective doses of estrogen, a liquid substance which separates the connective-tissue elements makes its
+ appearance, and that this represents one of the earliest changes induced by the hormone. It may be
+ accompanied, or soon followed, by the deposit of a hyaline substance which occurs first between the
+ connective-tissue cells, but may extend also to the muscle fibers." "...the deposit of hyaline which
+ progressively becomes more and more devoid of connective-tissue cells and blood vessels, is so marked that
+ the material acts like a foreign body...." "While it may be found also around blood vessels, such deposits
+ are less conspicuous than in other organs in mice, such as the mammary gland.... There is a tendency for the
+ hyaline substance to form sheaths around various organs and it is more prominent at the border separating
+ different tissues and organs." "In its appearance and in the foreign body reactions which it initiates this
+ substance somewhat resembles amyloid, which is readily produced in mice in various groups. The application
+ of stains differentiating amyloid from other hyaline material, however, gave negative results."
+
+
+ Leo Loeb, V. Suntzeff, and E. L. Burns, "The effects of age and estrogen on the stroma of vagina, cervix and
+ uterus in the mouse," Science 88(22, Nov. 4), 1938. "...large amounts of a hyaline substance are deposited,
+ which act as foreign bodies and cause the formation of epithelioid and giant cells and an ingrowth of
+ connective tissue. Thus an organization of this substance is attempted, which is interrupted, however, by
+ renewed deposition of this hyaline material." "No definite statement can be made at present as to the
+ chemical nature of this substance and its possible relation to a plasma constituent, except that it is not
+ amyloid." "...a very intense fibrosis and hyalinization of the stroma which may induce abnormal reactions in
+ the surrounding tissue. In this way it seems to be possible to accelerate and intensify very much some of
+ the old age changes in certain organs."
+
+
+
+ P. H. Chan and R. A. Fishman, "Brain edema: Induction in cortical slices by polyunsaturated fatty acids,"
+ Science 201, 358-369, 1978. "This cellular edema was specific, since neither saturated fatty acids nor a
+ fatty acid containing a single double bond had such effect."
+
+
+ C. LarssonBackstrom, et al., "Effects of dietary alpha- and gamma-linolenic acids on liver fatty acids,
+ lipid metabolism, and survival in sepsis," Shock 4(1), 11-20, 1995. "Dietary GLA reduced survival from
+ sepsis."
+
+
+ D. Chemla, et al., "Influence of dietary polyunsaturated fatty acids on contractility, inotropy and
+ compliance of isolated rat myocardium, J mol Cell Cardiol 27(8), 1745-1755, 1995. "There was a trend towards
+ a lower peak lengthening velocity at preload in the LC (n-3) group...together with an unchanged peak rate of
+ isometric force decline. This resulted in a significant impairment of the two mechanical indexes testing the
+ load dependence of myocardial relaxation." See B. Pieske, Circul. 92(5), 1169-78
+
+
+
+ R. Lerner, et al., "Development and characterization of essential fatty acid deficiency in human endothelial
+ cells in culture," Proc Natl Acad Sci USA 92(4), 1147-1151, 1995. Oleic acid derivative
+ 5,8,11-eicosatrienoic acid (20:3 omega 9) (5,8,11,14,17 eicosapentaenoic, 20-5 omega 3)); 20:3 omega 9
+ impaired the Ca2(i) response, indicating a suppressive effect of it. (Agonist-induced increases in
+ concentrations of prostacycline PGI 2, and cytosolic Ca2+ were reduced in efad cells.)
+
+
+ K. Imaizumi, et al., "Dissociation of protein kinase C activities and diacylglycerol levels in liver plasma
+ membranes of rats on coconut oil and safflower oil diets," J. Nutr Biochem 6(10), 528-533, 1995. "The
+ activation of PKC is affected differently in vitro by different fatty acids." "Rats on coconut oil...had a
+ markedly lower PKC activity in liver plasma membranes with slight but significant reduction of the activity
+ in the cytosol than did rats fed safflower oil...." "...coconut oil resulted in a higher content of
+ diacylglycerols in these membranes than did ingestion of safflower oil, whereas the proportions of saturated
+ fatty acids and phospholipids and membrane fluidity were similar between rats ingesting different fats." "It
+ seems likely that saturated fats exert various physiological effects on lipid and lipoprotein metabolism, in
+ part through PKC pathways."
+
+
+
+ V. Boutard, et al., "Fish oil supplementation and essential fatty acid deficiency reduce nitric oxide
+ synthesis by rat macrophages," Kidney Int. 46(5), 1280-1286, 1994. "Both...have been shown to exert
+ anti-inflammatory effects...."
+
+
+ A A Farooqui, K Wells, L A Horrocks, "Breakdown of membrane phospholipids in Alzheimer disease--involvement
+ of excitatory amino acid receptors," Mol Chem Neuropathol 25(2-3) 155-173, 1995. "The release of
+ arachidonate from the sn-2 position of glycerophospholipids is catalyzed by phospholipases and lipases.
+ These enzymes are coupled to EAA receptors. Overstimulation of these receptors may be involved in abnormal
+ calcium homeostasis, degradation of membrane phospholipids, and the accumulation of free fatty acids,
+ prostaglandins, and lipid peroxides. Accumulation of the mentioned metabolites, as well as abnormalities in
+ signal transduction owing to stimulation of lipases and phospholipases, may be involved in the pathogenesis
+ of the neurodegeneration in AD."
+
+
+ P. H. Chan and R. A. Fishman, "Transient formation of superoxide radicals in polyunsaturated fatty
+ acid-induced brain swelling," J. of Neurochemistry 35, 1004-1007, 1980.
+
+
+
+ J. S. Jensen, et al., "Microalbuminuria reflects a generalized transvascular albumin leakiness in clinically
+ healthy subjects," Clin Sci 88(6), 629-633, 1995. "In epidemiological studies microalbuminuria, i.e.,
+ slightly elevated urinary albumin excretion rate, predicts increased atherosclerotic vascular morbidity and
+ mortality." "In animal experiments the outflux of albumin and lipids to the arterial wall are highly
+ correlated, and both are elevated in atherosclerosis." "...microalbuminuria is an independent marker of
+ systemic transvascular albumin leakiness in clinically healthy subjects."
+
+
+ H. M. Wisniewski and P. B. Kozlowski, "Evidence for blood-brain barrier changes in senile dementia of the
+ alzheimer type (SDAT)", Ann. N. Y. Acad. Sci. 396, 119-129, 1982. "...one would expect that the chronic
+ "flooding" of the neuronal elements with serum proteins would affect their performance." "The cause of the
+ increased BBB permeability in SDAT is unknown."
+
+
+
+ F. Laszlo, et al., "Association of microvascular leakage with induction of nitric oxide synthase: Effects of
+ nitric oxide synthase inhibitors in various organs," Eur. J. Pharmacol. 283(1-3), 47-53, 1995. "...assessed
+ by the vascular leakage of ... albumin." "Endotoxin...induced the expression of a calcium-independent nitric
+ oxide synthase...."
+
+
+ C. Nilsson, et al., "The nocturnal increase in human cerebrospinal fluid production is inhibited by a
+ beta(1)-receptor antagonist," Amer. J. Physiol.--Regul. Integr. C 36(6), R1445-R1448, 1994.
+
+
+ S. Capsoni, et al., "Reduction of regional cerebral blood flow by melatonin in young rats," Neuroreport
+ 6(9), 1346-1348, 1995. "...reduced in the cerebral areas supplied by circle of Willis and the basilar
+ arteries. [Also to the] ...choroid plexuses."
+
+
+ A. C. Bowling and M. F. Beal, "Bioenergetic and oxidative stress in neurodegenerative diseases," Life Sci.
+ 56(14), 1151-1171, 1995. "Defects in energy metabolism and increased cortical lactate levels have been
+ detected in Huntington's disease patients. Studies of Alzheimer's disease patients have identified decreased
+ [mitochondrial] complex IV activity...." "The age-related onset and progressive course of these
+ neurodegenerative diseases may be due to a cycling process betwen impaired energy metabolism and oxidative
+ stress."
+
+
+ K. Nakai, et al., "Regeneration of norepinephrine-containing fibers in occipital cortex of adult cats,"
+ Brain Res. Bull. 35(5-6), 409-412, 1994. "The present results indicate that the regenerative ability of the
+ central NE neurons is universal, not limited to the immature brain. ...equipped with a transmitter-specific
+ repair mechanism throughout life."
+
+
+
+ A. Bhatnagar, "Biochemical mechanism, of irreversible cell injury caused by free radical-initiated
+ reactions," Mol. Cell. Biochem. 137(1), 9-16, 1994. "...free radical-induced irreversible cell injury
+ results from a loss of protein thiols."
+
+
+ L. Balazs and M. Leon, "Evidence of an oxidative challenge in the Alzheimer's brain," Neurochem. Res. 19(9),
+ 1131-1137, 1994. "These data suggest that the entire Alzheimer's brain may be subject to an oxidative
+ challenge, but that some brain areas may be more vulnerable than others to the consequent neural damage that
+ characterizes the disease."
+
+
+ J. A. Court and E. K. Perry, "CNS nicotinic receptors--possible therapeutic targets in neurodegenerative
+ disorders," CNS Drugs 2(3), 216-233, 1994. "...epidemiological evidence suggests that later in life tobacco
+ smoking may offer some protection against Parkinson's and Alzheimer's diseases."
+
+
+
+ N. A. Simonian and B. T. Hyman, "Functional alterations in Alzheimer's disease: Selective loss of
+ mitochondrial-encoded cytochrome oxidase mRNA in the hippocampal formation," J. Neuropathol. Exp. Neurol.
+ 53(5), 508-512, 1994.
+
+
+ A. M. Proenze, et al., "Estrogen effects on blood amino acid compartmentation," Life Sci. 57(17), 1589-1587,
+ 1995.
+
+
+ S. S. Smith, "Sensorimotor-correlated discharge recorded from ensembles of cerebellar Purkinje cells varies
+ across the estrous cycle of the rat," J. Neurophysiol. 74(3), 1095-1108, 1995. "...estradiol augments
+ excitatory responses of cerebellar Purkinje cells to...glutamate...."
+
+
+
+ C. F. Lim, et al., "Influence of nonesterified fatty acid and lysolecithins on thyroxine binding to
+ thyroxine-binding globulin and transthyretin," Thyroid 5(4), 319-324, 1995. "Unsaturated nonesterified fatty
+ acids...inhibited T4 binding to TBG." "Saturated NEFAs...were inactive."
+
+
+ O. V. Sviridov, "Specific binding of thyroid hormones by human plasma apolipoproteins: A new property of
+ known proteins," Biochemistry (Engl. translation) 59(5), 457-466, 1884.
+
+
+ T. Parasassi, et al., "Cholesterol protects the phospholipid bilayer from oxidative damage," Free Radical
+ Biology & Medicine 19(4), 511-516, 1995.
+
+
+
+ A. G. Herzog, "Progesterone therapy in women with complex partial and secondary generalized seizures,"
+ Neurology 45(9), 1660-1662, 1995.
+
+
+ Z. Q. Ma, et al., Estrogenic control of monoamine oxidase A activity in human neuroblastoma cells expressing
+ physiological concentrations of estrogen receptor," Eur. J. Pharmacol. 284(1-2), 171-176, 1995.
+
+
+ J. G. Belasco and G. Brawerman, Control of Messenger RNA Stability, Academic Press, NY, 1994.
+
+
+ Leo Loeb, V. Suntzeff, and E. L. Burns, "Changes in the nature of the stroma in vagina, cervix and uterus of
+ the mouse produced by long-continued injections of estrogen and by advancing age," The American Journal of
+ Cancer 35(2), 159-174, 1939. Loeb, et al., speak of collagenous deposits as fibrous-hyaline tissue, varying
+ from a fibrillar to a homogeneous appearance, and varying in consistency from very dense and glassy in
+ appearance, to the softer gelatinous substance between cells and around arteries and glands. This material
+ increases with aging and eventually appears between cells in the muscular part of the uterus. With the
+ injection of moderate amounts of estrogen, the quantity of the material is increased. When large amounts of
+ estrogen are injected, "The connective tissue and muscle appear rarefied, almost as though they were
+ perforated by a large number of small holes." "...this condition is presumably due to a deposit of a mixture
+ of hyaline material and edematous fluid...." "This process of hyalinization...is counteracted by invasion by
+ connective tissue." In this way there may take place in many areas a substitution and organization of the
+ hyaline material by connective tissue, in which dilated capillaries may also be visible." "There is a second
+ process which in many cases accompanies the invasion and organization of hyaline substance by connective
+ tissue, namely a formation, at the margin of the hyaline material, of epithelioid and of small giant cells
+ possessing more than one nucleus." "As a rule, the epithelioid cells are seen alone; giant cells are more
+ rare." "...the connective-tissue fibrils may in places appear somewhat separated, perhaps by edematous
+ fluid." "The first changes consist very likely in the transudation of fluid from the vessels into the
+ connective tissue." "It seems, then, that at a very early stage after the beginning of the injections of
+ effective doses of estrogen, a liquid substance which separates the connective-tissue elements makes its
+ appearance, and that this represents one of the earliest changes induced by the hormone. It may be
+ accompanied, or soon followed, by the deposit of a hyaline substance which occurs first between the
+ connective-tissue cells, but may extend also to the muscle fibers." "...the deposit of hyaline which
+ progressively becomes more and more devoid of connective-tissue cells and blood vessels, is so marked that
+ the material acts like a foreign body...." "While it may be found also around blood vessels, such deposits
+ are less conspicuous than in other organs in mice, such as the mammary gland.... There is a tendency for the
+ hyaline substance to form sheaths around various organs and it is more prominent at the border separating
+ different tissues and organs." "In its appearance and in the foreign body reactions which it initiates this
+ substance somewhat resembles amyloid, which is readily produced in mice in various groups. The application
+ of stains differentiating amyloid from other hyaline material, however, gave negative results."
+
+
+ Leo Loeb, V. Suntzeff, and E. L. Burns, "The effects of age and estrogen on the stroma of vagina, cervix and
+ uterus in the mouse," Science 88(22, Nov. 4), 1938. "...large amounts of a hyaline substance are deposited,
+ which act as foreign bodies and cause the formation of epithelioed and giant cells and an ingrowth of
+ connective tissue. Thus an organization of this substance is attempted, which is interrupted, however, by
+ renewed deposition of this hyaline material." "No definite statement can be made at present as to the
+ chemical nature of this substance and its possible relation to a plasma constituent, except that it is not
+ amyloid." "...a very intense fibrosis and hyalinization of the stroma which may induce abnormal reactions in
+ the surrounding tissue. In this way it seems to be possible to accelerate and intensify very much some of
+ the old age changes in certain organs."
+
+
+
+ Winfried G. Rossmanith, "Gonadotropin secretion during aging in women: Review article," Exp. Gerontology
+ 30(3/4) 369-381, 1995. "...major functional derangements, primarily at a hypothalamic rather than a
+ pituitary site, have been determined as concomitants of aging in women." "...aging may impair the negative
+ feedback sensitivity to ovarian sex steroids...." Hormonal changes at menopause "may represent the sum of
+ functional aberrations that were initiated much earlier in life...." "...prolonged estrogen exposure
+ facilitates the loss of hypothalamic neurons...."
+
+
+ J. R. Brawer, et al., "Ovary-dependent degeneration in the hypothalamic arcuate nucleus," Endocrinology 107,
+ 274-279, 1980.
+
+
+
+ G. C. Desjardins, "Estrogen-induced hypothalamic beta-endorphin neuron loss: A possible model of
+ hypothalamic aging," Exp. Gerontology 30(3/4), 253-267, 1995. "This loss of opioid neurons is prevented by
+ treatment with antioxidants indicating that it results from estradiol-induced formation of free radicals."
+ "...this beta-endorphin cell loss is followed by a compensatory upregulation of mu opioid receptors in the
+ vicinity of LHRH cell bodies." Resulting supersensitivity of the cells results "in chronic opioid
+ suppression of the pattern of LHRH release, and subsequently that of LH." The neurotoxic effects of
+ estradiol causes a "cascade of neuroendocrine aberrations resulting in anovulatory acyclicity." Treatment
+ with an opiod antagonist "reversed the cystic morphology of ovaries and restored normal ovarian cycles" in
+ estrogen-treated rats.
+
+
+
+ G. B. Melis, et al., "Evidence that estrogens inhibit LH secretion through opioids in postmenopausal women
+ using naloxone," Neuroendocrinology 39, 60-63, 1984.
+
+
+ H. J. Sipe, et al., "The metabolism of 17 beta-estradiol by lactoperoxidase: A possible source of oxidative
+ stress in breast cancer," Carcinogenesis 15(11), 2637-2643, 1994. "...molecular oxygen is consumed by a
+ sequence of reactions initiated by the glutathione thiyl radical. ...the estradiol phenoxyl radical
+ abstracts hydrogen from...NADH to generate the NAD radical." "...the futile metabolism of micromolar
+ quantities of estradiol catalyzes the oxidation of much greater concentrations of biochemical reducing
+ cofactors, such as glutathione and NADH, with hydrogen peroxide produced as a consequence."
+
+
+ S. Santagati, et al., "Estrogen receptor is expressed in different types of glial cells in culture," J.
+ Neurochem. 63(6), 2058-2064, 1994. "...in all three types of glial cell analyzed in almost equal amounts..."
+
+
+
+ D. X. Liu and L. P. Li, "Prostaglandin F-2 alpha rises in response to hydroxyl radical generated in vivo,"
+ Free Radical Biol. Med. 18(3), 571-576, 1995. "Free radicals and some free fatty acids, such as arachidonic
+ acid metabolites...may form a feedback loop in which generation of one type leads to formation of the
+ other." "Prostaglandin F-2 alpha dramatically increased in response to hydroxyl radical generation...."
+
+
+ J. Owens and P. A. Schwartzkroin, "Suppression of evoked IPSPs by arachidonic acid and prostaglandin F-2
+ alpha," Brain Res. 691(1-2), 223-228, 1995. "These findings suggest that high levels of AA and its
+ metabolites may bias neurons towards excitation."
+
+
+ E. A. Quail and G. C. T. Yeoh, "The effect of iron status on glyceraldehyde 3-phosphate dehydrogenase
+ expression in rat liver," FEBS Lett. 359(2-3), 126-128, 1995. "...the overexpression of GAPDH mRNA in iron
+ deficiency is probably due to increased message stability." [This is one of the points discussed by Henics.
+ Estrogen, which increases iron retention, also modifies mRNA stability.]
+
+
+
+ J. G. Liehr, et al., "4-hydroxylation of estradiol by human uterine myometrium and myoma microsomes:
+ Implications for the mechanism of uterine tumorigenesis," Proc Natl Acad Sci USA 92(20), 9220-9224, 1995.
+ "... elicits biological activities distinct from estradiol, most notably an oxidant stress response induced
+ by free radicals generated by metabolic redox cycling reactions."
+
+
+ J. G. Liehr and D. Roy, "Free radical generation by redox cycling of estrogens," Free Rad. Biol. Med. 8,
+ 415-423, 1990.
+
+
+ F. Fourrier, Circ. Shock 43(4), 171-178, 1994, "High estrogen levels were specifically observed in patients
+ with sepsis and septic shock, either males or females." "Circulating T levels were decreased in all male
+ patients."
+
+
+
+ J. A. Jarvis, et al., "H-1 NMR analysis of fibril-forming peptide fragments of transthyretin," Int. J. Pept.
+ Protein Res. 44(4), 388-398, 1994. "...fragments of the protein transthyretin, previously shown to form
+ cross beta-sheet amyloid-like fibrils in vitro, were investigated...."
+
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
+
diff --git a/raypeat-articles/processed/aspirin-brain-cancer.html b/raypeat-articles/processed/aspirin-brain-cancer.html
new file mode 100644
index 0000000..9fd3986
--- /dev/null
+++ b/raypeat-articles/processed/aspirin-brain-cancer.html
@@ -0,0 +1,662 @@
+
+ Aspirin, brain, and cancer
+
+
+ Aspirin, brain, and cancer
+
+
+
+ When a drug such as caffeine or aspirin turns out to have a great variety of protective effects, it's
+ important to understand what it's doing.
+
+
+ Because aspirin has been abused by pharmaceutical companies that have competing products to sell, as well as
+ by the original efforts to promote aspirin itself, people can easily find reasons why they shouldn't take
+ it.
+
+
+ Early in the 20th century, people were told that fevers were very bad, and that aspirin should be used
+ whenever there is a fever.
+
+
+ In the 1980s, there was a big publicity campaign warning parents that giving aspirin to a child with the flu
+ could cause the potentially deadly Reye syndrome. Aspirin sales declined sharply, as sales of acetaminophen
+ (Tylenol, etc.) increased tremendously. But in Australia, a study of Reye syndrome cases found that six
+ times as many of them had been using acetaminophen as had used aspirin. (Orlowski, et al., 1987)
+
+
+ Until the 1950s and 1960s, when new products were being promoted, little was said about the possibility of
+ stomach ulceration from aspirin. Lately, there has been more publicity about the damage it can do to the
+ stomach and intestine, much of it in connection with the sale of the new "COX-2 inhibitors." (These new
+ drugs, rather than protecting the circulatory system as aspirin does, damage it.) Aspirin rapidly breaks
+ down into acetic acid and salicylic acid (which is found in many fruits), and salicylic acid is protective
+ to the stomach and intestine, and other organs. When aspirin was compared with the other common
+ antiinflammatory drugs, it was found that the salicylic acid it releases protects against the damage done by
+ another drug. (Takeuchi, et al, 2001; Ligumsky, et al., 1985.) Repeated use of aspirin protects the stomach
+ against very strong irritants. The experiments in which aspirin produces stomach ulcers are designed to
+ produce ulcers, not to realistically model the way aspirin is used.
+
+
+
+ Recently, the public has been led to believe that drugs are being designed to fit certain cellular
+ "receptors." The history of the "COX-2 inhibitors" is instructive, in a perverse way. The structures of DES
+ and other synthetic estrogens were said to relate to "the estrogen receptor." Making these estrogenic
+ molecules more soluble in water made them somewhat anti-estrogenic, leading to products such as Tamoxifen.
+ But some of the molecules in this group were found to be antiinflammatory. The structure of Celecoxib and
+ other "COX-2 inhibitors" is remarkably similar to the "designer estrogens." Considering this, it's a little
+ odd that so few in the U.S. are openly discussing the possibility that estrogen's function is directly
+ related to inflammation, and involves the production of many inflammatory mediators, including COX-2. (See
+ Lerner, et al., 1975; Luo, et al., 2001; Cushman, et al, 2001; Wu, et al., 2000; Herrington, et al., 2001.)
+
+
+
+ Soot and smoke contain many chemicals that produce inflammation (Brune, et al., 1978). In the 1930s, soot
+ was known to be both carcinogenic and estrogenic, and analysis of its components led to the production of
+ the early commercial estrogens. Any intelligent person reading the chemical and biological publications of
+ that time will see how closely associated cancer, inflammation, and estrogen are.
+
+
+ Soon after vitamin E was discovered, tocopherol was defined as a brain-protective, pregnancy protective,
+ male fertility protective, antithrombotic, antiestrogenic agent. But very soon, the estrogen industry made
+ it impossible to present ideas that explained vitamin E, progesterone, vitamin A, or thyroid hormone in
+ terms of the protection they provide against estrogenic substances. Since the polyunsaturated fats caused
+ the same conditions that were caused by unopposed estrogen, vitamin E came to be known as an "antioxidant,"
+ because it reduced their toxicity. (Vitamin E is now known to suppress COX-2, synergizing with aspirin and
+ opposing estrogen.)
+
+
+ In 1970, when I was beginning to see the ways in which unopposed estrogen and accumulated polyunsaturated
+ fats interacted with a vitamin E deficiency during aging and in infertility, I got some prostaglandins to
+ experiment with, since they are products of the oxidation of linoleic acid. The prostaglandins are an
+ interesting link between estrogens and inflammation, in normal physiology as well as in disease.
+
+
+ I wanted to test their effects on the uterus, especially the sites where the embryos implant. There was a
+ theory that the electrical charge of the surface of the uterus was decreased at the implantation sites, to
+ reduce the repulsion between two negatively charged things. Although there were regions of lower surface
+ charge along the lining of the uterus, the charge changed as waves of muscle contraction moved along the
+ uterus, and the prostaglandins affected the contractions.
+
+
+ To understand the differences between the different types of prostaglandin, I tested them on my arm, and
+ those with the most hydroxyl groups produced regions with an increased negative charge. For comparison, I
+ exposed another spot to sunlight for an hour, and found that there was a similar increase in the negative
+ charge in that spot. Apparently the prostaglandins were causing an injury or excitation, a mild
+ inflammation, in the skin cells.
+
+
+
+ A few years later, aspirin was found to inactivate the enzyme that forms prostaglandins, by the transfer of
+ the acetyl radical to the enzyme. This became the orthodox "explanation" for what aspirin does, though it
+ neglected to explain that salicylic acid (lacking the acetyl radical) had been widely known in the previous
+ century for its very useful antiinflammatory actions. The new theory did explain (at least to the
+ satisfaction of editors of medical magazines) one of aspirin's effects, but it distracted attention from all
+ the other effects of aspirin and salicylic acid.
+
+
+ Aspirin is an antioxidant that protects against lipid peroxidation, but it also stimulates mitochondrial
+ respiration. It can inhibit abnormal cell division, but promote normal cell division. It can facilitate
+ learning, while preventing excitotoxic nerve injury. It reduces clotting, but it can decrease excessive
+ menstrual bleeding. These, and many other strangely beneficial effects of aspirin, strongly suggest that it
+ is acting on very basic biological processes, in a coherent way.
+
+
+ In explaining aspirin's effects, as in explaining those of estrogen and progesterone, or polyunsaturated
+ fats and vitamin E, I think we need concepts of a very broad sort, such as "stability and instability."
+
+
+ The COX (cyclooxygenase) enzymes, that make prostaglandins, are just one system among many that are
+ activated by stress. Aromatase, that makes estrogen, enzymes that make histamine, serotonin and nitric
+ oxide, the cytokines, and the stress-induced hormones of the pituitary and adrenal glands, are turned on in
+ difficult situations, and have to be turned off when the threat has been overcome. The production of energy
+ is the basis for overcoming all threats, and it has to be conserved in readiness for future needs.
+
+
+
+ The fetus produces saturated fats such as palmitic acid, and the monounsaturated fat, oleic acid, which can
+ be turned into the Mead acid, ETrA (5,8,11-eicosatrienoic acid), and its derivatives, which are
+ antiinflammatory, and some of which act on the "bliss receptor," or the cannibinoid receptor. In the adult,
+ tissues such as cartilage, which are protected by their structure or composition from the entry of exogenous
+ fats, contain the Mead acid despite the presence of linoleic acid in the blood.
+
+
+ At birth, the baby's mitochondria contain a phospholipid, cardiolipin, containing palmitic acid, but as the
+ baby eats foods containing polyunsaturated fatty acids, the palmitic acid in cardiolipin is replaced by the
+ unsaturated fats. As the cardiolipin becomes more unsaturated, it becomes less stable, and less able to
+ support the activity of the crucial respiratory enzyme, cytochrome oxidase.
+
+
+ The respiratory activity of the mitochondria declines as the polyunsaturated oils replace palmitic acid, and
+ this change corresponds to the life-long decline of the person's metabolic rate.
+
+
+ In old age, a person's life expectancy strongly depends on the amount of oxygen that can be used. When the
+ mitochondria can't use oxygen vigorously, cells must depend on inefficient glycolysis for their energy.
+
+
+ Estrogen activates the glycolytic pathway, while interfering with mitochondrial respiration. This resembles
+ the aged or stressed metabolism, in which lactic acid is produced instead of carbon dioxide.
+
+
+
+ Aspirin activates both glycolysis and mitochondrial respiration, and this means that it shifts the
+ mitochondria away from the oxidation of fats, toward the oxidation of glucose, resulting in the increased
+ production of carbon dioxide. Its action on the glycolytic enzyme, GAPDH, is the opposite of estrogen's.
+
+
+ The shift away from fat oxidation under the influence of aspirin doesn't lead to an accumulation of free
+ fatty acids in the circulation, since aspirin inhibits the release of fatty acids from both phospholipids
+ and triglycerides. Estrogen has the opposite effects, increasing fat oxidation while increasing the level of
+ circulating free fatty acids, since it activates lipolysis, as do several other stress-related hormones.
+
+
+ The polyunsaturated fatty acids, such as linolenic, linoleic, arachidonic, EPA, and DHA, have many directly
+ toxic, antirespiratory actions, apart from the production of the prostaglandins or eicosanoids. Just by
+ preventing the release of these fatty acids, aspirin would have broadly antiinflammatory effects.
+
+
+ Since the polyunsaturated fats and prostaglandins stimulate the expression of aromatase, the enzyme that
+ synthesizes estrogen, aspirin decreases the production of estrogen. So many of aspirin's effects oppose
+ those of estrogen, it would be tempting to suggest that its "basic action" is the suppression of estrogen.
+ But I think it's more likely that both estrogen and aspirin are acting on some basic processes, in
+ approximately opposite ways.
+
+
+ Bioelectrical functions, and the opposition between carbon dioxide and lactic acid, and the way water is
+ handled in cells, are basic conditions that have a general or global effect on all of the other more
+ specific biochemical and physiological processes. Originally, estrogen and progesterone were each thought to
+ affect only one or a few biochemical events, but it has turned out that each has a multitude of different
+ biochemical actions, which are integrated in globally meaningful ways. The salicylic acid molecule is much
+ smaller and simpler than progesterone, but the range of its beneficial effects is similar. Because of
+ aspirin's medical antiquity, there has been no inclination to explain its actions in terms of an "aspirin
+ receptor," as for valium and the opiates, leaving its biochemistry, except for the inadequate idea of
+ COX-inhibition, simply unexplained.
+
+
+ If we didn't eat linoleic acid and the other so-called "essential fatty acids," we would produce large
+ amounts of the "Mead acid," n-9 eicosatrienoic acid, and its derivatives. This acid in itself is
+ antiinflammatory, and its derivatives have a variety of antistress actions. The universal toxicity of the
+ polyunsaturated fats that suppress the Mead fats as they accumulate, and the remarkable vitality of the
+ animals that live on a diet deficient in the essential fatty acids, indicate that the Mead fats are
+ important factors in the stability of our mammalian tissues. This protective lipid system probably interacts
+ with cellular proteins, modifying the way they bind water and carbon dioxide and ions, affecting their
+ electrons and their chemical reactivity.
+
+
+ If salicylic acid and the structurally similar antiinflammatories, local anesthetics, muscle relaxants,
+ expectorants, and antihistamines, act as surrogates for the absent Mead acid family, and thereby act as
+ defenses against all the toxic effects of the unstable fats, it would explain the breadth and apparent
+ coherence of their usefulness. And at the same time it explains some of the ways that estrogen goes out of
+ control, when it exacerbates the toxicity of the accumulated unstable fats.
+
+
+ The competition between aspirin and salicylic acid, and other antiinflammatories, for the active site on the
+ COX enzyme (Rao, et al., 1982), shows that the structural features of these molecules are in some ways
+ analogous to those of the polyunsaturated fatty acids. Wherever there are phospholipids, free fatty acids,
+ fatty acid esters, ethers, etc. (i.e., in mitochondria, chromosomes, cytoskeleton, collagen
+ networks--essentially everywhere in and around the cell), the regulatory influence of specific fatty
+ acids--or their surrogates--will be felt.
+
+
+
+ Although it would undoubtedly be best to grow up eating foods with relatively saturated fats, the use of
+ aspirin preventively and therapeutically seems very reasonable under the present circumstances, in which,
+ for example, clean and well ripened fruits are not generally available in abundance. Preventing blindness,
+ degenerative brain diseases, heart and lung diseases, and cancer with aspirin should get as much support as
+ the crazy public health recommendations are now getting from government and foundations and the medical
+ businesses.
+
+
+ When people with cancer ask for my recommendations, they usually think I'm joking when I tell them to use
+ aspirin, and very often they don't take it, on the basis of what seems to be a very strong cultural
+ prejudice. Several years ago, a woman whose doctors said it would be impossible to operate on her extremely
+ painful "inflammatory breast cancer," had overnight complete relief of the pain and swelling from taking a
+ few aspirins. The recognized anti-metastatic effect of aspirin, and its ability to inhibit the development
+ of new blood vessels that would support the tumor's growth, make it an appropriate drug to use for pain
+ control, even if it doesn't shrink the tumor. In studies of many kinds of tumor, though, it does cause
+ regression, or at least slows tumor growth. And it protects against many of the systemic consequences of
+ cancer, including wasting (cachexia), immunosuppression, and strokes.
+
+
+ Opiates are the standard medical prescription for pain control in cancer, but they are usually prescribed in
+ inadequate quantities, "to prevent addiction." Biologically, they are the most inappropriate means of pain
+ control, since they increase the release of histamine, which synergizes with the tumor-derived factors to
+ suppress immunity and stimulate tumor growth.
+
+
+ It has recently become standard practice in most places to advise a person who is having a heart attack to
+ immediately chew and swallow an aspirin tablet.
+
+
+
+ The same better-late-than-never philosophy can be applied to Alzheimer's disease, Parkinson's disease, and
+ other degenerative nerve diseases. Aspirin protects against several kinds of toxicity, including
+ excitotoxicity (glutamate), dopamine toxicity, and oxidative free radical toxicity. Since its effects on the
+ mitochondria are similar to those of thyroid (T3), using both of them might improve brain energy production
+ more than just thyroid. (By activating T3, aspirin can sometimes increase the temperature and pulse rate.)
+ Magnesium, niacinamide, and other nerve protective substances work together.
+
+
+ In multiple organ failure, which can be caused by profound shock caused by trauma, infection, or other
+ stress, aspirin is often helpful, but carbon dioxide and hypertonic glucose and sodium are more important.
+
+
+ Aspirin, like progesterone or vitamin E, can improve fertility, by suppressing a prostaglandin, and
+ improving uterine circulation.
+
+
+ Although the animal studies that showed stomach damage from aspirin often used single doses equivalent to 10
+ or 100 aspirin tablets, the slight irritation produced by a normal dose of aspirin can be minimized by
+ dissolving the aspirin in water. The stomach develops a tolerance for aspirin over a period of a few days,
+ allowing the dose to be increased if necessary. And both aspirin and salicylic acid can be absorbed through
+ the skin, so rheumatic problems have been treated by adding the drug to bath water.
+
+
+ The unsaturated (n-6 and n-3) fats that accumulate in our tissues, instead of being part of the system for
+ reestablishing order and stability, tend to amplify the instability that is triggered by excitation, by
+ estrogen, or by external stresses.
+
+
+ I think it's important that we don't allow the drug publicists to obscure the broad importance of substances
+ such as aspirin, vitamin E, progesterone, and thyroid. For 60 years, a myth that was created to sell
+ estrogen has harmed both science and the health of many people.
+
+
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+
+
+
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+
+
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+
+
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+ steroids and aromatase activity in the brain of the male lizard Podarcis sicula sicula during
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+
+
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+
+
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+
+
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+
+
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+
+
+
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+
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+ human breast cancer. Hwang D, Scollard D, Byrne J, Levine E "Our results suggest that
+ overexpression of COX may not be unique to colon cancer and may be a feature common to other epithelial
+ tumors."
+
+
+
+ Ginekol Pol 1999 Mar;70(3):126-34. [Evaluation of the effectiveness of a low-dose aspirin in the
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+ Laudanski T, Suzin J
+
+
+ J Cardiovasc Pharmacol 1995 Feb;25(2):273-81. Inhibitory effects of aspirin on coronary
+ hyperreactivity to autacoids after arterial balloon injury in miniature pigs. Kuga T, Ohara Y,
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+ serotonin were examined angiographically before, 1 h, 1 week, and 1 month after balloon injury in 29
+ hypercholesterolemic miniature pigs." "Hyperconstriction induced by the autacoids 1 h after injury were
+ significantly less in groups B and C than in group A (p < 0.01). Hyperconstriction induced by autacoids 1
+ week after injury were significantly less in group B than in group A (p < 0.01) and were significantly
+ less in group C than in group A (p < 0.01) or group B (p < 0.05)."
+
+
+
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+ (38532). Lerner EJ, Carminati P, Schiatti P.
+
+
+ Proc Soc Exp Biol Med 1985 Feb;178(2):250-3. Salicylic acid blocks indomethacin-induced
+ cyclooxygenase inhibition and lesion formation in rat gastric mucosa. Ligumsky M, Guth PH,
+ Elashoff J, Kauffman GL Jr, Hansen D, Paulsen G. "Salicylic acid has been shown to decrease gastric mucosal
+ lesions induced by indomethacin in the rat."
+
+
+ Z Naturforsch [C] 2001 May-Jun; 56(5-6):455-63. Constant expression of cyclooxygenase-2 gene in
+ prostate and the lower urinary tract of estrogen-treated
+ male rats. Luo C, Strauss L, Ristimaki A, Streng T, Santti R.
+
+
+
+ Neuropharmacology 2000 Apr 27;39(7):1309-18. Mechanisms of the neuroprotective effect of aspirin
+ after oxygen and glucose deprivation in rat forebrain slices. Moro MA, De Alba J, Cardenas A,
+ De Cristobal J, Leza JC, Lizasoain I, Diaz-Guerra MJ, Bosca L, Lorenzo P "Apart from its preventive actions
+ against stroke due to its antithrombotic properties, recent data in the literature suggest that high
+ concentrations of ASA also exert direct neuroprotective effects." "We have found that ASA inhibits neuronal
+ damage at concentrations lower than those previously reported (0.1-0.5 mM), and that these effects correlate
+ with the inhibition of excitatory amino acid release, of NF-kappaB translocation to the nucleus and iNOS
+ expression caused by ASA." "Our results also show that the effects of ASA are independent of COX inhibition.
+ Taken together, our present findings show that ASA is neuroprotective in an in vitro model of brain
+ ischaemia at doses close to those recommended for its antithrombotic effects."
+
+
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+
+
+
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+ cyclo-oxygenase. Rao GH, Reddy KR, White JG. "Recent studies have shown that salicylic acid, a
+ metabolite of aspirin, effectively competes for the same site on the platelet cyclo-oxygenase enzyme."
+
+
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+ chemical hypoxia. Riepe MW, Kasischke K, Raupach A.
+
+
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+ acetylsalicylic acid and NS-398. Rioux N, Castonguay A
+
+
+
+ J Endocrinol 1989 Jun;121(3):513-9. Indomethacin inhibits the effects of oestrogen
+
+ in the anterior pituitary gland of the rat. Rosental DG, Machiavelli GA, Chernavsky AC,
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+
+
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+ invasiveness and angiogenesis. Rozic JG, Chakraborty C, Lala PK.
+
+
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+ (aspirin) to scavenge radiation induced free radicals in J774A.1 macrophage cells. Saini T,
+ Bagchi M, Bagchi D, Jaeger S, Hosoyama S, Stohs SJ.
+
+
+
+ Mol Cell Biochem 1999 Sep;199(1-2):93-102.
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+ lipid peroxidation, DNA damage, NF-kappaB activation, and TNF-alpha production. Shi X, Ding M,
+ Dong Z, Chen F, Ye J, Wang S, Leonard SS, Castranova V, Vallyathan V
+
+
+ J Physiol Paris 2001 Jan-Dec;95(1-6):51-7. Protection by aspirin of indomethacin-induced small
+ intestinal damage in rats: mediation by salicylic acid. Takeuchi K, Hase S, Mizoguchi H,
+ Komoike Y, Tanaka A. "Most of non-steroidal anti-inflammatory drugs (NSAIDs) except aspirin (ASA) produce
+ intestinal damage in rats." "ASA did not provoke any damage, despite inhibiting (prostaglandin) PG
+ production, and prevented the occurrence of intestinal lesions induced by indomethacin, in a dose-related
+ manner."
+
+
+
+ FASEB J 2001 Oct;15(12):2057-72. Cyclooxygenase-independent actions of cyclooxygenase
+
+ inhibitors. Tegeder I, Pfeilschifter J, Geisslinger G.
+
+
+ J Indian Med Assoc 1997 Feb;95(2):43-4, 47. Role of low dose aspirin in prevention of pregnancy
+ induced hypertension. Tewari S, Kaushish R, Sharma S, Gulati N
+
+
+ J Chromatogr B Biomed Appl 1995 Jul 21;669(2):404-7. Aspirin inhibits collagen-induced platelet
+ serotonin release, as measured by microbore high-performance liquid chromatography with electrochemical
+ detection. Tsai TH, Tsai WJ, Chen CF.
+
+
+
+ Clin Exp Immunol 1991 Nov;86(2):315-21. Piroxicam, indomethacin
+
+ and aspirin action on a murine fibrosarcoma. Effects on tumour-associated and peritoneal
+ macrophages. Valdez JC, Perdigon G. "We also studied the effect on tumour development of three inhibitors of
+ prostaglandin synthesis: indomethacin, piroxicam and aspirin. Intraperitoneal administration of these drugs
+ during 8 d was followed by the regression of palpable tumours. Indomethacin (90 mg/d) induced 45%
+ regression, while with piroxicam (two 400 mg/d doses and six 200 mg/d doses) and aspirin (1 mg/d) 32% and
+ 30% regressions, respectively, were observed. The growth rate of nonregressing tumours, which had reached
+ different volumes by the end of the treatment, was delayed to a similar extent by the three
+ anti-inflammatory non-steroidal drugs (NSAID)."
+
+
+ Int J Radiat Biol 1995 May;67(5):587-96. Amelioration of radiation nephropathy by acetylsalicylic
+ acid. Verheij M, Stewart FA, Oussoren Y, Weening JJ, Dewit L.
+
+
+
+ Semin Perinatol 1986 Oct;10(4):334-55. The role of arachidonic acid metabolites in
+ preeclampsia. Walsh SW, Parisi VM.
+
+
+ Proc Natl Acad Sci U S A 1999 Apr 27;96(9):5292-7. Suppression of inducible cyclooxygenase 2 gene
+ transcription by aspirin and sodium salicylate. Xu XM, Sansores-Garcia L, Chen XM,
+ Matijevic-Aleksic N, Du M, Wu KK. "Aspirin and sodium salicylate at therapeutic concentrations equipotently
+ blocked COX-2 mRNA and protein levels induced by interleukin-1beta and phorbol 12-myristate 13-acetate."
+
+
+ Hum Reprod 1994 Oct;9(10):1954-7. The benefits of low-dose aspirin therapy in women with impaired
+ uterine perfusion during assisted conception.
+
+ Wada I, Hsu CC, Williams G, Macnamee MC, Brinsden PR. "Higher pregnancy rates (47 versus 17%) were achieved
+ in those taking aspirin from day 1 of HRT." "The addition of low-dose aspirin to a standard HRT protocol in
+ women with impaired uterine perfusion is associated with improved blood flow and satisfactory pregnancy
+ rates."
+
+
+ J Ethnopharmacol 1991 Sep;34(2-3):215-9. Radiation-protective and platelet aggregation inhibitory
+ effects of five traditional Chinese drugs and acetylsalicylic acid following high-dose
+ gamma-irradiation.
+ Wang HF, Li XD, Chen YM, Yuan LB, Foye WO.
+
+
+ Fertil Steril 1997 Nov;68(5):927-30. Low-dose aspirin for oocyte donation recipients with a thin
+ endometrium: prospective, randomized study. Weckstein LN, Jacobson A, Galen D, Hampton K,
+ Hammel J. "Low-dose aspirin therapy improves implantation rates in oocyte donation recipients with a thin
+ endometrium."
+
+
+
+ Dermatologica 1978;156(2):89-96. Effect of topical salicylic acid on animal epidermopoiesis. Weirich EG, Longauer JK, Kirkwood AH. In contrast to its antihyperplastic effect on pathological
+ proliferation of the epidermis, salicylic acid promotes epidermopoiesis in the normal guinea pig skin. After
+ the application of 1% w/w salicylic acid in acetone-ethanol for 4 weeks, the thickness of the surface
+ epithelium was increased by 40% and that of the deep epithelium by 19%. The mitotic index rose by 17%.
+
+
+ Arch Exp Veterinarmed 1981;35(3):465-70. [Control of implantation in rats and sows by peroral
+ administration of prostaglandin synthetase inhibitors. 2. Effects of prostaglandin F2 alpha,
+ progesterone/estrone, and acetylsalicylic acid on implantation and various biochemical parameters of
+ amniotic fluid in the rat] Wollenhaupt K, Steger H. "The highest number of normally developed
+ (97 per cent) and the lowest number of degenerated foetuses (three per cent) were recorded following
+ acetylsalicylic acid treatment, as compared to the control group (91 and nine per cent)."
+
+
+ Biomed Pharmacother 1999 Aug;53(7):315-8. Aspirin induced apoptosis in gastric cancer cells. Wong BC, Zhu GH, Lam SK
+
+
+
+ Scand J Immunol 2000 Oct;52(4):393-400. Tamoxifen decreases renal inflammation and alleviates
+ disease severity in autoimmune NZB/W F1 mice. Wu WM, Lin BF, Su YC, Suen JL, Chiang BL. "It has
+ been documented that sex hormone may play a role in the pathogenesis of murine lupus."
+
+
+ Science 2001 Aug 31;293(5535):1673-7. Reversal of obesity- and diet-induced insulin resistance with
+ salicylates or targeted disruption of Ikkbeta. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li
+ ZW, Karin M, Shoelson SE.
+
+
+
+
+ Since the 1970s, aspirin has been thought of as an inhibitor of prostaglandin synthesis, but
+ that is only part of its effect. Sometimes its effect is the opposite of the effects of other
+ prostaglandin inhibitors.
+
+
+ It protects against the harmful effects of estrogen, prolactin, serotonin, cortisol, histamine,
+ and radiation (u.v., x-rays, gamma rays).
+
+
+
+ It prevents cancer, and can cause its regression. It inhibits vascular proliferation. It
+ inhibits interleukin 6 (and other inflammatory cytokines), which is a factor in heart disease and
+ breast and liver cancer.
+
+
+ It protects the brain, and can improve learning. It's an antioxidant, prevents cataracts, and
+ protects against glycation in diabetes.
+
+
+
+ It prevents premature birth and prevents birth defects caused by diabetes, preeclampsia, and
+ exposure to alcohol. It prevents recurrence of neural tube defects and protects against many of the
+ gestational problems associated with lupus.
+
+
+ Although aspirin protects against uncontrolled cell proliferation, as in cancer and psoriasis,
+ salicylic acid increases normal cell division in the skin.
+
+
+ Aspirin protects against many forms of shock and stess, and corrects imbalances in the nervous
+ system.
+
+ It protects against several kinds of toxins involved in brain degeneration.
+
+
+ "Aspirin elevated ATP levels not only in intact cortical neurons but also in isolated brain
+ mitochondria, an effect concomitant with an increase in NADH-dependent respiration by brain
+ submitochondrial particles."
+
+
+
+ De Cristobal, et al., 2002
+
+
+ "The pharmacological action of salicylate cannot be explained by its inhibition of
+ cyclooxygenase (COX) activity." ". . . salicylate exerts its antiinflammatory action in part by
+ suppressing COX-2 induction. . . ." XM Xu, et al., 1999
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Academic authoritarians, language, metaphor, animals, and science
+
+
+ Academic authoritarians, language, metaphor, animals, and science
+
+
+
+ Academic authoritarians, language, metaphor, animals, & science
+
+ A few years ago a group of researchers in Scotland studying learning in apes did some experiments (involving
+ opening boxes to get a piece of candy inside) that showed that chimpanzees learn in a variety of "flexibly
+ adaptive" ways, and that 3 year old children being presented with a similar task most often did it in ways that
+ appear to be less intelligent than the apes. They "suggest that the difference in performance of chimpanzees and
+ children may be due to
+ a greater susceptibility of children to cultural conventions." (Horner and Whiten, 2005; Whiten, et al.,
+ 2004).
+
+ In my newsletter on puberty, I described some of the effects of foods and hormones on intelligence. Here, I
+ want to consider the effects of culture on the way people learn and think. Culture, it seems, starts to make
+ us stupid long before the metabolic problems appear.
+
+
+ For many years I described culture as the perceived limits of possibility, but people usually prefer to
+ think of it as the learned rules of conduct in a society. In the late 1950s I was talking with a
+ psychologist about the nature of "mental maps," and I said that I found my way around campus by reference to
+ mental pictures of the locations of things, and he said that his method was to follow a series of rules, "go
+ out the front door and turn left, turn left at the first corner, walk three blocks and turn right, ....up
+ the stairs, turn right, fourth office on the left." He had been studying mental processes for about 40
+ years, so his claim made an impression on me.
+
+
+ I thought this style of thinking might have something to do with the growing technological preference for
+ digital, rather than analog, devices. The complexity and continuity of the real world is made to seem more
+ precise and concrete by turning it into rules and numbers.
+
+
+ Around the same time, I found that some people dream in vivid images, while others describe dreams as
+ "listening to someone tell a story."
+
+
+
+ Several years later, a graduate student of "language philosophy" from MIT told me that I was just confused
+ if I believed that I had mental images that I could use in thinking. His attitude was that language, in its
+ forms and in the ways it could convey meaning, was governed by rules. He was part of an effort to define
+ consciousness in terms of rules that could be manipulated formally. This was just a new variation on the
+ doctrine of an "ideal language" that has concerned many philosophers since Leibniz, but now its main use is
+ to convince people that cultural conventions and authority are rooted in the nature of our minds, rather
+ than in particular things that people experience and the ways in which they are treated.
+
+
+ George Orwell, whose novels showed some of the ways language is used to control people, believed that
+ language should be like a clear window between minds, but knew that it was habitually used to distort,
+ mislead, and control. Scientific and medical practices often follow the authority of culture and
+ indoctrination, instead of intelligently confronting the meaning of the evidence, the way chimpanzees are
+ able to do.
+
+
+ Not so many years ago, people believed that traits were "determined by genes," and that the development of
+ an organism was the result of--was caused by--the sequential expression of genes in the nucleus of the
+ fertilized egg. When B.F. Skinner in the 1970s said "a gestating baby isn't influenced by what happens to
+ its mother," he was expressing a deeply rooted bio-medical dogma. Physicians insisted that a baby couldn't
+ be harmed by its mother's malnutrition, as long as she lived to give birth. People could be quite vicious
+ when their dogma was challenged, but their actions were systematically vicious when they weren't challenged.
+
+
+ An ovum doesn't just grow from an oocyte according to instructions in its genes, it is constructed, with
+ surrounding nurse cells adding substances to its cytoplasm. Analogously, the fertilized egg doesn't just
+ grow into a human being, it is constructed, by interactions with the mother's physiology. At birth, the
+ environment continues to influence the ways in which cells develop and interact with each other.
+
+
+
+ Even during adulthood, the ways in which our cells--in the brain, immune system, and other organs--develop
+ and interact are shaped by the environment. When Skinner was writing, many biologists still believed that
+ each synapse of a nerve was directed by a gene, and couldn't be influenced by experience.
+
+
+ Our brain grows into our culture, and the culture lives in our nervous system. If a person grows up without
+ hearing people speak, he will have grown a special kind of brain, making it difficult to learn to speak.
+ (Genie, wolf boy, Kaspar Hauser, for example.)
+
+
+ When we ask a question and find an answer, we are changed. Thinking with learning is a developmental
+ process. But many people learn at an early age not to question. This changes the nature of subsequent
+ learning and brain development.
+
+
+ In the 1960s, many textbooks were published that claimed to use scientific language theory to improve the
+ instruction of English, from grade school level to college level. They didn't work, and at the time they
+ were being published they appeared fraudulent to people who didn't subscribe to the incipient cults of
+ "Generative Grammar" and "Artificial Intelligence" that later developed into "Cognitive Science."
+
+
+ At the time that Artificial Intelligence was coming to the attention of investors and academicians,
+ Neodarwinism had already cleansed the university biology departments of its opponents who advocated more
+ holistic views, and the idea of a brain that was "hard-wired" according to genetic instructions had entered
+ both neurology and psychology. The field concept was disappearing from developmental biology, as Gestalt
+ psychology was disappearing from the universities and journals.
+
+
+
+ In the humanities and social sciences, a fad appeared in the 1960s, in which a theory of grammar advocated
+ by Noam Chomsky of MIT was said to explain human thinking and behavior, and specialists in anthropology,
+ psychology, literature, rhetoric, sociology, and other academic fields, claimed that it informed their work
+ in an essential way. The rapid spread of a doctrine for which there was essentially no evidence suggests
+ that it was filling a need for many people in our culture. This doctrine was filling some of the gaps left
+ by the failure of genetic determinism that was starting to be recognized. It gave new support to the
+ doctrine of inborn capacities and limitations, in which formulaic indoctrination can be justified by the
+ brain's natural structure.
+
+
+ Chomsky was committed to an idealistic, "rationalist" doctrine of innate ideas, and to argue for that
+ doctrine, which held that there are transcendent forms (or "deep structures") that control mind, he disposed
+ of the opposing "empiricist" approach to mind by claiming that children simply learn language so rapidly
+ that it would be impossible to explain on the basis of learning from experience. Separating vocabulary from
+ grammar, he acknowledged that each language is different, and can be learned as easily by the children of
+ immigrants of different ethnicity as by children whose ancestors spoke it, but that all humans have a
+ genetically encoded "universal grammar," a "language organ." It is this "inborn grammar" that allows
+ children to learn what he said would be inconceivable to learn so quickly from experience.
+
+
+ The abstract, computational nature of the "inborn" functions of the "language organ" would make a nice
+ program for a translating machine, and the absence of such a useful program, after more than 50 years of
+ trying to devise one, argues against the possibility of such a thing.
+
+
+ Since Plato's time, some people have believed that, behind the changing irregularities of real languages,
+ there is a timeless, context-free language. In the late 1950s, when I was studying language and the "ideal
+ languages" of the philosophers, I realized that George Santayana was right when he pointed out that each
+ time an artificial language is used by real people in real situations, it is altered by the experience that
+ accrues to each component, from the context in which it is used. If real language were the model for
+ mathematics, then the values of numbers would change a little with every calculation.
+
+
+ Adults are usually slower than children at learning a new language, but they can make the process much
+ quicker by memorizing paradigms. With those models, they can begin speaking intelligible sentences when they
+ know only a few words. These basics of grammar are often outlined in just a few pages, but listing
+ irregularities and exceptions can become very detailed and complex. The grammar that children use isn't as
+ subtle as the grammar some adults use, and college freshmen are seldom masters of the grammar of their
+ native language.
+
+
+
+ There have been various studies that have investigated the number of words understood by children at
+ different ages.
+
+
+ The Virginia Polytechnic Institute website says that
+
+
+ By age 4 a person probably knows 5,600 words
+
+
+ By age 5 a person probably knows 9,600 words
+
+
+ By age 6 a person probably knows 14,700 words
+
+
+ By age 7 a person probably knows 21,200 words
+
+
+
+ By age 8 a person probably knows 26,300 words
+
+
+ By age 9 a person probably knows 29,300 words
+
+
+ By age 10 a person probably knows 34,300 words
+
+
+ By age 20 a college sophomore probably knows 120,000 words
+
+
+ A dictionary with 14,000 words is a substantial book. The grammar used by a 6 year old person isn't very
+ complex, because at that age a person isn't likely to know all of the subtleties of their language. There is
+ no reason to assume that a mind that can learn thousands of words and concepts in a year can't learn the
+ grammatical patterns of a language--a much smaller number of patterns and relationships--in a few years.
+
+
+
+ Idioms and clich"s are clusters of words that are frequently used together in the same pattern to express a
+ stereotyped meaning. There are thousands of them in English, and some of them have existed for centuries,
+ while others are regional and generational. It is possible to speak or write almost completely in clich"s,
+ and they are such an important part of language that their acquisition along with the basic vocabulary
+ deserves more attention than linguists have given it. A mind that can learn so many clich"s can certainly
+ learn the relatively few stereotypical rules of phrasing that make up the grammar of a language. In fact, a
+ grammar in some ways resembles a complex clich".
+
+
+ Recognition of patterns, first of things that are present, then of meaningful sequences, is what we call
+ awareness or consciousness. There is biological evidence, from the level of single cells through many types
+ of organism, both plant and animal, that pattern recognition is a basic biological function. An organism
+ that isn't oriented in space and time isn't an adapted, adapting, organism. Environments change, and the
+ organization of life necessarily has some flexibility.
+
+
+ A traveling bird or dog can see a pattern once, and later, going in the opposite direction, can recognize
+ and find specific places and objects. An ant or bee can see a pattern once, and communicate it to others.
+
+
+ If dogs and birds lived in colonies or cities, as bees and ants do, and carried food home from remote
+ locations, they might have a need to communicate their knowledge. The fact that birds and dogs use their
+ vocal organs and brains to communicate in ways that people have seldom cared to study doesn't imply that
+ their brains differ radically from human brains in lacking a "language organ."
+
+
+ People whose ideology says that "animals use instinct rather than intelligence," and that they lack "the
+ language instinct," refuse to perceive animals that are demonstrating their ability to generalize or to
+ understand language.
+
+
+
+ Organisms have genes, so a person could say that pattern recognition is genetically determined, but it would
+ be a foolish and empty thing to say. (Nevertheless, people do say it.) The people who believe that there are
+ "genes for grammar" believe that these mind-controlling genes give us the ability to generalize, and
+ therefore say that animals aren't able to generalize, though their "instinctive behaviors" might sometimes
+ seem to involve generalization.
+
+
+ In language, patterns are represented symbolically by patterned sounds, and some of those symbolically
+ represented patterns are made up of other patterns. Different languages have different ways of representing
+ different kinds of patterns.
+
+
+ "Things" are recognizable when they are far or near, moving or still, bright or dark, or upside down,
+ because the recognition of a pattern is an integration involving both spatial and temporal components. The
+ recognition of an object involves both generalization and concreteness.
+
+
+ Things that are very complex are likely to take longer to recognize, but the nature of any pattern is that
+ it is a complex of parts and properties.
+
+
+ A name for "a thing" is a name for a pattern, a set of relationships.
+
+
+ The method of naming or identifying a relationship can make use of any way of patterning sound that can be
+ recognized as making distinctions. Concepts and grammar aren't separable things, "semantics" and "syntax"
+ are just aspects of a particular language's way of handling meaning.
+
+
+
+ As a child interacts with more and more things, and learns things about them, the patterns of familiar
+ things are compared to the patterns of new things, and differences and similarities are noticed and used to
+ understand relationships. The comparison of patterns is a process of making analogies, or metaphors.
+ Similarities perceived become generalizations, and distinctions allow things to be grouped into categories.
+
+
+ When things are explored analogically, the exploration may first identify objects, and then explore the
+ factors that make up the larger pattern that was first identified, in a kind of analysis, but this analysis
+ is a sort of expansion inward, in which the discovered complexity has the extra meaning of the larger
+ context in which it is found.
+
+
+ When something new is noticed, it excites the brain, and causes attention to be focused, in the "orienting
+ reflex." The various senses participate in examining the thing, in a physiological way of asking a question.
+ Perception of new patterns and the formation of generalizations expands the ways in which questions are
+ asked. When words are available, questions may be verbalized. The way in which questions are answered
+ verbally may be useful, but it often diverts the questioning process, and provides rules and arbitrary
+ generalizations that may take the place of the normal analogical processes of intelligence. The vocabulary
+ of patterns no longer expands spontaneously, but tends to come to rest in a system of accepted opinions.
+
+
+ A few patterns, formulated in language, are substituted for the processes of exploration through
+ metaphorical thinking. In the first stages of learning, the process is expansive and metaphorical. If a
+ question is closed by an answer in the form of a rule that must be followed, subsequent learning can only be
+ analytical and deductive.
+
+
+ Learning of this sort is always a system of closed compartments, though one system might occasionally be
+ exchanged for another, in a "conversion experience."
+
+
+ The exploratory analogical mind is able to form broad generalizations and to make deductions from those, but
+ the validity of the generalization is always in a process of being tested. Both the deduction and the
+ generalization are constantly open to revision in accordance with the available evidence.
+
+
+
+ If there were infallible authorities who set down general rules, language and knowledge could be idealized
+ and made mathematically precise. In their absence, intelligence is necessary, but the authorities who would
+ be infallible devise ways to confine and control intelligence, so that, with the mastery of a language, the
+ growth of intelligence usually stops.
+
+
+ In the 1940s and '50s, W.J.J. Gordon organized a group called Synectics, to investigate the creative
+ process, and to devise ways to teach people to solve problems effectively. It involved several methods for
+ helping people to think analogically and metaphorically, and to avoid stereotyped interpretations. It was a
+ way of teaching people to recover the style of thinking of young children, or of chimps, or other
+ intelligent animals.
+
+
+ When the acquisition of language is burdened by the acceptance of clich"s, producing the conventionalism
+ mentioned by Horner and Whiten, with the substitution of deductive reasoning for metaphorical-analogical
+ thinking, the natural pleasures of mental exploration and creation are lost, and a new kind of personality
+ and character has come into existence.
+
+
+ Bob Altemeyer spent his career studying the authoritarian personality, and has identified its defining
+ traits as conventionalism, submission to authority, and aggression, as sanctioned by the authorities. His
+ last book, The Authoritarians (2006) is available on the internet.
+
+
+ Altemeyer found that people who scored high on his scale of authoritarianism tended to have faulty
+ reasoning, with compartmentalized thinking, making it possible to hold contradictory beliefs, and to be
+ dogmatic, hypocritical, and hostile.
+
+
+
+ Since he is looking at a spectrum, focusing on differences, I think he is likely to have underestimated the
+ degree to which these traits exist in the mainstream, and in groups such as scientists, that have a
+ professional commitment to clear reasoning and objectivity. With careful training, and in a culture that
+ doesn't value creative metaphorical thinking, authoritarianism might be a preferred trait.
+
+
+ Konrad Lorenz (who with Niko Tinbergen got the Nobel Prize in 1973) believed that specific innate structures
+ explained animal communication, and that natural selection had created those structures. Chomsky, who said
+ that our genes create an innate "Language Acquisition Device," distanced himself slightly from Lorenz's view
+ by saying that it wasn't certain that natural selection was responsible for it. However, despite slightly
+ different names for the hypothetical innate "devices," their views were extremely similar.
+
+
+ Both Lorenz and Chomsky, and their doctrine of innate rule-based consciousness, have been popular and
+ influential among university professors. When Lorenz wrote a book on degeneration, which was little more
+ than a revised version of the articles he had written for the Nazi party's Office for Race Policy in the
+ late 1930s and early 1940s, advocating the extermination of racial "mongrels" such as jews and gypsies, most
+ biologists in the US praised it. Lorenz identified National Socialism with evolution as an agent of racial
+ purification. His lifelong beliefs and activities--the loyalty to a strong leader, advocating the killing of
+ the weak--identified Lorenz as an extreme authoritarian.
+
+
+ When a famous professor went on a lecture tour popularizing and affirming the scientific truth and
+ importance of those publications, and asserting that all human actions and knowledge, language, work, art,
+ and belief, are specified and determined by genes, he and his audience (which, at the University of Oregon,
+ included members of the National Academy of Sciences and Jewish professors who had been refugees from
+ Nazism, who listened approvingly) were outraged when a student mentioned the Nazi origin and intention of
+ the original publications.
+
+
+ They said "you can't say that a man's work has anything to do with his life and political beliefs," but in
+ fact the lecturer had just finished saying that everything a person does is integral to that person's
+ deepest nature, just as Lorenz said that a goose with a pot belly and odd beak, or a person with non-nordic
+ physical features and behavior and cultural preferences--should be eliminated for the improvement of the
+ species. Not a single professor in the audience questioned the science that had justified Hitler's racial
+ policies, and some of them showed great hostility toward the critic.
+
+
+
+ In the 1960s, a professor compared graduate students' scores on the Miller Analogies Test, which is a widely
+ used test of analogical thinking ability, to their academic grades. She found that the students who scored
+ close to the average on the test had the highest grades and the greatest academic success, and those who
+ deviated the most from the average on that test, in either direction, had the worst academic grades. If the
+ ability to think analogically is inversely associated with authoritarianism, then her results would indicate
+ that graduate schools select for authoritarianism. (If not, then they simply select for mediocrity.)
+
+
+ Although Bob Altemeyer's scale mainly identified right-wing, conservative authoritarians, he indicated that
+ there could be left-wing authoritarians, too. Noam Chomsky is identified with left-wing political views, but
+ his views of genetic determinism and a "nativist" view of language learning, and his anti-empiricist
+ identification of himself as a philosophical Rationalist, have a great correspondence to the authoritarian
+ character. The "nativist" rule-based nature of "Cognitive Science" is just the modern form of an
+ authoritarian tradition that has been influential since Plato's time.
+
+
+ The first thing a person is likely to notice when looking at Chomsky's work in linguistics is that he offers
+ no evidence to support his extreme assertions. In fact, the main role evidence plays in his basic scheme is
+ negative, that is, his doctrine of "Poverty of the Stimulus" asserts that children aren't exposed to enough
+ examples of language for them to be able to learn grammar--therefore, grammar must be inborn.
+
+
+ I think Chomsky discovered long ago that the people around him were sufficiently authoritarian to accept
+ assertions without evidence if they were presented in a form that looked complexly technical. Several people
+ have published their correspondence with him, showing him to be authoritarian and arrogant, even rude and
+ insulting, if the person questioned his handling of evidence, or the lack of evidence.
+
+
+
+ For example, people have argued with him about the JFK assassination, US policy in the Vietnam war, the
+ HIV-AIDS issue, and the 9/11 investigation. In each case, he accepts the official position of the
+ government, and insults those who question, for example, the adequacy of the Warren Commission report, or
+ who believe that the pharmaceutical industry would manipulate the evidence regarding AIDS, or who doubt the
+ conclusions of the 9/11 Commission investigation.
+
+
+ He says that investigation of such issues is "diverting people from serious issues," as if those aren't
+ serious issues. And "even if it's true" that the government was involved in the 9/11 terrorism, "who cares?
+ I mean, it doesn't have any significance. I mean it's a little bit like the huge amount of energy that's put
+ out on trying to figure out who killed John F. Kennedy. I mean, who knows, and who cares"plenty of people
+ get killed all the time. Why does it matter that one of them happens to be John F. Kennedy?"
+
+
+ "If there was some reason to believe that there was a high level conspiracy" in the JFK assassination, "it
+ might be interesting, but the evidence against that is just overwhelming." "And after that it's just a
+ matter of, uh, if it's a jealous husband or the mafia or someone else, what difference does it make?" "It's
+ just taking energy away from serious issues onto ones that don't matter. And I think the same is true here,"
+ regarding the events of 9/11. These reactions seem especially significant, considering his reputation as
+ America's leading dissenter.
+
+
+
+ The speed with which Chomskyism spread through universities in the US in the 1960s convinced me that I was
+ right in viewing the instruction of the humanities and social sciences as indoctrination, rather than
+ objective treatment of knowledge. The reception of the authoritarian ideas of Lorenz and his apologists in
+ biology departments offered me a new perspective on the motivations involved in the uniformity of the
+ orthodox views of biology and medicine.
+
+
+ In being introduced into a profession, any lingering tendency toward analogical-metaphoric thinking is
+ suppressed. I have known perceptive, imaginative people who, after a year or two in medical school, had
+ become rigid rule-followers.
+
+
+ One of the perennial questions people have asked when they learn of the suppression of a therapy, is "if the
+ doctors are doing it to defend the profitable old methods, how can they refuse to use the better method even
+ for themselves and their own family?" The answer seems to be that their minds have been radically affected
+ by their vocational training.
+
+
+ For many years, cancer and inflammation have been known to be closely associated, even to be aspects of a
+ single process. This was obvious to "analog minded" people, but seemed utterly improbable to the
+ essentialist mentality, because of the indoctrination that inflammation is a good thing, that couldn't
+ coexist with a bad thing like cancer.
+
+
+ The philosophy of language might seem remote from politics and practical problems, but Kings and advertisers
+ have understood that words and ideas are powerfully influential in maintaining relationships of power.
+
+
+ Theories of mind and language that justify arbitrary power, power that can't justify itself in terms of
+ evidence, are more dangerous than merely mistaken scientific theories, because any theory that bases its
+ arguments on evidence is capable of being disproved.
+
+
+
+ In the middle ages, the Divine Right of Kings was derived from certain kinds of theological reasoning. It
+ has been replaced by newer ideologies, based on deductions from beliefs about the nature of mind and matter,
+ words and genes, "Computational Grammar," or numbers and quantized energy, but behind the ideology is the
+ reality of the authoritarian personality.
+
+
+ I think if we understand more about the nature of language and its acquisition we will have a clearer
+ picture of what is happening in our cultures, especially in the culture of science.
+
+ REFERENCES
+
+ New Yorker, April 16, 2007, "The Interpreter: Has a remote Amazonian tribe upended
+ our understanding of language?"
+
+ by John Colapinto. "Dan Everett believes that Pirah" undermines Noam Chomsky's idea of a universal grammar."
+
+
+
+ Language & Communication Volume 23, Issue 1, January 2003, Pages 1-43.
+ "Remarks on the origins of morphophonemics in American structuralist linguistics,"
+ E. F. K. Koerner. Chomsky has led the public to believe that he originated things which he borrowed
+ from earlier linguists.
+
+
+ Science. 2008 Feb 1;319(5863):569; author reply 569. Comparing social skills of children and
+ apes. De Waal FB, Boesch C, Horner V, Whiten A. Letter
+
+
+ Curr Biol. 2007 Jun 19;17(12):1038-43. Epub 2007 Jun 7.
+ Transmission of multiple traditions within and between chimpanzee groups. Whiten A, Spiteri A,
+ Horner V, Bonnie KE, Lambeth SP, Schapiro SJ, de Waal FB. Centre for Social Learning and Cognitive Evolution
+ and Scottish Primate Research Group, School of Psychology, University of St Andrews, St Andrews KY16 9JP,
+ United Kingdom. A.whiten@st-andrews.ac.uk
+ Field reports provide increasing evidence for local behavioral traditions among fish, birds, and mammals.
+ These findings are significant for evolutionary biology because social learning affords faster adaptation
+ than genetic change and has generated new (cultural) forms of evolution. Orangutan and chimpanzee field
+ studies suggest that like humans, these apes are distinctive among animals in each exhibiting over 30 local
+ traditions. However, direct evidence is lacking in apes and, with the exception of vocal dialects, in
+ animals generally for the intergroup transmission that would allow innovations to spread widely and become
+ evolutionarily significant phenomena. Here, we provide robust experimental evidence that alternative
+ foraging techniques seeded in different groups of chimpanzees spread differentially not only within groups
+ but serially across two further groups with substantial fidelity. Combining these results with those from
+ recent social-diffusion studies in two larger groups offers the first experimental evidence that a nonhuman
+ species can sustain unique local cultures, each constituted by multiple traditions. The convergence of these
+ results with those from the wild implies a richness in chimpanzees' capacity for culture, a richness that
+ parsimony suggests was shared with our common ancestor.
+
+
+
+ J Comp Psychol. 2007 Feb;121(1):12-21. Learning from others' mistakes? limits on understanding a
+ trap-tube task by young chimpanzees (Pan troglodytes) and children (Homo sapiens).
+ Horner V, Whiten A. Centre for Social Learning and Cognitive Evolution, School of Psychology,
+ University of St Andrews, Fife, Scotland, UK. Vhorner@rmy.emory.edu A trap-tube task was used to determine whether chimpanzees (Pan troglodytes) and
+ children (Homo sapiens) who observed a model's errors and successes could master the task in fewer trials
+ than those who saw only successes. Two- to 7-year-old chimpanzees and 3- to 4-year-old children did not
+ benefit from observing errors and found the task difficult. Two of the 6 chimpanzees developed a successful
+ anticipatory strategy but showed no evidence of representing the core causal relations involved in trapping.
+ Three- to 4-year-old children showed a similar limitation and tended to copy the actions of the
+ demonstrator, irrespective of their causal relevance. Five- to 6-year-old children were able to master the
+ task but did not appear to be influenced by social learning or benefit from observing errors.
+
+
+ Proc Biol Sci. 2007 Feb 7;274(1608):367-72. Spread of arbitrary conventions among chimpanzees: a
+ controlled experiment. Bonnie KE, Horner V, Whiten A, de Waal FB. Living Links, Yerkes National
+ Primate Research Center, Atlanta, GA 30329, USA. Kebonni@emory.edu Wild chimpanzees (Pan troglodytes) have a rich cultural repertoire--traditions common
+ in some communities are not present in others. The majority of reports describe functional, material
+ traditions, such as tool use. Arbitrary conventions have received far less attention. In the same way that
+ observations of material culture in wild apes led to experiments to confirm social transmission and identify
+ underlying learning mechanisms, experiments investigating how arbitrary habits or conventions arise and
+ spread within a group are also required. The few relevant experimental studies reported thus far have relied
+ on cross-species (i.e. human-ape) interaction offering limited ecological validity, and no study has
+ successfully generated a tradition not involving tool use in an established group. We seeded one of two
+ rewarded alternative endpoints to a complex sequence of behaviour in each of two chimpanzee groups. Each
+ sequence spread in the group in which it was seeded, with many individuals unambiguously adopting the
+ sequence demonstrated by a group member. In one group, the alternative sequence was discovered by a low
+ ranking female, but was not learned by others. Since the action-sequences lacked meaning before the
+ experiment and had no logical connection with reward, chimpanzees must have extracted both the form and
+ benefits of these sequences through observation of others.
+
+
+
+ Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13878-83. Faithful replication of foraging techniques
+ along cultural transmission chains by chimpanzees and children. Horner V, Whiten A, Flynn E, de
+ Waal FB. Centre for Social Learning and Cognitive Evolution, School of Psychology, University of St.
+ Andrews, Fife KY16 9JP, United Kingdom. Observational studies of wild chimpanzees (Pan troglodytes) have
+ revealed population-specific differences in behavior, thought to represent cultural variation. Field studies
+ have also reported behaviors indicative of cultural learning, such as close observation of adult skills by
+ infants, and the use of similar foraging techniques within a population over many generations. Although
+ experimental studies have shown that chimpanzees are able to learn complex behaviors by observation, it is
+ unclear how closely these studies simulate the learning environment found in the wild. In the present study
+ we have used a diffusion chain paradigm, whereby a behavior is passed from one individual to the next in a
+ linear sequence in an attempt to simulate intergenerational transmission of a foraging skill. Using a
+ powerful three-group, two-action methodology, we found that alternative methods used to obtain food from a
+ foraging device ("lift door" versus "slide door") were accurately transmitted along two chains of six and
+ five chimpanzees, respectively, such that the last chimpanzee in the chain used the same method as the
+ original trained model. The fidelity of transmission within each chain is remarkable given that several
+ individuals in the no-model control group were able to discover either method by individual exploration. A
+ comparative study with human children revealed similar results. This study is the first to experimentally
+ demonstrate the linear transmission of alternative foraging techniques by non-human primates. Our results
+ show that chimpanzees have a capacity to sustain local traditions across multiple simulated generations.
+
+
+ Nature. 2005 Sep 29;437(7059):737-40. Conformity to cultural norms of tool use in
+ chimpanzees. Whiten A, Horner V, de Waal FB. Centre for Social Learning and Cognitive
+ Evolution, School of Psychology, University of St Andrews, St Andrews, Fife, KY16 9JP, UK. A.whiten@st-and.ac.uk Rich circumstantial evidence suggests that the extensive behavioural diversity
+ recorded in wild great apes reflects a complexity of cultural variation unmatched by species other than our
+ own. However, the capacity for cultural transmission assumed by this interpretation has remained difficult
+ to test rigorously in the field, where the scope for controlled experimentation is limited. Here we show
+ that experimentally introduced technologies will spread within different ape communities. Unobserved by
+ group mates, we first trained a high-ranking female from each of two groups of captive chimpanzees to adopt
+ one of two different tool-use techniques for obtaining food from the same 'Pan-pipe' apparatus, then
+ re-introduced each female to her respective group. All but two of 32 chimpanzees mastered the new technique
+ under the influence of their local expert, whereas none did so in a third population lacking an expert. Most
+ chimpanzees adopted the method seeded in their group, and these traditions continued to diverge over time. A
+ subset of chimpanzees that discovered the alternative method nevertheless went on to match the predominant
+ approach of their companions, showing a conformity bias that is regarded as a hallmark of human culture.
+
+
+
+ Anim Cogn. 2005 Jul;8(3):164-81. Causal knowledge and imitation/emulation switching in chimpanzees
+ (Pan troglodytes) and children (Homo sapiens).
+ Horner V, Whiten A. Centre for Social Learning and Cognitive Evolution, School of Psychology, University of
+ St Andrews, St Andrews, KY16 9JU, UK. Vkh1@st-andrews.ac.uk This study explored whether the tendency of chimpanzees and children to use
+ emulation or imitation to solve a tool-using task was a response to the availability of causal information.
+ Young wild-born chimpanzees from an African sanctuary and 3- to 4-year-old children observed a human
+ demonstrator use a tool to retrieve a reward from a puzzle-box. The demonstration involved both causally
+ relevant and irrelevant actions, and the box was presented in each of two conditions: opaque and clear. In
+ the opaque condition, causal information about the effect of the tool inside the box was not available, and
+ hence it was impossible to differentiate between the relevant and irrelevant parts of the demonstration.
+ However, in the clear condition causal information was available, and subjects could potentially determine
+ which actions were necessary. When chimpanzees were presented with the opaque box, they reproduced both the
+ relevant and irrelevant actions, thus imitating the overall structure of the task. When the box was
+ presented in the clear condition they instead ignored the irrelevant actions in favour of a more efficient,
+ emulative technique. These results suggest that emulation is the favoured strategy of chimpanzees when
+ sufficient causal information is available. However, if such information is not available, chimpanzees are
+ prone to employ a more comprehensive copy of an observed action. In contrast to the chimpanzees,
+ children employed imitation to solve the task in both conditions, at the expense of efficiency.
+ We suggest that the difference in performance of chimpanzees and children may be due to
+ a greater susceptibility of children to cultural conventions, perhaps combined with a
+ differential focus on the results, actions and goals of the demonstrator.
+
+
+ Learn Behav. 2004 Feb;32(1):36-52. How do apes ape? Whiten A, Horner V, Litchfield CA,
+ Marshall-Pescini S. Centre for Social Learning and Cognitive Evolution, Scottish Primate Research Group,
+ School of Psychology, University of St. Andrews, St. Andrews, Fife, Scotland. A.whiten@st-and.ac.uk
+
+ In the wake of telling critiques of the foundations on which earlier conclusions were based, the last 15
+ years have witnessed a renaissance in the study of social learning in apes. As a result, we are able to
+ review 31 experimental studies from this period in which social learning in chimpanzees, gorillas, and
+ orangutans has been investigated. The principal question framed at the beginning of this era, Do apes ape?
+ has been answered in the affirmative, at least in certain conditions. The more interesting question now is,
+ thus, How do apes ape? Answering this question has engendered richer taxonomies of the range of
+ social-learning processes at work and new methodologies to uncover them. Together, these studies suggest
+ that apes ape by employing a portfolio of alternative social-learning processes in flexibly adaptive
+ ways, in conjunction with nonsocial learning. We conclude by sketching the kind of decision
+ tree that appears to underlie the deployment of these alternatives.
+
+
+ http://www.ucc.vt.edu/stdysk/vocabula.html
+
+
+ © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Autonomic systems
+
+
+ Autonomic systems
+
+
+
+ Historically, functions such as reason, emotion, and instinct were associated with particular nervous
+ structures, and there was a reluctance to think that consciousness, like instinct, could be based on
+ "reflexes." Eventually, this led to the idea of an autonomous nervous system which produced emotions and
+ adjusted the body's functions, while the "central nervous system" was the seat of conscious thought,
+ perception, and behavior.
+
+
+
+ Our individual cells have a degree of autonomy, consisting of the ability to sense their situation,
+ integrate stimuli, and act adaptively. Their behavior is intelligently adaptive. The cells that make up
+ the nervous system have this basic capacity for complex adaptive integration, but they also have the
+ specialized role of serving as links between cells, and between cells and the environment.
+
+
+ The integration of the organism is most complete when the energy of each cell is optimal. The "autonomic
+ nervous system," including nerves that are closely associated with the diverse organs and tissues, is
+ easiest to understand as a system for integrating and optimizing energy throughout the organism.
+
+
+ This view suggests new ways of understanding imbalance in these nervous functions, and the diseases that
+ develop under the imbalanced conditions--e.g., asthma, polycystic ovaries, menopausal symptoms, some
+ skin diseases, multiple sclerosis, heart disease, and tumors.
+
+
+ Every organ has its own intrinsic nerve net, and the cortex of the brain adjusts each system to meet the
+ adaptive needs of the organism.
+
+
+
+
+ When every cell is functioning optimally, and the organism is adapted to its environment, there is
+ little need for intervention by the "transmitter substances."
+
+
+
+
+ People like Walter Cannon and Wilhelm Reich popularized the idea of the autonomic nervous system, but they
+ were just systematizing ideas that had been developing since the beginning of the century. Their views were
+ the context in which Selye"s idea of stress developed.
+
+
+
+ The anatomical components of the nervous system that were called the sympathetic ("fight or flight,"
+ adrenergic) system and the parasympathetic ("vegetative") system are still important factors in
+ physiological thinking, and despite the great complexity that has grown up around them, there is still a
+ tendency to identify the systems with polarities of mood or emotion. The idea of polarities is useful, but
+ it easily leads to error.
+
+
+ (The sympathetic system includes a chain of ganglia along the spine, and its functions include dilating the
+ pupils and accelerating the heart. The parasympathetic system is also called the cranio-sacral system, from
+ the location of its ganglia, and among its functions are slowing the heart and constricting the pupils.
+ However, despite several decades of research, the actions of "sympathetic" and "parasympathetic" nerves in
+ most organs aren"t understood.)
+
+
+ If the "adrenaline side" of the nervous system is responsible for the reactions to pain and threat,
+ reactions of fear and rage, then the opposite side tends to be given attributes such as peace and pleasure,
+ and the fact that these oppositions are often true has led to a climate in which the adrenergic reactions
+ are seen as "bad," and the opposite reactions as "good." When adrenalin was identified as an agent of the
+ sympathetic nervous system, there was a search for the "opposing" agent of the parasympathetic system.
+ Histamine was an early candidate, before acetylcholine was discovered to be the main parasympathetic agent.
+ This view of histamine was fostered by the older idea of "trophic nerves," which easily became identified
+ with the parasympathetic system. When acetylcholine was identified as the transmitter or agent of the
+ parasympathetic system, it tended to take on many of the qualities, including the "trophic" functions, that
+ had grown up around the idea of the parasympathetic system, but the emphasis on acetylcholine led to a
+ general neglect of the associations of histamine, and the mast cells that produce much of it, with the
+ autonomic nervous system. (The current trend seems to be emphasizing a close integration of mast cell
+ function with nervous function.) Nitric oxide has recently been identified as another parasympathetic
+ "transmitter." Nitric oxide and histamine are both very important factors in degenerative inflammatory
+ diseases, but their association with the parasympathetic nervous system has given them an aura of
+ benevolence.
+
+
+ I think it"s useful to compare the autonomic nervous system with the pituitary, not just because some of the
+ pituitary hormones are called "trophic" hormones (e.g., luteotrophic, adrenocorticotrophic), but because
+ their important adaptive functions can themselves be the cause of serious problems. An excess of the thyroid
+ stimulating hormone, for example, causes degeneration and cancer development in the thyroid gland, and
+ animals deprived of their pituitary gland, but given thyroid, live longer than intact animals.
+
+
+ If slaves are starved and beaten frequently, they aren"t very productive, they don"t live long, and they
+ might rebel. Workers that are healthy and working for a common goal that they understand are more
+ productive. Cells that are well energized perform their functions with minimal cues, but deprived cells that
+ have to be forced to function are likely to die unexpectedly, or to reproduce inappropriately, or to change
+ their identity.
+
+
+ Professors often make a strong impression on their students, but, especially in technical or scientific
+ fields, they usually do this by controlling the discourse, so that radical questioning is excluded. What
+ they don"t know "isn"t knowledge." Under the pressure of "getting a professional education," students
+ appreciate organizing principles and mnemonic devices, but this gives traditional ways of systematizing
+ knowledge tremendous power that, in practice, is far more important than mere experimental results.
+ (Experiments that don"t acknowledge the ruling metaphors are almost universally considered inadmissable,
+ unpublishable.)
+
+
+
+ Some obvious questions about the autonomic system have been commonly ignored or minimized by physiologists.
+ If "stress" is the stimulus that causes the sympathetic system to increase its activity, what is the
+ stimulus for increased activity of the parasympathetic system? What accounts for the relative balance
+ between the two sides of the system, or their imbalance? The fact that the answers aren"t obvious has left
+ the questions largely to psychiatrists and psychologists. Wilhelm Reich, who tried to provide answers in
+ terms of developmental interactions between the organism and its environment, found that the question led
+ him to investigate psychosomatic disease, sexual repression, cancer, and fascism, with disastrous results
+ for himself.
+
+
+ Chinese medicine was familiar with many of the functions of the autonomic nervous system at a time when
+ western medicine was organized around "the humors." It"s easy for contemporary "western" people to see that
+ the "winds" and the hot and cold principles of Chinese tradition are metaphors, but they are reluctant to
+ see that their own system has grown up within very similar traditional metaphoric polarities.
+
+
+ The successes of even a good metaphor can cause people to neglect details that could support a more complete
+ and accurate image of reality.
+
+
+ Contemporary science carries a load of bad metaphors, because the educational system doesn"t tolerate a
+ critical attitude. Potentially, a good metaphor (e.g., Vernadsky"s suggestion that an organism is "a
+ whirlwind of atoms") could blow away many bad metaphors, but the present organization of science is tending
+ in the other direction: Commercial interests are creating a culture in which their
+ metaphors are replacing the traditional science in which there was a certain amount of honest intellectual
+ exploration.
+
+
+
+ In talking about consciousness, sleep, stress, biological rhythms, aging, and energy, I have often focussed
+ on the efficient use of oxygen for energy production by the mitochondria, i.e., cellular respiration. Every
+ situation demands a special kind of adaptation, and each kind of adaptation requires a special distribution
+ of cellular and organic activity, with its supporting local respiratory activity.
+
+
+ There is a lot of local self-regulation in the adapting organism, for example when the activated tissue
+ produces increased amounts of carbon dioxide, which dilates blood vessels, delivering more oxygen and
+ nutrients to the tissue. But the distribution of excitation, and the harmonious balancing of the organism"s
+ resources and activities, is achieved by the actions of the cortex of the brain, acting on the subordinate
+ nerve nets, adjusting many factors relating to energy production and use.
+
+
+ On the level of the mitochondria, adrenaline and acetylcholine have slightly different effects. (Metabolic
+ studies with isolated mitochondria are so remote from the normal cellular condition that their results are
+ nothing more than a hint of what might be occurring in the cell.) Acetylcholine appears to shift the
+ proportion of the fuels used (increasing the oxidation of alpha-ketoglutarate, with the production of carbon
+ dioxide) and increasing the efficiency of energy conservation (phosphorylation, producing ATP) so that less
+ oxygen is needed, while adrenaline increases the rate of oxygen consumption (and succinate oxidation). This
+ would be consistent with F. Z. Meerson"s conception of the parasympathetic function as one of the "stress
+ limiting" systems.
+
+
+ On the level of the whole cell, organ, and organism, the parasympathetic function limits oxygen consumption
+ in a variety of ways, including the reduction of blood flow. Acetylcholine, like histamine and serotonin,
+ activates glycolysis, the conversion of glucose to lactic acid, which provides energy in the absence of
+ oxygen.
+
+
+ The effects of a little adrenaline, and a lot of adrenaline, are very different, with a high concentration
+ of adrenaline decreasing the efficiency of phosphorylation. In the stressed heart, this effect of excess
+ adrenaline can be fatal, especially when it is combined with adrenaline"s acceleration of clotting,
+ liberation of fatty acids, and frequently of calcium, and constriction of blood vessels.
+
+
+ Seventy years ago, autonomic control of blood vessels seemed to be a matter of nerve fibers that constrict
+ them, and other fibers that cause them to dilate, but that idea hasn"t worked for a long time.
+
+
+
+ Ever since I noticed that the students in our physiology lab who tried to use adrenaline to revive their
+ rats weren"t successful, I have wondered about the television shows in which adrenaline is given to patients
+ with heart problems. Under some conditions adrenaline does increase circulation to the heart, but extreme
+ stress doesn"t seem to be among those conditions.
+
+
+ Too much serotonin, histamine, acetylcholine, and polyunsaturated fatty acids, like too much adrenalin, can
+ cause spasms of the coronary arteries, along with disturbances of mitochondrial respiration. In stress,
+ these substances are almost sure to be present in excess. (Anti-serotonin drugs are effective for a variety
+ of heart problems, and other degenerative diseases.)
+
+
+ By increasing the production of lactic acid and the loss of carbon dioxide, exaggerated nervous stimulation
+ (especially the excess of acetylcholine, histamine, and serotonin) can cause a variety of problems,
+ including generalized vasoconstriction and systemic alkalosis, as well as increased intracellular
+ alkalinity. This metabolic pattern is characteristic of many kinds of stress, including cancer. (Elsewhere,
+ I have referred to this pattern as "relative hyperventilation.") The metabolic effects probably account for
+ some of the "paradoxical" effects of the autonomic agents.
+
+
+ When nutrition and thyroid function, light, atmospheric pressure, and other conditions are favorable, the
+ autonomic transmitters (e.g., acetylcholine, histamine, serotonin, adrenalin) and pituitary hormones and
+ other "signal substances" are kept within safe limits.
+
+
+ Because the substances released from various cells under the influence of the autonomic nerves (histamine
+ and serotonin, for example) stimulate cell division, injuries which produce clots and vascular spasms will
+ also stimulate the formation of new blood vessels, a process that is essential for the adaptation of tissues
+ to prolonged stress.
+
+
+ These stress-induced agents are appropriately included in the "vegetative" (parasympathetic) nervous system,
+ because they promote vegetation, i.e., the proliferation of substance.
+
+
+
+ Adrenaline, and the sympathetic nerves, have the opposite function, of restraining cell division, and they
+ also oppose the pro-inflammatory functions of those parasympathetic agents.
+
+
+ Estrogen tends to shift autonomic balance toward the parasympathetic side, away from the
+ sympathetic/adrenergic. Recalling that stress, hypothyroidism, and aging increase the activity of aromatase
+ in various tissues, with local production of estrogen, and that tissue-bound estrogen stays at a high level
+ in postmenopausal women despite the lower level of estrogen in the serum, it"s worthwhile looking at the
+ effects of estrogen on the various components of the so-called autonomic nervous system.
+
+
+ One injection of estrogen can induce a large increase in the number of sympathetic nerves in the ovaries. At
+ menopause, a similar "invasion" of sympathetic nerves occurs. The polycystic ovary (which is even more
+ common after menopause than before, and some studies have found the condition in 20% of premenopausal women)
+ responds to estrogen by producing nerve growth factor(s), and growing a large number of new sympathetic
+ nerves. Although the hyperestrogenism associated with the polycystic ovary syndrome has many harmful
+ effects, the invasion of the ovary by adrenergic nerves apparently protects it from the development of
+ cancer.
+
+
+ Parasympathetic nerves, pituitary hormones and mast cells activate the ovaries. The number of mast cells in
+ the ovaries is increased by the pituitary hormones (including the thyroid stimulating hormone), and by
+ estrogen (Jaiswal and Krishna, 1996). Estrogen is the most potent of these hormones in causing the cells to
+ release histamine. The overgrowth of the sympathetic nerves in the polycystic ovary causes the number and
+ activity of mast cells to decrease, possibly as a protective adaptation against excessive stimulation from
+ the many pro-inflammatory factors. The mast cells are needed for the follicles to rupture, so their
+ suppression prevents ovulation.
+
+
+ The nervous system is closely involved in controlling the growth of tissues, and it has been argued (R.E.
+ Kavetsky reviewed the subject in his book, emphasizing the role of depression in development of cancer) that
+ cancer results from reduced activity of the sympathetic nerves, or unopposed action of the parasympathetic
+ system. That stress has a role in cancer is acknowledged by the scientific establishment, but the nervous
+ system"s direct involvement in the regulation of cellular metabolism, cell division, and other processes
+ that are central to the cancerous state is either flatly denied or simply ignored.
+
+
+ Although mast cells have been known to be a common component of tumors for many years, it is only recently
+ that antihistamines and other antiinflammatory drugs have been recognized as valuable therapies in cancer.
+ The whole issue of the role of nerves in tumor development and physiology has been submerged by the mystique
+ of the "intrinsically bad cancer cell."
+
+
+
+ In Alzheimer"s disease, there has been a great investment in the doctrine that drugs to promote the function
+ of cholinergic (acetylcholine forming) nerves will restore lost mental function, or at least retard the
+ progression of the disease. The success of anticholinergic drugs in treating
+ several degenerative brain diseases is probably embarrassing to the companies whose cholinergic-intensifying
+ drugs aren"t very successful. Conveniently for them, these formerly "anticholinergic" drugs are now being
+ called anti-excitotoxic or anti-glutamatergic drugs. There is no serious conflict in the terminology, since
+ the cholinergic processes (like the serotonergic processes) are closely associated with excitotoxic nerve
+ damage. The cholinergic drugs will probably be sold as long as their patents are effective, and then will be
+ quietly forgotten.
+
+
+ The modern conception of pharmacology, with receptors and transmitters turning functions on or off, has
+ turned into an unproductive and dangerous scholasticism. No one will ever successfully count the number of
+ transmitter angels dancing on the variable sites of the variable receptor molecules. The functional
+ "meaning" of a receptor or transmitter changes according to circumstances, and the effect of activating a
+ particular nerve depends on surrounding conditions, and on preceding conditions. Each cell integrates
+ stimuli adaptively.
+
+
+ If no reflex is simply mechanical and innate, then all reflexes are conditional. (M. Merleau-Ponty argued
+ against the validity of the reflex concept itself, because of this conditionality.) P. K. Anokhin"s concept
+ of the "Acceptor of Action" (described in my book, Mind and Tissue) provides an
+ image in which we can see the "set-points" for the relatively "autonomic" reflexes as reflections of the
+ general needs of the organism. The local tissue reflexes, the organ reflexes, the spinal reflexes, etc., are
+ variable, according to their energetic resources, and according to the way in which they are organized under
+ the influence of the cerebral cortex and the environment.
+
+
+ The reality is more complex than the philosophy of the drug industry imagines, but the solutions of problems
+ can be much simpler, if we think in terms of energetic support, rather than the over-concretized
+ interventions of the pharmacologists. In hypothyroidism, it is common for there to be an excess of
+ adrenalin/noradrenalin, serotonin, histamine, and some of the pituitary hormones. Correcting thyroid
+ function can immediately correct many problems, but especially when the energy deficiency has caused
+ anatomical adjustments (redistribution of blood vessels and mast cells, for example) it"s important to make
+ the environment supportive in as many ways as possible.
+
+
+ In polycystic ovaries, menopausal symptoms, arthritis, angina pectoris, multiple sclerosis, some kinds of
+ dementia, migraine, and emphysema, the relief achieved with a simple improvement of cellular energy can be
+ rapid and complete. Presumably a similar process of biological reorganization is involved in the occasional
+ spontaneous regression of tumors.
+
+
+
+ Although I don"t think the autonomic nervous system, with its sympathetic and parasympathetic divisions,
+ exists in the way it has traditionally been conceived, the idea can be useful if we think of using drugs and
+ other factors in ways that tend to "quiet an overactive autonomic nervous system."
+
+
+
+
+ REFERENCES
+
+
+ Am J Emerg Med 1989 Sep;7(5):485-8. Coronary artery spasm induced by intravenous epinephrine
+ overdose. Karch SB. A 27-year-old man was accidentally given 2 mg intravenous epinephrine
+ instead of 2 mg naloxone. He immediately developed chest pain, nausea, and diaphoresis. An ECG taken shortly
+ after the epinephrine administration showed widespread ischemia. Forty-five minutes later the tracing still
+ showed an early repolarization pattern, but ST elevation was less marked and the patient was asymptomatic.
+ Serum potassium was 3.2 mEq/L and serum catecholamines, drawn approximately 20 minutes after the epinephrine
+ administration, were 10 times normal (dopamine, 173 ng/L; epinephrine, 1,628 ng/L; norepinephrine, 1,972
+ ng/L). There are seven other reports of intravenous epinephrine overdose in the English literature. Two of
+ the previously reported cases had 12-lead ECGs within the first hour. In both there was evidence of
+ transient ischemia similar to that observed in this case. Most of the patients had symptoms consistent with
+ angina,
+ and several developed pulmonary edema. These findings suggest that, in humans, large intravenous doses
+ of epinephrine are likely to produce coronary artery spasm and may decrease coronary artery
+ perfusion.
+
+
+
+ Res Exp Med (Berl) 1987;187(5):385-93. Possible interaction of platelets and adrenaline in the early
+ phase of myocardial infarction. Seitz R, Leising H, Liebermann A, Rohner I, Gerdes H, Egbring
+ R. "It is known that in most cases of transmural acute myocardial infarction a platelet clot
+ originates within a coronary artery. In acute myocardial infarction patients increased levels of the
+ plasma catecholamines adrenaline and noradrenaline as well as the platelet release proteins platelet
+ factor 4 and beta-thromboglobulin have been reported."
+
+
+
+ Anesthesiology 1991 Jun;74(6):973-9. Comment in: Anesthesiology. 1992 Mar;76(3):475.
+ Magnesium inhibits the hypertensive but not the cardiotonic actions of low-dose epinephrine.
+
+
+
+ Jpn Heart J 1979 Jan;20(1):75-82. Inhibition of constrictor responses of dog coronary artery by
+ atropine. A possible effectiveness of atropine on variant form of angina pectoris. Sakanashi M,
+ Furukawa T, Horio Y. A possible effectiveness of atropine on variant form of angina pectoris was
+ investigated using the left circumflex coronary arterial strips of dogs. Acetylcholine 10(-5)--10(-3) Gm/ml
+ dose-dependently constricted the isolated arterial strips during potassium-contracture in 6 cases, and
+ repetitive applications of acetylcholine could produce the similar contractions to the control. In 18 strips
+ atropine 10(-6) Gm/ml significantly depressed the contractions of coronary arteries induced by acetylcholine
+ 10(-5)--10(-3) Gm/ml. In 5 arterial strips atropine 10(-6) Gm/ml
+ significantly inhibited norepinephrine-induced responses of these arteries, and by 10(-5) Gm/ml
+ further suppression of the responses was obtained. The results suggest that atropine may suppress
+ the contractile responses of the coronary artery induce by acetylcholine and nonrepinephrine through a
+ muscarinic-receptor blocking action and simultaneously partly through an adrenergic alpha-receptor
+ blocking action.
+
+
+ Eur J Clin Pharmacol 1981;20(4):245-50. Effect of long-term beta-blockade with alprenolol on
+ platelet function and fibrinolytic activity in patients with coronary heart disease. Jurgensen
+ HJ, Dalsgaard-Nielsen J, Kjoller E, Gormsen J.
+
+
+
+ C R Seances Soc Biol Fil 1987;181(3):242-8.
+ [Adrenaline activates oxidative phosphorylation of rat liver mitochondria through alpha
+ 1-receptors].
+ Breton L, Clot JP, Bouriannes J, Baudry M. We studied the effects and mode of action of epinephrine on the
+ oxidative phosphorylation of rat liver mitochondria. With either succinate or beta-hydroxybutyrate as
+ substrate, i.v. injection of 1.5 microgram/100 g epinephrine increased the respiratory rates by 30-40% in
+ state 3 (with ADP), and by 20-30% in state 4 (after ADP phosphorylation), so that the respiratory control
+ ratio (state 3/state 4) changed little. The respiratory stimulation by epinephrine was maximal 20 minutes
+ after its injection. The action of epinephrine on mitochondria was blocked by pretreatment of the animals
+ with the alpha 1-antagonist prazosin but not by treatment with the beta-antagonist propranolol. I. v.
+ injection of 10 micrograms/100 g phenylephrine evoked the same mitochondrial response as epinephrine. I. v.
+ administration of 50 micrograms/100 g dibutyryl cyclic AMP enhanced glycaemia but did not affect
+ mitochondrial respiration. Epinephrine therefore has an alpha 1-type of action on mitochondrial oxidative
+ phosphorylation.
+
+
+ Biochimie 1975;57(6-7):797-802. Effects of catecholamines on rat myocardial metabolism. I. Influence
+ of catecholamines on energy-rich nucleotides and phosphorylated fraction contents. Merouze P,
+ Gaudemer Y. 1. The influence of catecholamines (adrenaline and noradrenaline) on energy metabolism of the
+ rat myocardium has been studied by incubating slices of this tissue with these hormones and by following the
+ levels of the different phosphorylated fractions and adenylic nucleotides. 2. Similar effects are obtained
+ with both hormones, adrenaline being more effective. 3. Catecholamines decrease significantly the
+ total amount of phosphate while Pi content increases during the first 10 minutes of incubation; labile
+ and residual phosphate contents increase at the beginning of incubation and decrease to the initial
+ values afterwards. 4. ATP and ADP levels decrease significantly with both hormones; however,
+ the effect of noradrenalin on the ATP level needs a longer time of incubation.
+ The ATP/ADP ratios decrease after 5 minutes incubation and the total adenylic nucleotide content is
+ severely decreased (35 per cent with adrenalin, after 20 minutes incubation). 5. Similar results have
+ been obtained with other tissues; these results can explain the decrease of aerobic metabolism we
+ observed under the same conditions.
+
+
+ Eur J Pharmacol 1982 Jul 30;81(4):569-76. Actions of serotonin antagonists on dog coronary
+ artery. Brazenor RM, Angus JA. "Serotonin released from platelets may initiate coronary
+ vasospasm in patients with variant angina. If this hypothesis is correct, serotonin antagonists
+ without constrictor activity may be useful in this form of angina. We have investigated drugs classified as
+ serotonin antagonists on dog circumflex coronary artery ring segments in vitro. Ergotamine,
+ dihydroergotamine,
+ bromocriptine, lisuride, ergometrine, ketanserin, trazodone, cyproheptadine and pizotifen caused
+ non-competitive antagonism of serotonin concentration-response curves. In addition, ketanserin,
+ trazodone, bromocriptine and pizotifen inhibited noradrenaline responses in concentrations similar to those
+ required for serotonin antagonism. All drugs with the exception of ketanserin, cyproheptadine and pizotifen
+ showed some degree of intrinsic constrictor activity." "Of the
+ drugs tested, ketanserin may be the most useful in variant angina since it is a potent 5HT antagonist,
+ lacks agonist activity and has alpha-adrenoceptor blocking activity."
+
+
+
+ Arch Mal Coeur Vaiss 1983 Feb;76 Spec No:3-6.
+ Role of autonomic nervous system in the pathogenesis of angina pectoris. Yasue H. "The attacks
+ of vasospastic angina or coronary spasm can be induced by injection of epinephrine, cold pressor test,
+ Valsalva maneuver, and exercise." "The attacks of vasospastic angina can also be induced by injection of
+ methacholine, a parasympathomimetic agent, and this reaction is suppressed by atropine, a parasympathetic
+ blocking agent. Thus,
+ parasympathetic nervous system also seems to play a role in the production of vasospastic angina. The
+ attacks of vasospastic angina can be easily induced by adrenergic or parasympathetic stimuli from
+ midnight to early morning but is usually not provoked by these stimuli in the daytime. Thus,
+ there is circadian variation in the reactivity of coronary arteries to adrenergic or parasympathetic
+ stimuli. There are also weekly, monthly and yearly variations of the reactivity of coronary arteries to
+ these stimuli. Thus, alpha adrenergic or parasympathetic activity is not the sole factor in the
+ production of vasospastic angina. Angina pectoris caused by increased myocardial oxygen demand
+ is induced by infusion of isoproterenol, a beta adrenergic stimulant, and is suppressed by propranolol but
+ not by phentolamine."
+
+
+ Nippon Yakurigaku Zasshi 1986 Mar;87(3):281-90. [Vasoconstrictor responses of isolated pig coronary
+ arteries]. [Article in Japanese] Ikenoue K, Kawakita S, Toda N.
+ "In helical strips of pig coronary arteries, histamine, serotonin, acetylcholine and a stable analogue
+ of thromboxane A2 (9, 11-epithio-11, 12-methano TXA2: s-TXA2) produced a dose-dependent contraction. The
+ histamine-induced contraction was suppressed by treatment with chlorpheniramine, suggesting an
+ involvement of H1 receptors. Contractile responses to serotonin were attenuated by not only
+ ketanserin, an S2 antagonist, but also by cinanserin and methysergide." "Contractile responses
+ to histamine were potentiated by treatment with low concentrations of serotonin or s-TXA2. Contractile
+ responses to serotonin were also potentiated by low concentrations of histamine or s-TXA2. Removal of the
+ endothelium from pig coronary arterial strips potentiated contractions induced by serotonin, histamine and
+ norepinephrine. These results suggest that, in addition to damaged endothelium, integrating action
+ of endogenous vasoconstrictors, including histamine, serotonin, TXA2 and norepinephrine, may play an
+ important role in producing coronary vasospasm."
+
+
+
+ Jpn Heart J 1987 Sep;28(5):649-61. The role of parasympathetic nerve activity in the pathogenesis of
+ coronary vasospasm. Suematsu M, Ito Y, Fukuzaki H. To evaluate the role of the autonomic
+ nervous system, especially the parasympathetic nervous system, in the initiation mechanism of vasospastic
+ angina pectoris (AP), the coefficient of R-R interval variation (CV) on the electrocardiogram (ECG) and
+ plasma catecholamine concentration were measured in 25 patients with vasospastic AP, 10 patients with effort
+ AP and 12 control subjects. CV which has been recognized as reflecting parasympathetic nervous system
+ activity was calculated from 100 consecutive heart beats on the ECG and represented as the percentage of
+ standard deviation of the R-R interval per mean R-R interval. Repeated measurements of plasma
+ catecholamine concentration revealed higher values at any sampling point throughout a day in patients
+ with vasospastic AP than those in
+
+ control subjects. A distinctly higher CV was observed at night in the vasospastic AP group. This
+ elevated CV was abolished by atropine sulfate (1.5 mg/day per os). Pilocarpine injection (1.3 mg/10 kg
+ B.W. subcutaneously) induced a marked increase in CV that preceded the occurrence of chest pain
+ and/or ischemic ECG changes in 5 patients with vasospastic AP. The
+ increment in CV at 10 min after pilocarpine administration was greater in vasospastic AP than in control
+ subjects (p less than 0.05). It is concluded that enhanced parasympathetic activity may play a role in
+ the initiation of coronary vasospasm associated with sympathetic hyperactivity.
+
+
+ Science 1984 Mar 30;223(4643):1435-7.
+ Coronary arteries of cardiac patients are hyperreactive and contain stores of amines: a mechanism for
+ coronary spasm. Kalsner S, Richards R. Coronary arteries from hearts of cardiac patients
+ contain significantly higher concentrations of histamine than do those from noncardiac patients. The
+ coronary vessels of cardiac patients are also hyperresponsive to histamine and serotonin. These differences
+ between groups of patients suggest an explanation for coronary artery spasm in heart disease.
+
+
+
+ Fed Proc 1985 Feb;44(2):321-5. Coronary artery reactivity in human vessels: some questions and some
+ answers. Kalsner S. "It is now clear that human coronary arteries in vitro contract to
+ acetylcholine but that relaxation is the only response observed in dog coronary vessels.
+ Acetylcholine is as powerful a constrictor of human coronary arteries, in terms of tension induced, as
+ 5-hydroxytryptamine (5-HT) or histamine and is a substantially more powerful constrictor than
+ norepinephrine. Field stimulation of coronary artery strips caused a vasoconstriction that was
+ partially antagonized by atropine (3.45 X 10(-6) M)." "Coronary tissue from cardiac patients also contains
+ stores of 5-HT and histamine, and the histamine levels are substantially increased above the values in
+ vessels from noncardiac patients. Coronary artery spasm or contraction
+ probably can be initiated by diverse intrinsic and extrinsic influences, including autonomic discharge
+ from either the parasympathetic or sympathetic nervous system or from histamine or 5-HT, and probably no
+ one agent or entity is causative in all cases."
+
+
+ Ann N Y Acad Sci 1969 Oct 14;164(2):517-9. Induced carcinogenesis under various influences on the
+ hypothalamus. Kavetsky RE, Turkevich NM, Akimova RN, Khayetsky IK, Matveichuck YD.
+
+
+
+ Kavetsky RE, (editor) The Neoplastic Process and the Nervous System,Kiev, 1958.
+
+
+ Ann N Y Acad Sci 1966 Jan 21;125(3):933-45. On the psychophysiological mechanism of the organism's
+ resistance to tumor growth. Kavetsky RE, Turkevich NM, Balitsky KP.
+
+
+ Patol Fiziol Eksp Ter 1971 Sep-Oct;15(5):3-10. [Role of disorders in intra-cellular and
+ neuro-humoral regulation in the development of the tumor process].
+ [Article in Russian] Kavetskii RE, Balitskii KP.
+
+
+ Mil"man, M.S., The sympathetic nervous system and the source of tumors,
+ Problems of Oncology IX, 162-173, 1936.
+
+
+ Obstet Gynecol Surv 1977 May;32(5):267-81. Estrogen and endometrial carcinoma.
+ Knab DR. "1. It has become evident that the estrogen secreting tumors of the ovary are associated
+ with endometrial carcinoma, but this association is most easily observed in the postmenopausal patient where
+ the incidence of carcinoma has been
+ reported at 10.3% (1. 02) to 24% (83). 2. The most consistent association of endometrial carcinoma is
+ with polycystic ovarian disease, where 19 (34), 21 (152), and 25% (150) of young women with endometrial
+ carcinoma had Stein-Leventhal syndrome (67).
+
+ 3. A very significant discovery became known in 1967 when the peripheral aromatization of delta4
+ androstenedione to estrone was reported by Kase (94) and MacDonald (111,112). Since that time we have
+ learned that endometrial carcinoma patients have an increased peripheral conversion (139) (0.1% compared to
+ 0.027%), which is similar to that found in obese and aging patients, by Hemsell, et al (77). This can be 2
+ to 4 times greater than the young adult or the patient without cancer." "Similarly patients with polycystic
+ ovary disease, hyperthecosis and lipoid cell tumors of the ovary demonstrate androgen excess with
+ extraglandular conversion to estrone (2). 4. It has become apparent that the principal estrogen in the
+ postmenopausal patient is estrone and that the estrone-estradiol ratio in the serum is higher in
+ postmenopausal women with corpus cancer than similar patients without cancer (135)." "5. With the lack of
+ ovarian estrogen there is a relative excess of adrenal testosterone, dihydrotestosterone and delta4
+ androstenedione, the available precursors of extraglandular estrone (1). 6. With the passage of time it appears that endometrial carcinoma is associated with hypothalamic "hyperactivity"
+
+ (31)...."
+
+
+ Endocrinology 2000 Mar;141(3):1059-72.
+ An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal
+ component of steroid-induced polycystic ovary in the rat. Lara HE, Dissen GA, Leyton V, Paredes
+ A, Fuenzalida H, Fiedler JL, Ojeda SR. A form of polycystic ovary (PCO) resembling some aspects of the human
+ PCO syndrome can be induced in rats by a single injection of estradiol valerate (EV). An increase in
+ sympathetic outflow to the ovary precedes, by several weeks, the appearance of cysts, suggesting the
+ involvement of a neurogenic component in the pathology of this ovarian dysfunction. The present study was
+ carried out to test the hypotheses that this change in sympathetic tone is related to an augmented
+ production of ovarian nerve growth factor (NGF), and that this abnormally elevated production of NGF
+ contributes to the formation of ovarian cysts induced by EV. Injection of the steroid resulted in
+ increased intraovarian synthesis of NGF and its low affinity receptor, p75 NGFR. The increase
+ was maximal 30 days after EV, coinciding with the elevation in sympathetic tone to the ovary and preceding
+ the appearance of follicular cysts. Intraovarian injections of the retrograde tracer fluorogold combined
+ with in situ hybridization to detect tyrosine hydroxylase (TH) messenger RNA-containing neurons in the
+ celiac ganglion revealed that these changes in NGF/p75 NGFR synthesis are accompanied by selective
+ activation of noradrenergic neurons projecting to the ovary. The levels of RBT2 messenger RNA, which encodes
+ a beta-tubulin presumably involved in slow axonal transport, were markedly elevated, indicating that
+ EV-induced formation of ovarian cysts is preceded by functional activation ofceliac ganglion neurons,
+ including those innervating the ovary. Intraovarian administration of a neutralizing antiserum to NGF in
+ conjunction with an antisense oligodeoxynucleotide to p75 NGFR, via Alzet osmotic minipumps,
+ restored estrous cyclicity and ovulatory capacity in a majority of EV-treated rats. These
+ functional changes were accompanied by restoration of the number of antral follicles per ovary that had been
+ depleted by EV and a significant reduction in the number of both precystic follicles and
+ follicular cysts. The results indicate that the hyperactivation of ovarian sympathetic nerves seen in
+ EV-induced PCO is related to an overproduction of NGF and its low affinity receptor in the gland. They
+ also suggest that activation of this neurotrophic-neurogenic regulatory loop is a component of the
+ pathological process by which EV induces cyst formation and anovulation in rodents. The
+ possibility exists that a similar alteration in neurotrophic input to the ovary contributes to the etiology
+ and/or maintenance of the PCO syndrome in humans.
+
+
+
+ Acta Physiol Hung 1996;84(2):183-90.
+ Effects of hormones on the number, distribution and degranulation of mast cells in the ovarian complex
+ of mice. Jaiswal K, Krishna A. The changes in the number and degranulation pattern of mast
+ cells varied with the types of hormonal treatment and ovarian compartment. Luteinizing hormone (LH),
+ follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH) and 17-beta estradiol (E2)
+ treatment caused increase (P < 0.05) in the number of mast cells in the hilum as compared
+ with the controls. Increase (P < 0.05) in the number of mast cells in the whole ovarian complex was
+ observed only following FSH and E2 treatment. All the hormones used in the present study increased the
+ percentage degranulation of mast cells in the hilum. However, only LH, FSH and E2 increased the percentage
+ degranulation of mast cells in other compartments of the ovary (medulla, bursa and cortex). TSH and ACTH
+ failed to cause any increase in the percentage degranulation of mast cells in these compartments. The
+ present findings indicate E2 to be the most potent among the hormones tested in causing degranulation of
+ mast cells in all ovarian compartments.
+
+
+ Fertil Steril 2001 Jun;75(6):1141-7. Increase in nerve fibers and loss of mast cells in polycystic
+ and postmenopausal ovaries.
+
+ with increasing nerve fiber density in polycystic ovaries, the number of mast cells decreased
+ strikingly compared with cyclic ovaries (p<.001). Almost no mast cells were seen in postmenopausal
+ ovaries with and without hyperthecosis. The number of leukocyte antigen-positive leukocytes was
+ similar in all groups. CONCLUSION(S): The high density of nerve fibers in polycystic and postmenopausal
+ ovaries, together with a conspicuous decrease in mast cells, indicates altered neuroimmune communication.
+
+
+ Endocrinology 1993 Dec;133(6):2696-703. Ovarian steroidal response to gonadotropins and
+ beta-adrenergic stimulation is enhanced in polycystic ovary syndrome: role of sympathetic
+ innervation. Barria A, Leyton V, Ojeda SR, Lara HE. Experimental induction of a polycystic
+ ovarian syndrome (PCOS) in rodents by the
+ administration of a single dose of estradiol valerate (EV) results in activation of the peripheral
+ sympathetic neurons that innervate the ovary. This activation is evidenced by an increased capacity of
+ ovarian nerve terminals to incorporate and release norepinephrine (NE), an increase in ovarian NE
+ content, and a decrease in ovarian beta-adrenergic receptor number in the ovarian compartments
+ receiving catecholaminergic innervation. The present experiments were undertaken to examine the functional
+ consequences of this
+ enhanced sympathetic outflow to the ovary. The steroidal responses of the gland to
+ beta-adrenergic receptor stimulation and hCG were examined in vitro 60 days after EV administration, i.e. at
+ the time when follicular cysts are well established. EV-treated rats exhibited a remarkable increase
+ in ovarian progesterone and androgen responses to isoproterenol, a beta-adrenergic receptor agonist,
+ with no changes in estradiol responsiveness. Basal estradiol release was, however, 50-fold higher than
+ the highest levels released from normal ovaries at any phase of the estrous cycle.
+ The ovarian progesterone and androgen responses to hCG were enhanced in EV-treated rats, as were the
+ responses to a combination of isoproterenol and hCG. Transection of the superior ovarian nerve (SON), which
+ carries most of the catecholaminergic fibers innervating endocrine ovarian cells, dramatically reduced the
+ exaggerated responses of all three steroids to both beta-adrenergic and gonadotropin stimulation. SON
+ transection also reduced the elevated levels of ovarian NE resulting from EV treatment and caused
+ up-regulation of beta-adrenoreceptors. Most importantly, SON transection restored estrous cyclicity and
+ ovulatory capacity. The results indicate that the increased output of ovarian steroids in PCOS is at least
+ in part due to an enhanced responsiveness of the gland to both catecholaminergic and gonadotropin
+ stimulation. The ability of SON transection to restore a normal response indicates that the alteration in
+ steroid output results from a deranged activation of selective components of the noradrenergic innervation
+ to the ovary. These findings support the concept that an alteration in the neurogenic control of the
+ ovary contributes to the etiology of PCOS.
+
+
+
+ Wilderness Environ Med 2001 Spring;12(1):8-12. Alterations in autonomic nervous control of heart
+ rate among tourists at 2700 and 3700 m above sea level.
+ Kanai M, Nishihara F, Shiga T, Shimada H, Saito S. "RESULTS: Both HF and LF heart rate variability decreased according to the elevation of altitude." "CONCLUSIONS: At 2700 and 3700 m, the
+ activity of the autonomic nervous system measured by heart rate variability was decreased in
+ untrained office workers. The sympathetic nervous system was dominant to the parasympathetic at 3700 m.
+ These alterations in the autonomic nervous system might play some role in physical fitness at high
+ altitudes."
+
+
+ Acta Neuroveg (Wien) 1967;30(1):557-63. [Neuroautonomic reactivity of the skin during high mountain
+ climate treatment of skin diseases].
+ [Article in German] Chlebarov S.
+
+
+
+ Munch Med Wochenschr 1966 Mar 18;108(11):589-92. [Changes of the neurovegetative reactivity of the
+ skin after Alpine climatic therapy].
+ [Article in German] Borelli S, Chlebarov S.
+
+
+ J Appl Physiol 1978 May;44(5):647-51. Mechanism of the attenuated cardiac response to
+ beta-adrenergic stimulation in chronic hypoxia. Maher JT, Deniiston JC, Wolfe DL, Cymerman
+ A.
+ "A blunting of the chronotropic and inotropic responses of the heart to beta-adrenergic stimulation
+ occurs following chronic exposure to hypobaric hypoxia." "Neither monoamine oxidase activity
+ nor norepinephrine level of any region of the heart was altered by chronic hypoxia. However, a twofold
+ increase (P less than 0.001) in catechol O-methyltransferase activity above sea-level values was
+ found in both the atria and ventricles of the hypoxic animals. Thus, the attenuation in cardiac
+ responsiveness to beta-adrenoceptor stimulation in chronic hypoxia appears unrelated to the level of vagal
+ activity, but may be attributable to enhanced enzymatic inactivation of catecholamines."
+
+
+
+ Acta Physiol Scand 1976 Jun;97(2):158-65. Effects of respiratory alkalosis and acidosis on
+ myocardial excitation. Samuelsson RG, Nagy G. In anesthetized dogs electrocardiogram and
+ monophasic action potentials (MAPs) were recorded from the right atrium and the right ventricle by
+ intracardiac suction electrode technique. The animals were subjected, by means of ventilation with CO2 and
+ hyperventilation, to periods of respiratory acidosis and respiratory alkalosis, respectively.
+ Pronounced respiratory acidosis induced an increased sympathetic activity
+
+ followed by a decrease in heart rate and prolongation of the A-V conduction time whereas the shape and
+ duration of the atrial and ventricular MAPs remained unaltered. Arterial hypoxia in combination with
+ pronounced respiratory acidosis did not influence the MAP durations. Respiratory
+ alkalosis resulted in an increased sympathetic influence on the heart activity whereas the
+ shape and duration of the atrial and the ventricular MAPs remained unaffected. During pronounced
+ hyperventilation with increasing central venous pressure an increased parasympathetic influence
+
+ on the heart activity with decrease in the heart rate, prolongation of the A-V conduction time and
+ shortening of the atrial MAP duration was recorded.
+
+
+
+ Biull Eksp Biol Med 1978 Nov;86(11):525-8. [Effect of neuromediators on acid-base status].
+ [Article in Russian] Lazareva LV, Bazarevich GI, Makarova LV. A relationship between the state of
+ adrenergic, cholinergic, and serotoninergic systems, on the one hand, and the acid-alkaline balance of the
+ organism, on the other hand, was revealed in sharp and chronic experiments on dogs. A surplus of each of the
+ mediators was accompanied by respiratory alkalosis, and its deficiency--by combined respiratory and
+ metabolic acidosis.
+
+
+ Can J Physiol Pharmacol 1987 May;65(5):1078-85. Pathophysiology of pH and Ca2+ in bloodstream and
+ brain. Somjen GG, Allen BW, Balestrino M, Aitken PG. The highlights of the literature and our
+ work on tetany and hyperventilation are reviewed. Our studies concern the following: (1) the changes of
+ [Ca2+] in circulating plasma caused by respiratory and "metabolic" acidosis and alkalosis; (2) critical
+ plasma [Ca2+] levels associated with signs of tetany and neuromuscular blockade; (3) changes in cerebral
+ [Ca2+]o caused by hypo- and hyper-calcaemia, and the changes in cerebral [Ca2+]o and pHo caused by acute
+ systemic acidosis and alkalosis; and (4) effects of changing [Ca2+]o and pHo levels on synaptic transmission
+ in hippocampal formation. Our main conclusions are (1) changes of plasma [Ca2+] caused by "metabolic" pH
+ changes are greater than those associated with varying CO2 concentration; (2) acute systemic [Ca2+] changes
+ are associated with small cerebral [Ca2+]o changes; (3) the decreases in systemic and cerebral [Ca2+]o
+ caused by hyperventilation are too small to account for the signs and symptoms of hypocapnic tetany; (4)
+ moderate decrease of [Ca2+]o depresses and its increase enhances synaptic transmission in
+ hippocampal formation; and (5) H+ ions in extracellular fluid have a weak depressant effect on neuronal
+ excitability. CO2 is a strong depressant, which is only partly explained by the acidity of its solution.
+ CO2 concentration is a significant factor in controlling cerebral function.
+
+
+ J Hirnforsch 1991;32(5):659-664. Normalization of protein synthesis and the structure of brain
+ dystrophic neurons after the action of hypoxia, 10% NaCl and organ-specific RNA. Polezhaev LV,
+ Cherkasova LV, Vitvitsky VN, Timonin AV N. I. Vavilov Institute of General Genetics, USSR Academy of
+ Sciences, Moscow. It was shown previously (Polezhaev and Alexandrova, 1986) that hypoxic hypoxia causes mass
+ (up to 30%) diffuse dystrophy of brain cortex and hippocamp neurons in rats, disturbances in the higher
+ nervous activity, reduction of protein, RNA synthesis in neurons and of DNA synthesis in the whole brain
+ cortex. Transplantation of embryonic nervous tissue (ENT) in one of the hemispheres normalizes all the above
+ abnormalities observed in some neurologic and mental diseases in humans. However, transplantation may entail
+ injuries of parenchyma and brain blood vessels. This forces researchers to search for another biological
+ method similar by its action but safer and simpler. ENT transplantation has a dual action: 1) formation of
+ biologically active substances (BAS) releasing from the ENT transplant and from the host brain nervous
+ tissue upon operation; 2) establishment of synaptic connections between the transplant and host neurons.
+ Previously we (Vitvitsky, 1987) described the isolation of BAS from rat forebrain in the form of
+ organ-specific RNA. The latter was injected intraperitoneally several times to post-hypoxic rats in which 30
+ min prior to that the blood-brain barrier (BBB) was opened by injecting intravenously and intraperitoneally
+ 10% NaCl solution without damaging the host brain. At the beginning 10% NaCl increased the destruction of
+ brain cortical neurons and then stimulated protein synthesis in them. RNA injections stimulated the
+ synthesis in cortical neurons and normalized their structure. Thus, we propose a safe and simple method for
+ normalization of dystrophic neurons which can be used after certain improvement for curing neurodegenerative
+ and neuropsychic diseases in humans.
+
+
+
+ Group processes
+
+
+ The trouble with writing and painting is that they are considered to be solitary and individualistic
+ activities. In the 20th century, the idea developed that they were "expressive," rather than communicative,
+ as if there could be any sane distinction between those. The result was that much of 20th century poetry and
+ painting was insane. The products of insanity aren"t necessarily worthless, but they are less than they
+ could be.
+
+
+
+ When the writer and painter are in close contact with responsive people, their product is adjusted to, and
+ enriched by, the reactions they evoke.
+
+
+ J Cardiovasc Pharmacol 1987;10 Suppl 2:S94-8; discussion S99. The effect of beta-blockade on
+ platelet function and fibrinolytic activity. Winther K. Department of Clinical Chemistry,
+ Rigshospitalet, Copenhagen, Denmark. Two groups of hypertensives and a group of migraine sufferers were
+ tested during treatment with the nonselective beta-blocker propranolol and the beta 1-selective metoprolol.
+ During treatment with propranolol, an increased platelet aggregability and a decrease in platelet content of
+ cyclic AMP were seen when compared with metoprolol treatment. In addition, propranolol treatment increased
+ the plasma level of adrenaline as well as the euglobulin clot lysis time. types of monoamine oxidase,
+ adrenaline
+
+
+
+ 45: Br J Pharmacol 1982 Feb;75(2):269-86
+
+
+ Coronary vasoconstrictor and vasodilator actions of arachidonic acid in the
+
+ isolated perfused heart of the rat.
+
+ Belo SE, Talesnik J.
+
+
+ The administration of arachidonic acid (AA) to the isolated perfused heart of
+
+
+ the rat usually produced biphasic coronary responses characterized by initial
+
+
+
+ vasoconstriction followed by prolonged vasodilatation. However, some responses
+
+
+ were predominantly vasoconstrictor or vasodilator. The non-steroidal
+
+
+ anti-inflammatory agents (NSAA) indomethacin (1-5 mg/l) and naproxen (12.5-25
+
+
+ mg/1) reversibly inhibited both phases of the response induced by AA.
+
+
+ Pretreatment of animals with indomethacin (5 mg/kg) or naproxen (25 mg/kg)
+
+
+ daily, resulted in unaltered coronary response to AA. Subsequent addition of
+
+
+
+ NSAA to the perfusate produced inhibition of the AA effect. Short infusions of
+
+
+ acetylsalicylic acid at low concentrations (2.9 micrograms/ml), dipyridamole
+
+
+ (0.6 micrograms/ml) and sulphinpyrazone (28.7 micrograms/ml) selectively
+
+
+ inhibited the vasoconstrictor phase of the response to AA. It was confirmed that
+
+
+ metabolic coronary dilatation induced by cardiostimulation was inhibited by
+
+
+ prolonged AA administration; this effect was prevented by NSAA pretreatment.
+
+
+
+ Reactive hyperaemic responses to short lasting occlusions of coronary inflow
+
+ were unaffected by NSAA. Linolenic, linoleic, dihomo-gamma-linolenic and oleic
+ acid usually produced decreases in coronary flow which were unaffected by NSAA,
+ dipyridamole or sulphinpyrazone. Intra-aortic injections of AA, prostacyclin
+ (PGI2) and prostaglandin E2 (PGE2) in the intact rat produced a dose-dependent
+ decrease in blood pressure with the AA response inhibited by indomethacin. PGI2
+
+
+ and PGE2 produced long lasting coronary vasodilatation in the isolated heart.
+
+
+ The coronary actions of AA appear to be due to its transformation, within the
+
+
+ easily accessible vascular wall, into prostaglandin and thromboxane-like
+
+ substances. We suggest that a vasoconstrictor thromboxane A2-like substance may
+ be responsible for coronary vasospasm. Coronary insufficiency may also result
+ from an inhibition of compensatory metabolic coronary dilatation by increased
+
+ synthesis of PGE2 within the myocardial cell.
+
+ 42: Br Heart J 1983 Jan;49(1):20-5
+
+ Platelet reactivity and its dependence on alpha-adrenergic receptor function in
+ patients with ischaemic heart disease.
+
+ Yokoyama M, Kawashima S, Sakamoto S, Akita H, Okada T, Mizutani T, Fukuzaki H.
+
+
+ We studied 57 patients admitted to hospital with ischaemic heart disease,
+
+
+
+ including nine patients with variant angina, to evaluate platelet reactivity and
+
+
+ its dependence on alpha-adrenergic receptor function. The threshold
+
+
+ concentration for biphasic platelet aggregation in response to adrenaline and
+
+
+ adenosine diphosphate was measured in fresh platelet rich plasma. There were age
+
+
+ related alterations in platelet responsiveness to adrenaline. In 27 age matched
+
+
+ control subjects platelets showed adrenaline induced aggregation at a
+
+
+
+ concentration higher than 0.1 mumol. The threshold concentrations for adrenaline
+
+
+ and adenosine diphosphate were 0.91 mumol and 4.68 mumol. In 16 patients with
+
+
+ acute infarction, 14 with old infarction, nine with effort angina, and nine with
+
+
+ rest angina, mean values of platelet aggregation threshold for both adrenaline
+
+
+ and adenosine diphosphate were not altered significantly when compared with
+
+
+ control subjects. In contrast, the values for adrenaline and adenosine
+
+
+
+ diphosphate in nine patients with variant angina were 0.012 mumol and 2.24 mumol
+
+
+ and seven of them showed obvious platelet hyperactivity to adrenaline at a concentration lower than 0.1
+ mumol. The threshold concentration for adrenaline induced aggregation did not correlate with serum
+ cholesterol and triglyceride
+
+
+ levels.
+
+
+ Am Heart J 1985 Jun;109(6):1264-8. Reduction of plasma norepinephrine levels in response to brief coronary
+ occlusion in experimental dogs. Haneda T, Arai T, Kanda H, Ikeda J, Takishima T. Although an increased
+ plasma norepinephrine (NE) level is sometimes observed
+
+
+ during angina pectoris, it is difficult to say whether sympathetic overflow is
+
+
+
+ its cause. The left anterior descending coronary artery was occluded by
+
+
+ intracoronary balloon for 3 minutes in 12 closed-chest anesthetized dogs. During
+
+
+ occlusion, heart rate did not change but aortic pressure slightly decreased.
+
+
+ Occlusion caused a significant reduction in both NE levels in the aorta (177 +/-
+
+
+ 17 to 134 +/- 16 pg/ml, p less than 0.01) and in the great cardiac vein (GCV)
+
+
+ 296 +/- 44 to 249 +/- 44 pg/ml, p less than 0.01). After surgical vagotomy, the
+
+
+
+ occlusion increased NE levels in the aorta (227 +/- 44 to 278 +/- 43 pg/ml, p
+
+
+ less than 0.01) and in GCV (384 +/- 76 to 444 +/- 81 pg/ml, p less than 0.01),
+
+
+ showing the release of vagal inhibition. These results may be applicable to
+
+ patients with transient anterior myocardial ischemia; if plasma NE increases
+ without marked hemodynamic changes, it is suggested that the sympathetic
+ overflow is not a result but a possible cause of the ischemia.
+
+
+ 25: Exp Mol Pathol 1986 Apr;44(2):138-46
+
+ Intimal thickening and the distribution of vasomotor nerves in the mechanically
+ injured dog coronary artery.
+
+ Taguchi T, Ishii Y, Matsubara F, Tanaka K.
+
+
+ Intimal injury and atherosclerotic change seem to be causative factors linked to
+
+
+ spasm of the coronary artery. Intimal thickening was produced by mechanical
+
+
+
+ injury to the endothelium of the canine coronary artery and we investigated the
+
+
+ distribution of adrenergic, cholinergic, and peptidergic nerves in the coronary
+
+
+ arteries. Although adrenergic and cholinergic nerves were not altered in
+
+ density, neuron specific enolase positive nerve fibers were increased in number
+ in dogs killed 1 and 3 months after injury. Substance P-containing fibers were
+
+ also increased at 3 months after the induced injury.
+
+
+ 24: J Am Coll Cardiol 1986 Jul;8(1 Suppl A):42A-49A
+
+ Mechanisms of coronary spasm of isolated human epicardial coronary segments
+ excised 3 to 5 hours after sudden death.
+
+ Vedernikov YP.
+
+
+ Isolated segments of epicardial coronary artery with and without severe
+
+
+
+ atherosclerotic lesions excised from human hearts 3 to 5 hours after sudden
+
+
+ coronary death demonstrated spontaneous contractile activity that was dependent
+
+
+ on the external calcium level and was inhibited by calcium antagonists and
+
+
+ activation of beta-adrenoceptors (isoproterenol and high concentrations of
+
+
+ norepinephrine). Isoproterenol, with a median effective dose (ED50) of 6.3 X
+
+
+ 10(-7) M, relaxed coronary segments that had been precontracted with 30 mM
+
+
+ potassium. Stimulation of the alpha-adrenoceptors activated spontaneous
+ contractions and increased tension. Norepinephrine ED50 (in the presence of
+ 10(-6) M propranolol) was 2.3 X 10(-7) M, and tension at a maximal concentration
+ of 10(-4) M was 385.4 +/- 51.4 mg. The ED50 for acetylcholine and histamine, the
+ potent activators of coronary segment tone and phasic contractility, was 3.98 X
+
+ 10(-7) and 8.9 X 10(-7) M, respectively; the maximal increase in tension was
+
+
+
+ 1,079.5 +/- 175 (at 10(-4) M) and 1,131.3 +/- 302 mg (at 10(-5) M),
+
+
+ respectively. Acetylcholine and histamine increased whereas high concentrations
+
+
+ of norepinephrine failed to inhibit rhythmic activity and tension of coronary
+
+
+ artery segments with severe atherosclerotic lesions. Membrane electrogenic
+
+
+ mechanisms and ways of activating the contractile elements of human coronary
+
+
+ artery smooth muscle are discussed.
+
+
+
+ Pharmacol Rev 2000 Dec;52(4):595-638. The sympathetic nerve--an integrative interface between two
+ supersystems: the brain and the immune system. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES.
+ Inflammatory Joint Diseases Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and
+ Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA. The brain and the
+ immune system are the two major adaptive systems of the body. During an immune response the brain and the
+ immune system "talk to each other" and this process is essential for maintaining homeostasis. Two major
+ pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the
+ sympathetic nervous system (SNS). This overview focuses on the role of SNS in neuroimmune interactions, an
+ area that has received much less attention than the role of HPA axis. Evidence accumulated over the last 20
+ years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in
+ lymphoid organs. Thus, primary and secondary lymphoid organs receive extensive
+ sympathetic/noradrenergic innervation. Under stimulation, NE is released from the sympathetic nerve
+ terminals in these organs, and the target immune cells express adrenoreceptors. Through stimulation of these
+ receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte
+ traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of
+ different lymphoid cells. Although there exists substantial sympathetic innervation in the bone
+ marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the
+ sympathetic neural input on
+ hematopoiesis, thymocyte development, and mucosal immunity is extremely modest. In addition,
+ recent evidence is discussed that NE and epinephrine, through stimulation of the
+ beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory
+ cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by
+ antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type
+ 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta. Through
+ this
+ mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses
+ and cellular immunity, and a Th2 shift toward dominance of humoral immunity. On the other hand, in
+ certain local responses, and under certain conditions, catecholamines may actually boost regional
+ immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8
+ production. Thus, the activation of SNS during an immune response might be
+ aimed to localize the inflammatory response, through induction of neutrophil accumulation and
+ stimulation of more specific humoral immune responses, although systemically it may suppress Th1
+ responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and
+ other products of activated macrophages.
+
+ The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the
+ context of their clinical implication in certain infections, major injury and sepsis, autoimmunity,
+ chronic pain and fatigue syndromes, and tumor growth.
+ Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new
+ therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and
+ inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases,
+ fibromyalgia, and chronic fatigue syndrome.
+
+
+ Am J Physiol Cell Physiol 2000 Nov;279(5):C1665-74.
+ beta-adrenergic receptor/cAMP-mediated signaling and apoptosis of S49 lymphoma cells. Yan L,
+ Herrmann V, Hofer JK, Insel PA. Department of Pharmacology, University of California, San Diego, La Jolla,
+ California 92093-0636, USA.
+ beta-Adrenergic receptor (betaAR) activation and/or increases in cAMP regulate growth and proliferation
+ of a variety of cells and, in some cells, promote cell death. In the current studies we addressed the
+ mechanism of this growth reduction
+
+ by examining betaAR-mediated effects in the murine T-lymphoma cell line S49. Wild-type S49 cells, derived
+ from immature thymocytes (CD4(+)/CD8(+)) undergo growth arrest and subsequent death when treated with agents
+ that increase cAMP levels (e.g., betaAR agonists, 8-bromo-cAMP, cholera toxin, forskolin). Morphological and
+ biochemical criteria indicate that this cell death is a result of apoptosis. In cyc(-) and kin(-) S49 cells,
+ which lack G(s)alpha and functional protein kinase A (PKA), respectively, betaAR activation of G(s)alpha and
+ cAMP action via PKA are critical steps in this apoptotic pathway. S49 cells that overexpress Bcl-2 are
+ resistant to cAMP-induced apoptosis. We conclude that betaAR activation induces apoptosis in immature T
+ lymphocytes via G(s)alpha and PKA, while overexpression of Bcl-2 prevents cell death.
+ betaAR/cAMP/PKA-mediated apoptosis may provide a means to control proliferation of immature T cells in vivo.
+
+
+
+ Carcinogenesis 2001 Mar;22(3):473-9. Beta-adrenergic growth regulation of human cancer cell lines
+ derived from pancreatic ductal carcinomas. Weddle DL, Tithoff P, Williams M, Schuller HM.
+ Carcinogenesis and Developmental Therapeutics Program, College of Veterinary Medicine, University of
+ Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. Exocrine ductal carcinoma of the pancreas has been
+ associated with smoking, and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
+ (NNK) causes this cancer type in laboratory rodents. Current knowledge on the growth regulation of this
+ malignancy is extremely limited. Recent studies have shown overexpression of cyclooxygenase 2 (COX 2) and
+ 5-lipoxygenase (5-lipox) in exocrine pancreatic carcinomas, suggesting a potential role of the
+ arachidonic acid (AA) cascade in the regulation of this cancer type. In support of this interpretation,
+ our data show high basal levels of AA release in two human cell lines derived from exocrine ductal
+ pancreatic carcinomas. Both cell lines expressed m-RNA for beta2-adrenergic receptors and
+ beta1-adrenergic receptors. Radio-receptor assays showed that beta2-adrenergic receptors predominated over
+ beta1-adrenergic receptors. beta2-Adrenergic antagonist ICI118,551 significantly reduced basal AA
+ release and DNA synthesis when the cells were maintained in complete medium. DNA synthesis of
+ the cell line (Panc-1) with an activating point mutation in codon 12 of the ki-ras gene was significantly
+ stimulated by NNK when cells were maintained in complete medium and this response was inhibited by
+ the beta-blocker ICI118,551, the COX-inhibitor aspirin, or the 5-lipox-inhibitor MK-886. The
+ cell line without ras mutations (BXPC-3) did not show a significant response to NNK in complete medium. When
+ the assays were conducted in serum-free medium, both cell lines demonstrated increased DNA synthesis in
+ response to NNK, an effect inhibited by the beta2-blocker, aspirin, or MK-886. Panc-1 cells were more
+ sensitive to the stimulating effects of NNK and less responsive to the inhibitors than BXPC-3 cells. Our
+ findings are in accord with a recent report which has identified NNK as a beta-adrenergic agonist and
+ suggest beta-adrenergic, AA-dependent regulatory pathways in pancreatic cancer as a novel target for cancer
+ intervention strategies.
+
+
+ Shock 2000 Jul;14(1):60-7. Terbutaline prevents circulatory failure and mitigates mortality in rodents with
+ endotoxemia. Wu CC, Liao MH, Chen SJ, Chou TC, Chen A, Yen MH. Department of Pharmacology, National Defense
+ Medical Center, Taipei, ROC, Taiwan. Septic shock is characterized by a decrease in systemic vascular
+ resistance. Nevertheless, regional increases in vascular resistance can occur that may
+ predispose mammals to organ dysfunction, including the acute respiratory distress syndrome. In
+ the host infected by endotoxin (lipopolysaccharide, LPS), the expression and release of proinflammatory
+ tumor necrosis factor-alpha (TNFalpha) rapidly increases, and this cytokine production is regulated by
+ agents elevating cyclic AMP. In this report, we present evidence that
+ terbutaline, a beta2-agonist, inhibits TNFalpha production and enhances interleukin-10 (IL-10) release
+ in the anesthetized rat treated with LPS. In addition, an overproduction of nitric oxide (NO, examined
+ by its metabolites nitrite/nitrate) by inducible NO synthase (iNOS, examined by western blot analysis)
+ is attenuated by pretreatment of LPS rats with terbutaline. Overall, pretreatment of rats with
+ terbutaline attenuates the delayed hypotension and prevents vascular hyporeactivity to norepinephrine. In
+ addition, pretreatment of mice with terbutaline also improves the survival in a model of severe endotoxemia.
+ The infiltration of polymorphonuclear neutrophils into organs (e.g., lung and liver) from the surviving LPS
+ mice treated with terbutaline was reduced almost to that seen in the normal controls. These findings suggest
+ that the inhibition of TNFalpha and NO (via iNOS) production as well as the increment of IL-10 production
+ contribute to the beneficial effect of terbutaline in animals with endotoxic shock.
+
+
+ Ann Endocrinol (Paris) 1977;38(6):421-6. [Hyperestrogenism in the woman during the reproductive period].
+ [Article in French] Kuttenn F.
+
+
+ Br J Obstet Gynaecol 1976 Aug;83(8):593-602. Polycystic ovarian disease. Duignan NM.
+ Sex hormone binding globulin (SHBG) capacity was reduced in 9 of 31 patients with polycystic ovarian
+ (PCO) disease and the mean level in PCO patients was significantly less (p less than 0.001) than normal.
+ Serum testosterone levels
+
+
+ suggested that the normal cyclical release of LH is inhibited in PCO
+ disease by a negative feedback by androgens to the hypothalamus or the pituitary, and that wedge
+ resection should be reserved for patients in whom other forms of treatment have failed.
+
+
+
+ Nouv Presse Med 1976 Apr 10;5(15):975-9. [Secretion of gonadotropins during sleep. Changes during secondary
+ amenorrheas]. [Article in French] Passouant P, Crastes de Paulet A, Descomps B, Besset A, Billiard M. 4
+ females with secondary amenorrheas underwent sleep polygraphic recordings together with blood samples for
+ measurements of LH, FSH and GH, 3 normal females served as controls. Among normal subjects LH and FSH
+ secretion showed a pulsating pattern around the time of ovulation, appearing as secretory episodes
+ throughout the night, without any relationship with sleep stages. In amenorrheas, 3 types of abnormalities
+ could be identified: the first was a lack
+ of secretory episodes of LH and FSH associated with an abnormal pattern of GH (9 subjects). The second
+ was an hypersecretion of LH and a decrease of FSH secretion together with a normal secretion of GH in 4
+ subjects with a Stein-Leventhal syndrome. The last one was an hypersecretion of LH and FSH
+ together with a normal pattern of GH in a subject with an early menopause. These results are discussed
+ according to the present data on the part of neurotransmission in the regulation of ovulation and the 2
+ types of sleep. Furthermore secretory abnormalities of LH and FSH together with a disconnection between GH
+ secretion and the stages of sleep lead to question the possibility of interrelationships in the secretory
+ mechanisms of these different hormones.
+
+
+
+ Am J Epidemiol 1991 Oct 15;134(8):818-24. Comment in: Am J Epidemiol. 1992 Aug 1;136(3):372-3. Polycystic
+ ovaries and the risk of breast cancer. Gammon MD, Thompson WD. Division of Epidemiology, Columbia University
+ School of Public Health, New York, NY. Data from a case-control study that was conducted between 1980 and
+ 1982 were analyzed to investigate the possible association between polycystic ovaries and the risk of breast
+ cancer. The multicenter, population-based study included in-home interviews with 4,730 women with breast
+ cancer and 4,688 control women
+ aged 20-54 years. The age-adjusted odds ratio for breast cancer among women with a self-reported history
+ of physician-diagnosed polycystic ovaries was 0.52 (95% confidence interval 0.32-0.87). The inverse
+ association was not an artifact of infertility, age at first birth, or surgical menopause. Because women
+ with this syndrome have abnormal levels of certain endogenous hormones, the observation of a low risk of
+ breast cancer in this group may provide new insights into hormonal influences on breast cancer.
+
+
+ Clin Endocrinol (Oxf) 1996 Mar;44(3):269-76. Polycystic ovaries in pre and post-menopausal women. Birdsall
+ MA, Farquhar CM. Department of Obstetrics and Gynaecology, National Women's Hospital, Auckland, New
+ Zealand.
+ OBJECTIVE: Polycystic ovaries have been diagnosed in more than 20% of premenopausal women using
+ ultrasound. The aim of this study was to determine whether polycystic ovaries exist in post-menopausal
+ women. DESIGN: Two groups of women were studied; group 1 consisted of 18 post-menopausal
+ volunteers and group 2 comprised 142 women, 94 of whom were post-menopausal who had recently undergone
+ coronary angiography. MEASUREMENTS: Transabdominal and transvaginal ultrasound scans were performed and
+ measurements made of uterine area, endometrial thickness and ovarian volume. The morphological appearance of
+ the ovaries was also noted. Fasting blood samples were taken. Medical and menstrual questionnaires were
+ completed. RESULTS: Polycystic ovaries were found in 8/18
+ (44%) of group 1 and 60/142 (42%) in group 2. Polycystic ovaries were detected in 35/94 (37%) of the
+ post-menopausal women in group 2. Post-menopausal women with polycystic ovaries had larger ovaries
+ containing more follicles compared with post-menopausal women with normal ovaries. Post-menopausal women
+ with polycystic ovaries had higher serum concentrations of testosterone and triglycerides than
+ had post-menopausal women with normal ovaries. CONCLUSIONS: Polycystic ovaries can be detected in
+ post-menopausal women and have some of the same endocrine abnormalities which are evident in premenopausal
+ women with polycystic ovaries, that is, raised serum concentrations of testosterone and triglycerides.
+
+
+ Cancer Causes Control 1996 Nov;7(6):605-25. Comment in: Cancer Causes Control. 1996 Nov;7(6):569-71.
+ Nutrition, hormones, and breast cancer: is insulin the missing link? Kaaks R. International Agency for
+ Research on Cancer, Lyon, France. Breast cancer incidence rates are high in societies with a Western
+ lifestyle characterized by low levels of physical activity, and by an energy-dense diet rich in total and
+ saturated fat and refined carbohydrates. Epidemiologic studies, so far mostly on postmenopausal women, have
+ shown that breast cancer risk is increased in hyperandrogenic women, with decreased levels of plasma
+ sex-hormone binding globulin, and with increased levels of testosterone and of free estrogens. This paper
+ describes the role of hyperinsulinemia as a hysiologic link between nutritional lifestyle factors, obesity,
+ and the development of a hyperandrogenic endocrine profile, and reviews evidence that may or may not support
+ the theory that chronic hyperinsulinemia is an underlying cause of breast cancer. An hypothesis is
+ presented, stipulating that breast cancer risk is increased not only in hyperandrogenic postmenopausal
+ women, but also in premenopausal women with mild hyperandrogenism and normal (ovulatory) menstrual cycles.
+ The author suggests further investigation as to whether there is a positive association between risk of
+ breast cancer before menopause and ubclinical forms of the polycystic ovary syndrome (PCOS), and to what
+ extent iet and physical activity during childhood, by modulating the degree of insulin esistance during
+ adolescence, may or may not be determinants of a PCO-like hyperandrogenic endocrine profile persisting into
+ adulthood.
+
+
+
+ Akush Ginekol (Mosk) 1990 Sep;(9):61-3. [The therapeutic effect of parlodel in the polycystic ovary
+ syndrome]. [Article in Russian] Soboleva EL, Komarov EK, Potin VV, Svechnikova FA. Parlodel (2.5-50 mg/day)
+ has been given for 1 to 7 days to 33 patients with the polycystic ovary syndrome (POS). The ovulatory
+ menstrual cycle returned in 10 (30%) patients and 4 of them conceived. Pretreatment cycle disturbance
+ persisted in 6 (18%) patients. Parlodel reduced mid-follicular mean blood LH levels to
+ values of normal women. Some decrease in blood testosterone levels occurred only in the second phase of the
+ cycle. Estradiol test in 6 patients showed normal positive and negative feedbacks in the
+ hypothalamic-pituitary-ovarian axis. Parlodel treatment reduced basal and estradiol stimulated pituitary
+ gonadotropin secretion. It is suggested that parlodel may be used in ovulation induction in a proportion of
+ POS patients.
+
+
+ polycystic menopausal sympathetic estrogen parasympathetic, antimitochondrial, both can have a protective
+ function, though in excess the inhibition itself is toxic.
+
+
+
+ Mast cells: hair growth, angiogenesis, cancer, MS, asthma. Nervous control of insulin,7:
+
+
+ Am J Obstet Gynecol 1993 Nov;169(5):1223-6. Comment in: Am J Obstet Gynecol. 1994 Dec;171(6):1673 Excessive estradiol secretion in polycystic ovarian disease. Benjamin F, Toles AW, Seltzer VL,
+ Deutsch S. Department of Obstetrics and Gynecology, Queens Hospital Center, Jamaica, NY 11432. Polycystic
+ ovarian disease is both a hyperestrogenic and a hyperandrogenic syndrome, and all studies have shown that
+ hyperestrogenemia is the result of an elevation of estrone with plasma estradiol levels in the normal
+ follicular range. Because a literature search failed to reveal any report of polycystic ovarian disease with
+ significantly elevated estradiol levels, we report a case in which the plasma estradiol was so massively
+ elevated as to mimic an estrogen-producing neoplasm. This case also suggests that although polycystic
+ ovarian disease is a very rare cause of such excessive estradiol production, it should be included in the
+ differential diagnosis of estrogen-producing neoplasms.
+
+
+ Nephron 1983;33(4):253-6. Influence of inhibitor of glucose utilization on the blood platelet
+ function.
+ Tison P, Kubisz P, Cernacek P, Dzurik R. The inhibition of glycolysis by an inhibitor of
+ glucose utilization isolated from urine of the uremic subjects reflects in: (1) decreased platelet
+ aggregation induced by adenosine diphosphate, adrenaline, or collagen,
+ respectively; (2) decreased platelet factor 4 release induced by the same inductors; (3) decreased
+ availability of platelet factor 3, and (4) inhibition of retraction of reptilase clot. It is concluded that
+ the inhibition of glycolysis by 'inhibitor of glucose utilization' contributes to the functional changes of
+ platelets and thus to the alteration of hemostasis in uremic patients.
+
+
+ Energy: vasodilate, bronchoconstrict, secrete/leak, swell, grow, tumefy. Invasion by sympathetic balances
+ the chronic stimulation by mast cells, platelets, pituitary hormones, locally formed estrogen, and the other
+ mediators of stress.
+
+
+ Res Exp Med (Berl) 1987;187(5):385-93. Possible interaction of platelets and adrenaline in the early
+ phase of myocardial infarction. Seitz R, Leising H, Liebermann A, Rohner I, Gerdes H, Egbring
+ R. It is known that in most cases of transmural acute myocardial infarction a platelet clot
+ originates within a coronary artery. In acute myocardial infarction patients increased levels of the
+ plasma catecholamines adrenaline and noradrenaline as well as the platelet release proteins platelet
+ factor 4 and beta-thromboglobulin have been reported.
+
+
+
+
+
+ Jpn Heart J 1979 Jan;20(1):75-82. Inhibition of constrictor responses of dog coronary artery by
+ atropine. A possible effectiveness of atropine on variant form of angina pectoris. Sakanashi M,
+ Furukawa T, Horio Y. A possible effectiveness of atropine on variant form of angina pectoris was
+ investigated using the left circumflex coronary arterial strips of dogs. Acetylcholine 10(-5)--10(-3) Gm/ml
+ dose-dependently constricted the isolated arterial strips during potassium-contracture in 6 cases, and
+ repetitive applications of acetylcholine could produce the similar contractions to the control. In 18 strips
+ atropine 10(-6) Gm/ml significantly depressed the contractions of coronary arteries induced by acetylcholine
+ 10(-5)--10(-3) Gm/ml. In 5 arterial strips atropine 10(-6) Gm/ml
+ significantly inhibited norepinephrine-induced responses of these arteries, and by 10(-5) Gm/ml
+ further suppression of the responses was obtained. The results suggest that atropine may suppress
+ the contractile responses of the coronary artery induce by acetylcholine and nonrepinephrine through a
+ muscarinic-receptor blocking action and simultaneously partly through an adrenergic alpha-receptor
+ blocking action.
+
+
+ Eur J Clin Pharmacol 1981;20(4):245-50. Effect of long-term beta-blockade with alprenolol on
+ platelet function and fibrinolytic activity in patients with coronary heart disease. Jurgensen
+ HJ, Dalsgaard-Nielsen J, Kjoller E, Gormsen J. In 14 patients with coronary heart disease the effect of
+ long-term treatment (mean 16 months, range 12-33) with alprenolol on platelet function and fibrinolytic
+ activity was studied. While on the beta-blocker and two weeks after gradual withdrawal of it, the patients
+ performed a bicycle-ergometer test and blood samples were obtained before and following exercise.
+ Pre-exercise fibrinolytic activity, assessed by the euglobulin clot lysis time, was 183 +/- 27 min (mean +/-
+ SEM) while on alprenolol as compared to 111 +/- 18 min (p less than 0.01) after its withdrawal. Activation
+ of fibrinolysis following exercise was not significantly influenced by alprenolol. In patients treated with
+ alprenolol, the pre-exercise threshold level of ADP, producing platelet aggregation was 3.3 muM (geometric
+ mean) and 5.1 muM after stopping treatment (p less than or equal to 0.05). In patients receiving the
+ beta-blocker, the ADP- threshold value dropped from 3.3 muM before exercise to 2.3 muM immediately after
+ exercise (not significant). The corresponding values after withdrawal of alprenolol were 5.1 muM and 2.7 muM
+ (p less than or equal to 0.02). Adrenaline - stimulated aggregation was not significantly influenced by
+ alprenolol. Serotonin release from platelets following maximal ADP- and adrenaline stimuli was not
+ significantly changed by exercise in patients on beta-blockade. After stopping treatment, ADP-induced
+ serotonin release was 22 +/- 4.1% before and 15 +/- 4.7% after exercise (p less than 0.02). the
+ corresponding values using the adrenaline stimulus were 29 +/- 5.7% and 17 +/- 4.7% (p less than 0.05). It
+ is suggested that during physical stress alprenolol may protect platelets against aggregatory stimuli.
+
+
+ C R Seances Soc Biol Fil 1987;181(3):242-8.
+ [Adrenaline activates oxidative phosphorylation of rat liver mitochondria through alpha
+ 1-receptors].
+ Breton L, Clot JP, Bouriannes J, Baudry M. We studied the effects and mode of action of epinephrine on the
+ oxidative phosphorylation of rat liver mitochondria. With either succinate or beta-hydroxybutyrate as
+ substrate, i.v. injection of 1.5 microgram/100 g epinephrine increased the respiratory rates by 30-40% in
+ state 3 (with ADP), and by 20-30% in state 4 (after ADP phosphorylation), so that the respiratory control
+ ratio (state 3/state 4) changed little. The respiratory stimulation by epinephrine was maximal 20 minutes
+ after its injection. The action of epinephrine on mitochondria was blocked by pretreatment of the animals
+ with the alpha 1-antagonist prazosin but not by treatment with the beta-antagonist propranolol. I. v.
+ injection of 10 micrograms/100 g phenylephrine evoked the same mitochondrial response as epinephrine. I. v.
+ administration of 50 micrograms/100 g dibutyryl cyclic AMP enhanced glycaemia but did not affect
+ mitochondrial respiration. Epinephrine therefore has an alpha 1-type of action on mitochondrial oxidative
+ phosphorylation.
+
+
+
+ Biochimie 1975;57(6-7):797-802. Effects of catecholamines on rat myocardial metabolism. I. Influence
+ of catecholamines on energy-rich nucleotides and phosphorylated fraction contents. Merouze P,
+ Gaudemer Y. 1. The influence of catecholamines (adrenaline and noradrenaline) on energy metabolism of the
+ rat myocardium has been studied by incubating slices of this tissue with these hormones and by following the
+ levels of the different phosphorylated fractions and adenylic nucleotides. 2. Similar effects are obtained
+ with both hormones, adrenaline being more effective. 3. Catecholamines decrease significantly the
+ total amount of phosphate while Pi content increases during the first 10 minutes of incubation; labile
+ and residual phosphate contents increase at the beginning of incubation and decrease to the initial
+ values afterwards. 4. ATP and ADP levels decrease significantly with both hormones; however,
+ the effect of noradrenalin on the ATP level needs a longer time of incubation.
+ The ATP/ADP ratios decrease after 5 minutes incubation and the total adenylic nucleotide content is
+ severely decreased (35 per cent with adrenalin, after 20 minutes incubation). 5. Similar results have
+ been obtained with other tissues; these results can explain the decrease of aerobic metabolism we
+ observed under the same conditions.
+
+
+ Eur J Pharmacol 1982 Jul 30;81(4):569-76. Actions of serotonin antagonists on dog coronary
+ artery. Brazenor RM, Angus JA. Serotonin released from platelets may initiate coronary
+ vasospasm in patients with variant angina. If this hypothesis is correct, serotonin antagonists without
+ constrictor activity may be useful in this form of angina. We have investigated drugs classified as
+ serotonin antagonists on dog circumflex coronary artery ring segments in vitro. Ergotamine,
+ dihydroergotamine,
+ bromocriptine, lisuride, ergometrine, ketanserin, trazodone, cyproheptadine and pizotifen caused
+ non-competitive antagonism of serotonin concentration-response curves. In addition, ketanserin,
+ trazodone, bromocriptine and pizotifen inhibited noradrenaline responses in concentrations similar to those
+ required for serotonin antagonism. All drugs with the exception of ketanserin, cyproheptadine and pizotifen
+ showed some degree of intrinsic constrictor activity. Methysergide antagonized responses to serotonin
+ competitively but also constricted the coronary artery. The lack of a silent competitive serotonin
+ antagonist precludes a definite characterization of coronary serotonin receptors at this time. However, the
+ profile of activity observed for the antagonist drugs in the coronary artery differs from that seen in other
+ vascular tissues. Of the
+ drugs tested, ketanserin may be the most useful in variant angina since it is a potent 5HT antagonist,
+ lacks agonist activity and has alpha-adrenoceptor blocking activity.
+
+
+
+ Arch Mal Coeur Vaiss 1983 Feb;76 Spec No:3-6.
+ Role of autonomic nervous system in the pathogenesis of angina pectoris. Yasue H. The attacks
+ of vasospastic angina or coronary spasm can be induced by injection of epinephrine, cold pressor test,
+ Valsalva maneuver, and exercise. The attacks induced by these procedures can be suppressed by injection of
+ phentolamine, an alpha adrenergic blocking agent in 80 per cent of the patients. On the other hand,
+ propranolol, a beta adrenergic blocking agent, is not only ineffective in suppressing the attacks but
+ aggravates the attacks in 50 per cent of the patients. Thus, alpha adrenergic receptors seem to play an
+ important role in the production of vasospastic angina. The attacks of vasospastic angina can also be
+ induced by injection of methacholine, a parasympathomimetic agent, and this reaction is suppressed by
+ atropine, a parasympathetic blocking agent. Thus,
+ parasympathetic nervous system also seems to play a role in the production of vasospastic angina. The
+ attacks of vasospastic angina can be easily induced by adrenergic or parasympathetic stimuli from
+ midnight to early morning but is usually not provoked by these stimuli in the daytime. Thus,
+ there is circadian variation in the reactivity of coronary arteries to adrenergic or parasympathetic
+ stimuli. There are also weekly, monthly and yearly variations of the reactivity of coronary arteries to
+ these stimuli. Thus, alpha adrenergic or parasympathetic activity is not the sole factor in the
+ production of vasospastic angina. Angina pectoris caused by increased myocardial oxygen demand
+ is induced by infusion of isoproterenol, a beta adrenergic stimulant, and is suppressed by propranolol but
+ not by phentolamine. So, beta adrenergic receptors play an important role in the production of angina
+ pectoris caused by increased myocardial oxygen demand or organic angina pectoris.
+
+
+ Nippon Yakurigaku Zasshi 1986 Mar;87(3):281-90. [Vasoconstrictor responses of isolated pig coronary
+ arteries]. [Article in Japanese] Ikenoue K, Kawakita S, Toda N.
+ In helical strips of pig coronary arteries, histamine, serotonin, acetylcholine and a stable analogue of
+ thromboxane A2 (9, 11-epithio-11, 12-methano TXA2: s-TXA2) produced a dose-dependent contraction. The
+ histamine-induced contraction was suppressed by treatment with chlorpheniramine, suggesting an
+ involvement of H1 receptors. Contractile responses to serotonin were attenuated by not only ketanserin, an
+ S2 antagonist, but also by cinanserin and methysergide. Relaxation induced by serotonin in preparations
+ treated with high concentrations of ketanserin were inhibited by cinanserin and methysergide. Norepinephrine
+ contracted coronary arteries treated with propranolol. Contractile responses to norepinephrine were reversed
+ to relaxations by prazosin, which were abolished by treatment with yohimbine. Contractile responses to
+ histamine were potentiated by treatment with low concentrations of serotonin or s-TXA2. Contractile
+ responses to serotonin were also potentiated by low concentrations of histamine or s-TXA2. Removal of the
+ endothelium from pig coronary arterial strips potentiated contractions induced by serotonin, histamine and
+ norepinephrine. These results suggest that, in addition to damaged endothelium, integrating action of
+ endogenous vasoconstrictors, including histamine, serotonin, TXA2 and norepinephrine, may play an important
+ role in producing coronary vasospasm.
+
+
+
+ Jpn Heart J 1987 Sep;28(5):649-61. The role of parasympathetic nerve activity in the pathogenesis of
+ coronary vasospasm. Suematsu M, Ito Y, Fukuzaki H. To evaluate the role of the autonomic
+ nervous system, especially the parasympathetic nervous system, in the initiation mechanism of vasospastic
+ angina pectoris (AP), the coefficient of R-R interval variation (CV) on the electrocardiogram (ECG) and
+ plasma catecholamine concentration were measured in 25 patients with vasospastic AP, 10 patients with effort
+ AP and 12 control subjects. CV which has been recognized as reflecting parasympathetic nervous system
+ activity was calculated from 100 consecutive heart beats on the ECG and represented as the percentage of
+ standard deviation of the R-R interval per mean R-R interval. Repeated measurements of plasma
+ catecholamine concentration revealed higher values at any sampling point throughout a day in patients
+ with vasospastic AP than those in
+
+ control subjects. A distinctly higher CV was observed at night in the vasospastic AP group. This
+ elevated CV was abolished by atropine sulfate (1.5 mg/day per os). Pilocarpine injection (1.3 mg/10 kg
+ B.W. subcutaneously) induced a marked increase in CV that preceded the occurrence of chest pain
+ and/or ischemic ECG changes in 5 patients with vasospastic AP. The
+ increment in CV at 10 min after pilocarpine administration was greater in vasospastic AP than in control
+ subjects (p less than 0.05). It is concluded that enhanced parasympathetic activity may play a role in
+ the initiation of coronary vasospasm associated with sympathetic hyperactivity.
+
+
+ Science 1984 Mar 30;223(4643):1435-7.
+ Coronary arteries of cardiac patients are hyperreactive and contain stores of amines: a mechanism for
+ coronary spasm. Kalsner S, Richards R. Coronary arteries from hearts of cardiac patients
+ contain significantly higher concentrations of histamine than do those from noncardiac patients. The
+ coronary vessels of cardiac patients are also hyperresponsive to histamine and serotonin. These differences
+ between groups of patients suggest an explanation for coronary artery spasm in heart disease.
+
+
+
+ Fed Proc 1985 Feb;44(2):321-5. Coronary artery reactivity in human vessels: some questions and some
+ answers. Kalsner S. Spasm of a conduit coronary artery, converting it into a major resistance
+ vessel impeding myocardial blood flow, may have severe short- or long-term effects on cardiac rhythm and
+ systolic ejection of blood. It is now clear that human coronary arteries in vitro contract to acetylcholine
+ but that relaxation is the only response observed in dog coronary vessels. Acetylcholine is as
+ powerful a constrictor of human coronary arteries, in terms of tension induced, as 5-hydroxytryptamine
+ (5-HT) or histamine and is a substantially more powerful constrictor than norepinephrine. Field
+ stimulation of coronary artery strips caused a vasoconstriction that was partially antagonized by atropine
+ (3.45 X 10(-6) M). An enhanced reactivity of the epicardial arteries of cardiac and older patients to
+ several agonists was also observed and appears to provide a background against which a number of vasoactive
+ agents might induce spasm. Coronary tissue from cardiac patients also contains stores of 5-HT and histamine,
+ and the histamine levels are substantially increased above the values in vessels from noncardiac patients.
+ Coronary artery spasm or contraction
+ probably can be initiated by diverse intrinsic and extrinsic influences, including autonomic discharge
+ from either the parasympathetic or sympathetic nervous system or from histamine or 5-HT, and probably no
+ one agent or entity is causative in all cases.
+
+
+ Ann N Y Acad Sci 1969 Oct 14;164(2):517-9. Induced carcinogenesis under various influences on the
+ hypothalamus. Kavetsky RE, Turkevich NM, Akimova RN, Khayetsky IK, Matveichuck YD.
+
+
+
+ Ann N Y Acad Sci 1966 Jan 21;125(3):933-45. On the psychophysiological mechanism of the organism's
+ resistance to tumor growth. Kavetsky RE, Turkevich NM, Balitsky KP.
+
+
+ Patol Fiziol Eksp Ter 1971 Sep-Oct;15(5):3-10. [Role of disorders in intra-cellular and neuro-humoral
+ regulation in the development of the tumor process]. [Article in Russian] Kavetskii RE, Balitskii KP.
+
+
+ Obstet Gynecol Surv 1977 May;32(5):267-81. Estrogen and endometrial carcinoma.
+ Knab DR. 1. It has become evident that the estrogen secreting tumors of the ovary are associated
+ with endometrial carcinoma, but this association is most easily observed in the postmenopausal patient where
+ the incidence of carcinoma has been
+ reported at 10.3% (1. 02) to 24% (83). 2. The most consistent association of endometrial carcinoma is
+ with polycystic ovarian disease, where 19 (34), 21 (152), and 25% (150) of young women with endometrial
+ carcinoma had Stein-Leventhal syndrome (67). 3. A very significant discovery became known in
+ 1967 when the peripheral aromatization of delta4 androstenedione to estrone was reported by Kase (94) and
+ MacDonald (111,112). Since that time we have learned that endometrial carcinoma patients have an increased peripheral conversion (139) (0.1% compared to 0.027%), which is similar to that found in obese
+ and aging patients, by Hemsell, et al (77). This can be 2 to 4 times greater than the young
+ adult or the patient without cancer. Estrone produced peripherally in normal postmenopausal women can amount
+ to 40-60 microng/day and rise as high as 120-180 microng/day in the endometrial neoplasia group (39).
+ Similarly patients with polycystic ovary disease, hyperthecosis and lipoid cell tumors of the ovary
+ demonstrate androgen excess with extraglandular conversion to estrone (2). 4. It has become apparent that
+ the principal estrogen in the postmenopausal patient is estrone and that the estrone-estradiol ratio
+ in the serum is higher in postmenopausal women with corpus cancer than similar patients without
+ cancer (135). Clearly, we must find the effect of this estrone excess at the nuclear "acceptor"
+ level; and does this imbalance create a hormonal environment conducive to the development of endometrial
+ carcinoma when age (an extremely important factor) and an oncogenic agent are added? 5. With the lack of
+ ovarian estrogen there is a relative excess of adrenal testosterone, dihydrotestosterone and delta4
+ androstenedione, the available precursors of extraglandular estrone (1). 6. With the passage of time it appears that endometrial carcinoma is associated with hypothalamic "hyperactivity"
+ (31) which exhibits immunologic-biologic dissociation of LH as previously observed in persistent
+ trophoblastic disease when measuring hCG. The significance of this is still unknown. In a like fashion a
+ significant number of the at risk polycystic ovary disease patients have an increased LH secretion. 7.
+ Patient susceptibility is required as seen in animal experiments where prolonged administration of
+ stilbestrol is used and still only rabbits and mice developed a malignant change. 8. Long term exogenous
+ estrogen appears to have caused malignant changes in the endometrium, but it was universally given over a
+ prolonged period (4 or more years). The recent retrospective studies demonstrate an association of oral
+ estrogen therapy with endometrial cancer, but prospective studies investigating dose and duration of all
+ estrogen preparations need to be undertaken. 9...
+
+
+ Endocrinology 2000 Mar;141(3):1059-72.
+ An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal
+ component of steroid-induced polycystic ovary in the rat. Lara HE, Dissen GA, Leyton V, Paredes
+ A, Fuenzalida H, Fiedler JL, Ojeda SR. A form of polycystic ovary (PCO) resembling some aspects of the human
+ PCO syndrome can be induced in rats by a single injection of estradiol valerate (EV). An increase in
+ sympathetic outflow to the ovary precedes, by several weeks, the appearance of cysts, suggesting the
+ involvement of a neurogenic component in the pathology of this ovarian dysfunction. The present study was
+ carried out to test the hypotheses that this change in sympathetic tone is related to an augmented
+ production of ovarian nerve growth factor (NGF), and that this abnormally elevated production of NGF
+ contributes to the formation of ovarian cysts induced by EV. Injection of the steroid resulted in
+ increased intraovarian synthesis of NGF and its low affinity receptor, p75 NGFR. The increase
+ was maximal 30 days after EV, coinciding with the elevation in sympathetic tone to the ovary and preceding
+ the appearance of follicular cysts. Intraovarian injections of the retrograde tracer fluorogold combined
+ with in situ hybridization to detect tyrosine hydroxylase (TH) messenger RNA-containing neurons in the
+ celiac ganglion revealed that these changes in NGF/p75 NGFR synthesis are accompanied by selective
+ activation of noradrenergic neurons projecting to the ovary. The levels of RBT2 messenger RNA, which encodes
+ a beta-tubulin presumably involved in slow axonal transport, were markedly elevated, indicating that
+ EV-induced formation of ovarian cysts is preceded by functional activation ofceliac ganglion neurons,
+ including those innervating the ovary. Intraovarian administration of a neutralizing antiserum to NGF in
+ conjunction with an antisense oligodeoxynucleotide to p75 NGFR, via Alzet osmotic minipumps,
+ restored estrous cyclicity and ovulatory capacity in a majority of EV-treated rats. These
+ functional changes were accompanied by restoration of the number of antral follicles per ovary that had been
+ depleted by EV and a significant reduction in the number of both precystic follicles and
+ follicular cysts. The results indicate that the hyperactivation of ovarian sympathetic nerves seen in
+ EV-induced PCO is related to an overproduction of NGF and its low affinity receptor in the gland. They
+ also suggest that activation of this neurotrophic-neurogenic regulatory loop is a component of the
+ pathological process by which EV induces cyst formation and anovulation in rodents. The
+ possibility exists that a similar alteration in neurotrophic input to the ovary contributes to the etiology
+ and/or maintenance of the PCO syndrome in humans.
+
+
+
+ Acta Physiol Hung 1996;84(2):183-90.
+ Effects of hormones on the number, distribution and degranulation of mast cells in the ovarian complex
+ of mice. Jaiswal K, Krishna A. The changes in the number and degranulation pattern of mast
+ cells varied with the types of hormonal treatment and ovarian compartment. Luteinizing hormone (LH),
+ follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH) and 17-beta estradiol (E2)
+ treatment caused increase (P < 0.05) in the number of mast cells in the hilum as compared
+ with the controls. Increase (P < 0.05) in the number of mast cells in the whole ovarian complex was
+ observed only following FSH and E2 treatment. All the hormones used in the present study increased the
+ percentage degranulation of mast cells in the hilum. However, only LH, FSH and E2 increased the percentage
+ degranulation of mast cells in other compartments of the ovary (medulla, bursa and cortex). TSH and ACTH
+ failed to cause any increase in the percentage degranulation of mast cells in these compartments. The
+ present findings indicate E2 to be the most potent among the hormones tested in causing degranulation of
+ mast cells in all ovarian compartments.
+
+
+ Fertil Steril 2001 Jun;75(6):1141-7. Increase in nerve fibers and loss of mast cells in polycystic
+ and postmenopausal ovaries.
+
+ with increasing nerve fiber density in polycystic ovaries, the number of mast cells decreased
+ strikingly compared with cyclic ovaries (p<.001). Almost no mast cells were seen in postmenopausal
+ ovaries with and without hyperthecosis. The number of leukocyte antigen-positive leukocytes was
+ similar in all groups. CONCLUSION(S): The high density of nerve fibers in polycystic and postmenopausal
+ ovaries, together with a conspicuous decrease in mast cells, indicates altered neuroimmune communication.
+
+
+
+ Endocrinology 1993 Dec;133(6):2696-703. Ovarian steroidal response to gonadotropins and
+ beta-adrenergic stimulation is enhanced in polycystic ovary syndrome: role of sympathetic
+ innervation. Barria A, Leyton V, Ojeda SR, Lara HE. Experimental induction of a polycystic
+ ovarian syndrome (PCOS) in rodents by the
+ administration of a single dose of estradiol valerate (EV) results in activation of the peripheral
+ sympathetic neurons that innervate the ovary. This activation is evidenced by an increased capacity of
+ ovarian nerve terminals to incorporate and release norepinephrine (NE), an increase in ovarian NE
+ content, and a decrease in ovarian beta-adrenergic receptor number in the ovarian compartments
+ receiving catecholaminergic innervation. The present experiments were undertaken to examine the
+ functional consequences of this enhanced sympathetic outflow to the ovary. The steroidal
+ responses of the gland to beta-adrenergic receptor stimulation and hCG were examined in vitro 60 days after
+ EV administration, i.e. at the time when follicular cysts are well established. EV-treated rats exhibited a
+ remarkable increase in ovarian progesterone and androgen responses to isoproterenol, a beta-adrenergic
+ receptor agonist, with no changes in estradiol responsiveness. Basal estradiol release was, however, 50-fold
+ higher than the highest levels released from normal ovaries at any phase of the estrous cycle. The ovarian
+ progesterone and androgen responses to hCG were enhanced in EV-treated rats, as were the responses to a
+ combination of isoproterenol and hCG. Transection of the superior ovarian nerve (SON), which carries most of
+ the catecholaminergic fibers innervating endocrine ovarian cells, dramatically reduced the exaggerated
+ responses of all three steroids to both beta-adrenergic and gonadotropin stimulation. SON transection also
+ reduced the elevated levels of ovarian NE resulting from EV treatment and caused up-regulation of
+ beta-adrenoreceptors. Most importantly, SON transection restored estrous cyclicity and ovulatory capacity.
+ The results indicate that the increased output of ovarian steroids in PCOS is at least in part due to an
+ enhanced responsiveness of the gland to both catecholaminergic and gonadotropin stimulation. The ability of
+ SON transection to restore a normal response indicates that the alteration in steroid output results from a
+ deranged activation of selective components of the noradrenergic innervation to the ovary. These findings
+ support the concept that an alteration in the neurogenic control of the ovary contributes to the etiology of
+ PCOS.
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Bleeding, clotting, cancer
+
+
+ Bleeding, clotting, cancer
+
+
+
+ The balance between bleeding and clotting is easily disturbed. The condensation and dissolution of the
+ clotting protein, fibrinogen/fibrin, is a continuous process, sensitive to changes in stress, nutrition,
+ and hormones. Clots form, locally or systemically, when fibrin is formed faster than it is dissolved.
+ When fibrin is destroyed faster than it can be replaced, blood vessels become too permeable, and
+ bleeding can occur more easily.
+
+
+
+ Mental stress, exercise, estrogen, and serotonin activate both the formation and dissolution of clots.
+
+
+ Bleeding and clotting are not only very closely related with each other, such that a given stress can
+ induce either or both, but the condensation and dissolution of the clotting protein are involved in
+ edema, multiple organ failure, and the growth of cancers. The growth of tumors is as directly related to
+ the clotting system as are thromboses and hemorrhages.
+
+
+
+ Disordered clotting contributes to maladaptive inflammation and to the "diseases" of aging and
+ degeneration.
+
+
+ Metabolic energy is the basic defense against the stress reactions that disrupt circulation, healing,
+ and growth.
+
+
+ "It is commonly known that the ESR (red cell sedimentation rate) of cancer patients is always high."
+
+
+
+
+ "Thus far, completely unagglutinated blood has been found only in strictly healthy animals and men. No
+ severely ill person has yet been seen who did not have intravascular agglutination of the blood and
+ visibly pathologic vessel walls." Melvin H. Knisely, et al., 1947)
+
+
+
+
+ When science became a sort of "profession," in the 19th century, the old "natural philosophy" of Newton"s
+ time began to subdivide into many specialties. At that time, medicine had some general theories to account
+ for deviations from good health, such as the theory of the four humors and their balance, but as those
+ general theories disappeared, they weren"t replaced by any single scientific understanding of the nature of
+ good health and disease. Medical education has convinced doctors and the public that the reasons for
+ suffering, disability and death are mostly known, and that when medical experts agree to give a condition a
+ name, there must be some clear scientific evidence behind that disease name.
+
+
+
+ That mystique of diagnosing disease (specific, concrete, reified disease) was so strong that when Hans Selye
+ noticed (in the 1930s) something that underlies all sickness (he first called it the "syndrome of being
+ sick"), he was disregarded and disrespected, at least until his dangerous perceptions could be trimmed,
+ distorted, and subsumed under some proper medical categories. Selye observed that stress causes
+ internal bleeding (in lungs, adrenals, thymus, intestine, salivary and tear glands, etc.),
+ but instead of trying to understand what that means for the control of sickness, the medical schools and
+ journals have offered concrete, fragmentary, and false explanations for his observations. "Stomach acid"
+ causes bleeding in the stomach and duodenum;
+ stuff leaking out of the brain gets the blame for some cases of systemic bleeding, stuff leaking out of the
+ uterus, for other cases, and so on. Selye"s observations have been rendered harmless (to medicine) by these
+ falsely concrete explanations. While conventional medicine propagated its medical fantasies, it
+ characterized Selye"s work as "controversial."
+
+
+ In many cases, "diagnosis" consists of what could, at best, be called an educated guess, with no attempt to
+ find evidence to support it. Obviously, if every doctor in the country is guessing wrong about certain
+ deadly conditions, lots of people will die, and no one will see the need to even study the subject, since it
+ has a definite name and an explanation that seems to satisfy.
+
+
+ Instead of finding pseudo-reasons for the bleeding abnormalities caused by stress, it would be good to look
+ freshly at the nature of blood and its circulation. It might turn out that it"s a way to expand our
+ understanding of the stress reaction.
+
+
+ Most people are aware of some of the variations of bleeding and clotting that occur commonly. Bleeding gums,
+ nose-bleeds, menstruation and its variations, and the spontaneous bruising (especially on the thighs) that
+ many women have premenstrually, are familiar events that don"t seem to mean much to the medical world.
+ Sometimes nose-bleeds are clearly stress-related, but the usual "explanation" for that association is that
+ high blood pressure simply blows out weak blood vessels. Bleeding gums are sometimes stress related, but
+ high blood pressure is seldom invoked to explain that problem.
+
+
+
+ The whole issue of blood vessel fragility is usually disposed of as a "genetic trait," or a result of old
+ age. This is part of a general tendency to think of the blood vessels as an anatomically fixed,
+ "congenital," and genetically determined system. At least until recently, nearly all physicians have called
+ aneurysms "congenital defects." But varicose veins are merely low-pressure analogs of arterial aneurysms,
+ and they obviously develop under specific conditions, such as pregnancy and malnutrition. Spider veins are
+ another anatomical variation that commonly appears under the influence of estrogen. Subarachnoid
+ hemorrhages, which can put pressure on the brain, are usually considered to result from a ruptured aneurysm,
+ and these hemorrages are twice as common in women as in men, and probably result from a hormone imbalance.
+
+
+ Menstrual bleeding is a good place to start the investigation of bleeding problems, since its relatively
+ harmless abnormalities are physiologically related to some very serious health problems, such as pregnancy
+ bleeding, abruptio placentae, and eclampsia. Women who die from eclampsia have been found to have massively
+ clotted blood vessels in their brains, but the variety of names for the pregnancy disorders have prevented
+ most people from thinking of pregnancy as a time when there is a high risk of the "thrombohemorrhagic
+ disorders," a time when the clotting system is under stress. (For about fifteen years after Selye coined the
+ term, only he and some Russians were publishing research on it, and Americans still don"t show much interest
+ in the subject.)
+
+
+ Women with a chronic menstrual problem resulting from progesterone deficiency often continue to bleed each
+ month even when they are pregnant, and these women tend to develop toxemia, and to have a high incidence of
+ pregnancy complications, and to deliver premature, poorly developed babies.
+
+
+ In 1933 James Shute was recommending the use of vitamin E for preventing the clotting problems associated
+ with pregnancy, that often lead to miscarriage. He based his work on animal studies, that led to vitamin E"s
+ being known as the "fertility vitamin." Later, his sons Wilfred and Evan reported that vitamin E could
+ prevent heart attacks, birth defects, complications of diabetes, phlebitis, hypertension, and some
+ neurological problems.
+
+
+ Later, referring to the decades of hostility of the medical establishment to vitamin E, Dr. Shute said
+ "...an obstetrician was unduly hardy and audacious to try it." The spectrum of vitamin E"s protective
+ effects (like those of aspirin) has been consistently misrepresented in the medical literature.
+
+
+ Hematomas in many organs (pituitary, kidney, pancreas, liver, even around the abdominal muscles) can occur
+ because of hormone imbalances in these difficult pregnancies. Tom Brewer"s demonstration that a good diet,
+ with abundant protein, can prevent and cure pregnancy toxemia, is practically unknown in the medical world,
+ though a protein deficiency has been shown to increase the risk of blood clots under many other
+ circumstances besides pregnancy.
+
+
+
+ Abruptio placentae (premature detachment of the placenta) has often been blamed on the use of vitamin E,
+ because of vitamin E"s reputation for preventing abnormal clotting, though the evidence tends to suggest
+ instead that vitamin E (like aspirin) reduces the risk of pregnancy-related hemorrhaging.
+
+
+ One of the deadly clotting conditions related to childbirth has been called "pregnancy anaphylaxis," but it
+ is more often called "amniotic fluid embolism," despite the fact that amniotic fluid injected intravenously
+ is harmless (Petroianu, et al.), and only by grinding up and injecting massive amounts of the pregnancy
+ membranes can the clotting system be disturbed. The term is really a criminal misnomer, serving to blame a
+ preventable clotting/shock disorder on the patient.
+
+
+ "Consumption coagulopathy" refers to the bleeding that follows excessive activation of the clotting
+ system, combined with a defensive dissolving of the clots, when finally the fibrinogen or other
+ elements of the clotting system have been depleted, consumed. A blood test can show when clot degradation
+ products are being produced too rapidly, even while a person has no symptoms, so there should be time for
+ the accelerated clotting to be controlled, before major thromboses and bleeding and shock have developed.
+
+
+ In 1936 Albert Szent-Gyorgyi reported that some chemicals in lemon juice, which he called vitamin P (or
+ citrin), would prevent purpura, subcutaneous capillary bleeding. By 1938, he had decided that citrin, (which
+ he now called bioflavonoid) probably wasn"t a vitamin, and that its action was more like that of a drug,
+ substituting for a natural regulatory factor that was missing. Later research has confirmed that view,
+ showing that the bioflavonoids inhibit the enzyme hyaluronidase, which degrades the "ground substance" of
+ connective tissues. At least one natural endogenous inhibitor of hyaluronidase has now been identified. The
+ basement membrane that surrounds and unites the endothelial cells of capillaries is largely hyaluronic acid
+ and collagen. It isn"t thrombogenic (Buchanan, et al.), despite the common belief that collagen is
+ intrinsically a clot instigator. The breakdown of this ground substance is involved in growth and
+ reproduction, so an excess of bioflavonoids in the diet could conceivably interfere with fertility and fetal
+ development. Some bioflavonoids have been prescribed for menstrual problems, and are probably useful when
+ the physiological inhibitor isn"t adequate.
+
+
+
+ Hyaluronidase is activated by shock, and also by estrogen. Both hyaluronidase and estrogen have been used in
+ plastic surgery to "expand" tissue, weakening it and allowing it to be enlarged. During aging, hyaluronic
+ acid (the major water-retaining component of connective tissue that"s broken down by hyaluronidase)
+ decreases in the connective tissues, but increases in the blood stream. Shock allows hyaluronic acid to
+ increase in the serum. Fragments of degraded hyaluronic acid are pro-inflammatory.
+
+
+ In the 1940s Hans Selye studied the steroid hormones in a comprehensive way, defining their actions and
+ interactions. At that time he found that progesterone protected broadly against stress, and that a large
+ dose of estrogen created a condition that duplicated the initial shock phase of the stress reaction. Later
+ animal studies showed that estrogen quickly causes enlargement of the adrenal glands, followed by bleeding,
+ and, with large and continuous doses, death of the adrenal cells.
+
+
+ Estrogen promotes vascular permeability by a variety of mechanisms. Serotonin, histamine, lactic acid, and
+ various cytokines and prostaglandins contribute to the leakage stimulated by estrogen, trauma, irradiation,
+ poisoning, oxygen deprivation, and other factors that can induce shock. Even exercise, mental stress, and
+ aging can increase the tendency of capillaries to leak.
+
+
+ Progesterone and cortisol protect against shock and stress partly by maintaining the resistance and
+ integrity of the capillaries, preventing leakage of blood materials into the tissues. The maintenance of the
+ capillary barrier probably also prevents substances from the extracellular matrix from triggering the
+ clotting systems.
+
+
+ Clots are formed when soluble fibrinogen polymerizes, condenses, and becomes insoluble. Even before the
+ particles of fibrin become insoluble, a clot-dissolving system is continuously breaking it down into small
+ peptides. These peptides tend to cause capillaries to leak. If a massive amount of fibrinogen and fibrin
+ leak out of capillaries, clots are formed outside capillaries, and the peptides released in the process of
+ cleaning up this debris contribute to further leakage, and to inflammation. The inflammation stimulates the
+ production of collagen-rich connective tissue, and a fibrotic tissue replaces the functional tissues. Many
+ of Hans Selye"s experiments explored the conditions in which inflammation, exudation, and fibrosis
+ developed, sometimes ending with calcification of the region.
+
+
+ The presence of fibrin in the extracellular matrix interferes with the differentiated functioning of cells,
+ which depend on their contact with a normal matrix. When healing and regeneration occur in the normal
+ matrix, the remodeling of the tissue involves the breakdown of collagen, which releases peptides with
+ antiinflammatory, antiangiogenic and antiinvasive actions. When fibrin is present, the remodeling process
+ releases peptides that increase cell growth, invasiveness, inflammation, and the production of new blood
+ vessels, which in turn become leaky.
+
+
+
+ Leakage of fluid out of the blood is one of the main features of shock, and at first it is mainly the loss
+ of water and volume that creates a problem, by reducing the oxygenation of tissue and increasing the
+ viscosity of the remaining blood. Blood becomes more concentrated during strenuous exercise, during the
+ night, and in the winter, increasing the viscosity, and increasing the risk of strokes and other thrombotic
+ problems. The absence of light causes the metabolic and hormonal changes typical of stress.
+
+
+ Tom Brewer and his associates showed that pregnancy toxemia involves inadequate blood volume, and that using
+ extra sodium can alleviate the symptoms, including preventing albuminuria, one of the most characteristic
+ signs of toxemia/preeclampsia. (Besides causing loss of albumin through leaky capillaries, estrogen also
+ inhibits its synthesis by the liver;
+ the loss of colloid osmotic pressure in hypoalbuminemia has many consequences, including disturbances of
+ blood lipids.) Estrogen"s action in toxemia of pregnancy is paralleled by the fact that blood viscosity is
+ highest at the time of ovulation during the normal monthly cycle.
+
+
+ In the healthy person, some of the fibrin that is constantly being formed is deposited on the inside of
+ blood vessels (and on the surfaces of blood cells), and this layer forms an important part of the
+ capillary"s resistance to leaking. A.L. Copley, who pioneered the study of hemorrheology, called this the
+ "endoendothelial layer." This layer probably contains albumin, too, in close association with the
+ (carbohydrate) "glycocalyx" of the endothelial cell surface. Disturbances that accelerate the formation and
+ dissolution of the fibrin layer can be detected by an increase in the concentration of the fibrin
+ degradation products (FDP, or D-dimers) in the blood, even before any symptoms have appeared.
+
+
+ Although Selye described shock as the first (potentially lethal) phase of stress, usually followed by the
+ corrective adaptive processes, it"s useful to think of aging in terms of a lingering partial state of shock,
+ in which adaptation is less than perfect.
+
+
+ The loss of blood volume through leaky capillaries tends to be self-aggravating. The concentrated and
+ viscous blood doesn"t flow as well through the capillaries, and this energy deprivation leads to increased
+ leakiness of the cells, and to swelling of the endothelial cells, decreasing the internal diameter of the
+ small blood vessels. The energy-deprived state increases lactic acid, adrenaline, and free fatty acids, all
+ of which contribute to increased leakiness and impaired circulation.
+
+
+
+ In the bowel, the capillary malfunction increases the absorption of endotoxin, which intensifies the
+ systemic energy problem. (Polyunsaturated oils, especially fish oil, damage the bowel capillaries, allowing
+ more endotoxin to be absorbed.)
+
+
+ In the uterus, increased viscosity of the blood impairs the delivery of oxygen and nutrients to the fetus,
+ retarding its development. Dilution of the blood under the influence of progesterone reduces the hematocrit,
+ helping to compensate for the viscosity; in toxemic pregnancies this isn"t sufficient to
+ maintain normal viscosity and perfusion.
+
+
+ In the brain, hyperviscosity contributes to dementia. In the lung, to edema and reduced oxygenation ("shock
+ lung," "wet lung," respiratory distress; this lung edema is a major cause of mortality in
+ pregnancy). In the pancreas, to inflammation, and to the release of proteolytic enzymes, impairing the
+ clotting system even more.
+
+
+ During the development of cancer, hyperviscosity (and the associated hypoxia) contributes to the tumor"s
+ deranged metabolism, tending to increase its production of ammonia, clotting factors, and other
+ stress-inducing toxins.
+
+
+
+ Factors that increase the fluidity of the blood protect against all of the thrombohemorrhagic conditions,
+ and are especially protective against the estrogen-promoted cancers. Progesterone decreases the production
+ of fibrinogen, and increases the volume of the blood and the flexibility of the red blood cells, increasing
+ the ability of blood to flow freely, and it also decreases the leakiness of capillaries. Hypothyroid people
+ (who tend to have low progesterone and high estrogen) are highly susceptible to heart disease and cancer,
+ and have abnormally viscous blood. Hyperthyroid people have unusually fluid blood. Hypothyroidism increases
+ the leakiness of capillaries, and decreases the amount of albumin in the blood. Albumin itself decreases the
+ permeability of blood vessels.
+
+
+ In hypothyroidism and under the influence of estrogen, there is a chronic increase of free fatty acids, and
+ the free fatty acids are an important factor in increasing the production of fibrinogen (Pickart), and in
+ blocking fibrinolysis (Lindquist, et al.). If the body"s stores of fat are largely polyunsaturated fats, the
+ free fatty acids will combine with the fibrin as it polymerizes, making the clots especially resistant to
+ dissolution.
+
+
+ In the 1940s, Melvin Knisely noticed that all seriously sick people had "sludged" blood, that can be
+ observed microscopically in the small blood vessels on the surface of the person"s eye. The cells tend to
+ stick together, producing a sludgy appearance and slow flow. This probably corresponds to increased
+ viscosity of the plasma, increased red cell sedimentation rate, increased fibrinogen, decreased albumin, and
+ decreased thyroid and progesterone. Clumped red cells, when separated under the microscope, appear to be
+ bound together by fine filaments, possibly of fibrin.
+
+
+ Aspirin is known to have a variety of anticancer activities, including the prevention of metastasis, and
+ some people have reasoned that the clotting process simply helps migrating cancer cells to become anchored.
+ However, the clotting process is normally part of the healing and repair processes, and I think the role of
+ the fibrin clotting system in cancer is that the breakdown products of fibrin are growth-promoters, and that
+ their presence in the extracellular matrix in large quantity, distorting the normal composition of the
+ matrix, is what causes the formation of a tumor. It"s the leakage of the fibrin into the extracellular
+ matrix that leads to the development of tumors.
+
+
+ Heparin, a natural anticoagulant, is currently being tested as an anticancer agent.
+
+
+ All of the factors that promote stable oxidative energy production protect against the coagulative
+ derangements, largely by preventing capillary leakage, and it now seems that these processes protect against
+ cancer as well as protecting against all of the stress-related degenerative and inflammatory diseases.
+
+
+
+ Since hyperventilation can increase capillary leakage and cause the blood to become more concentrated,
+ breathing carbon dioxide (breathing in a bag) should help to restore capillary function.
+
+
+ Since the blood becomes more concentrated, viscous, and clottable during the night (especially during long
+ winter nights), the risk of a heart attack or stroke would probably be reduced by drinking orange juice
+ before getting out of bed (and at bed-time), to dilute the blood and decrease adrenaline and the free fatty
+ acids, which contribute to the increased tendency to form clots in the morning. (Assanelli, et al., discuss
+ the importance of adrenaline in morning/winter sudden death; Antoniades and Westmoreland show that the
+ availability of glucose can override major promoters of clotting and bleeding.)
+
+
+ Things to reduce the stress-related coagulopathies: Sugar and niacin to minimize the
+ liberation of fatty acids, progesterone and thyroid to protect against estrogen and to avoid hypoglycemia
+ (which increases adrenaline and free fatty acids and accelerates clotting), magnesium and gelatin (or
+ glycine), to protect against intracellular calcium overload and hypoxia, and vitamin E and salicylic acid
+ for antiinflammatory effects, are major nutrients that protect the circulatory system against clotting,
+ bleeding, edema, and tumefaction.
+
+
+ Even on the mornings that you don"t drop dead, there is reduced adaptive capacity and functional impairment
+ before eating breakfast. For example, men who went for a run before breakfast were found to have broken
+ chromosomes in their blood cells, but if they ate breakfast before running, their chromosomes weren"t
+ damaged.
+
+
+ REFERENCES
+
+
+ Vet Rec. 1988 Apr 2;122(14):329-32. Relationships between the erythrocyte sedimentation rate, plasma
+ proteins and viscosity, and leucocyte counts in thoroughbred racehorses. Allen BV. "The
+ influence of plasma proteins on erythrocyte aggregation was studied in a population of young thoroughbred
+ racehorses, using the 60 minute erythrocyte sedimentation rate (ESR) with and without haematocrit
+ standardisation. The ESR
+ was correlated inversely with the haematocrit,
+
+ but directly with fibrinogen, plasma viscosity and serum total globulins.
+ When ESR values were standardised to a common haematocrit the correlation coefficients for the same
+ plasma protein factors were increased. Albumin levels showed a strong direct relationship with
+ haematocrit which accounted for the inverse correlation found between albumin and ESR.
+
+
+
+
+ Ann N Y Acad Sci. 1976;275:28-46. Metabolic influences in experimental thrombosis.
+ Antoniades HN, Westmoreland N. Studies presented in this report demonstrate that intravascular coagulation
+ and thrombosis in the whole animal can be greatly influenced by noncoagulation factors, such as metabolic,
+ endocrinologic, and nutritional states. Injection of a partially purified human serum procoagulant
+ fraction produced no significant clotting abnormalities in normal fed rats; however, injection of an
+ identical preparation in fasted, diabetic, and obese rats produced hypercoagulability of blood,
+ thrombosis, and hemorrhage.
+ Glucose injection in fasted rats and insulin injection in diabetic rats reversed their
+ susceptibility to thrombosis. The concentrations of serum free fatty acids were shown to be
+ elevated in the susceptible animals; however, they returned to normal in fasted and diabetic rats after
+ injections of glucose and insulin, respectively. Infusion of free fatty acid-albumin preparations in normal
+ fed rats rendered the animals susceptible to thrombosis when challenged with the serum procoagulant
+ fraction.
+
+
+
+ Cardiologia. 1997 Jul;42(7):729-35.
+ [Circadian variation of sudden cardiac death in young people with and without coronary disease]
+ Assanelli D, Bersatti F, Turla C, Restori M, Amariti ML, Romano A, Ferrari M. "To clarify whether sudden
+ cardiac death has a circadian rhythm in young people we have studied 40 patients < 45 years who died in
+ Brescia between 1984 and 1993 of sudden cardiac death showing at autopsy features of coronary artery disease
+ (CAD) and 12 patients aged < 30 years who died of sudden cardiac death without autoptic features of CAD.
+ We observed a circadian rhythm in the hours of the morning in the two groups, more evident in patients
+ without CAD. In patients
+ with autoptic features of CAD, we also observed a higher rate of events during the winter months. We
+ would like to stress the importance of the adrenergic system as a trigger able to produce the
+ event."
+
+
+ An R Acad Nac Med (Madr). 2002;119(1):163-73; discussion 173-4. [HELLP syndrome and hemorrhagic
+ gestosis] Botella Llusia J. In the year 1817, Charlotte daughter of Georges IV and princess of
+ Wales, died on an unknown condition with uteroplacental hemorrhage
+ and fetal death called at the time "Uteroplacental Apoplexy" and later "Abruptio Placentae". This
+ affection was described in the classical books as an hemorrhagic complication of labor. In 1961 we have
+ at first related the Abruptio with acute toxemia (preeclampsia) and have proposed the term "Gestosis
+ hemorragica" to design
+
+ it. In 1982 Weinstein has described the called HELLP syndrome (Hemolysis, Elevated liver Enzymes, at Low
+ Platelets) which basically is the same pathological picture as the described by us as "hemorrhagic toxemia".
+ The aim of the paper is to demonstrate the identity of both syndromes and to claim for the priority of our
+ definition.
+
+
+ Thromb Haemost. 1987 Aug 4;58(2):698-704. The basement membrane underlying the vascular endothelium
+ is not thrombogenic: in vivo and in vitro studies with rabbit and human tissue. Buchanan MR,
+ Richardson M, Haas TA, Hirsh J, Madri JA.
+
+
+ Am J Physiol Heart Circ Physiol. 2003 Mar;284(3):H1028-34. Epub 2002 Nov 21. Endotoxemia stimulates
+ skeletal muscle Na+-K+-ATPase and raises blood lactate under aerobic conditions in humans.
+ Bundgaard H, Kjeldsen K, Suarez Krabbe K, van Hall G, Simonsen L, Qvist J, Hansen CM, Moller K, Fonsmark L,
+ Lav Madsen P, Klarlund Pedersen B.
+
+
+ Thromb Haemost. 2001 Jul;86(1):334-45.
+ Tissue factor--a
+
+ receptor involved in the control of cellular properties, including angiogenesis. Chen J,
+ Bierhaus A, Schiekofer S, Andrassy M, Chen B, Stern DM, Nawroth PP. "Tissue factor (TF), the major
+ initiator of blood coagulation, serves as a regulator of angiogenesis, tumor growth and
+ metastasis."
+
+
+
+ Thromb Res Suppl. 1983;5:105-45. The physiological significance of the endoendothelial fibrin lining
+ (EEFL) as the critical interface in the 'vessel-blood organ' and the importance of in vivo 'fibrinogenin
+ formation' in health and disease. Copley AL. "The author's theory of the endoendothelial fibrin lining (EEFL) . . .
+ localizes the homeostasis between steady fibrin formation and deposition, or 'fibrination', and
+ continuous fibrinolysis in the more or less immobile portion of the plasmatic zone next to the vessel wall.
+ In 1971, the author advanced, in relation to the EEFL, the theory of fibrinogen gel clotting without
+ thrombin action or 'fibrinogenin' formation in vivo." "The EEFL of the vessel-blood organ is
+ considered by the author as the crucial critical interface between the blood and the vessel wall. It
+ is the primary barrier, followed by the endothelium (comprising the endothelial cells and the
+ interendothelial cement substance which contains or is identical with 'cement fibrin') and the basement
+ membrane for the exchanges between the blood, the vessel wall and its surrounding tissues and spaces.
+ The EEFL acts as anticoagulant, is antithrombogenic, maintains vascular patency and aids cardiac action
+ by decreasing significantly the apparent viscosity of blood, referred to in the literature as
+ the 'Copley-Scott Blair phenomenon'. A new concept of leukocyte emigration traversing the capillary wall is
+ presented, affecting focal fibrinolysis of the EEFL and of fibrin contained in the interendothelial cement
+ substance and in the basement membrane. The physical property of capillary (or vascular) permeability is
+ related to the existence of the EEFL, since, as found by Copley et al, both fibrinopeptides, liberated in
+ the transition of fibrinogen to fibrin, and plasminopeptides, freed in the conversion of plasminogen to
+ plasmin, enhance capillary permeability. Capillary fragility, which is antagonistic to capillary
+ permeability, is in great part due to fibrinolytic action on fibrin as a constituent of the basement
+ membrane."
+
+
+ Am J Obstet Gynecol. 1995 Apr;172(4 Pt 1):1291-8. Blindness associated with preeclampsia and
+ eclampsia. Cunningham FG, Fernandez CO, Hernandez C.
+
+
+
+ East Afr Med J. 2002 Apr;79(4):181-3. Haemorheological changes during the menstrual cycle.
+ Dapper DV, Didia BC.
+
+
+ Cancer Res. 2001 Feb 1;61(3):795-8.
+ Tumor hypoxia,
+
+ the physiological link between Trousseau's syndrome (carcinoma-induced coagulopathy) and
+ metastasis. Denko NC, Giaccia AJ.
+
+
+ Lab Invest 1998 Jun;78(6):657-68. Development of porous defects in plasma membranes of adenosine
+ triphosphate-depleted Madin-Darby canine kidney cells and its inhibition by glycine. Dong Z,
+ Patel Y, Saikumar P, Weinberg JM, Venkatachalam MA
+
+
+
+ Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2692-7. Seasonal variations of rheological and
+ hemostatic parameters and acute-phase reactants in young, healthy subjects. Frohlich M, Sund M,
+ Russ S, Hoffmeister A, Fischer HG, Hombach V, Koenig W.
+
+
+ Respir Physiol Neurobiol. 2003 Oct 16;138(1):37-44. Lactate as a modulator of hypoxia-induced
+ hyperventilation.Gargaglioni LH, Bicego KC, Steiner AA, Branco LG.
+
+
+ Am J Vet Res. 1994 Jun;55(6):854-61.
+ Hemorheologic
+
+ alterations induced by incremental treadmill exercise in Thoroughbreds.
+
+
+ Geor RJ, Weiss DJ, Smith CM.
+
+
+ Vopr Pitan. 1995;(1):7-11. [Effects of dietary fat on permeability of the protective intestinal
+ barrier to
+
+ macromolecules in experimental anaphylaxis][Article in Russian]
+
+ Gmoshinskii IV, Ermekpaeva RA, Lysikov IuA, Kulakova SN, Mazo VK, Morozov IA.
+
+
+ Am J Physiol Cell Physiol 2000 Nov;279(5):C1495-505. Calcium regulates estrogen increase in
+ permeability of cultured CaSki epithelium by eNOS-dependent mechanism. Gorodeski GI.
+
+
+
+ J Reprod Med. 2002 Dec;47(12):1021-4. Documentation of amniotic fluid embolism via lung
+ histopathology. Fact or Fiction?
+
+ Hankins GD, Snyder R, Dinh T, Van Hook J, Clark S, Vandelan A.
+
+
+ Klin Wochenschr. 1990 Jun 5;68(11):559-64.
+ [Hemodynamic and hemorheologic findings in patients with pregnancy-induced hypertension: comparison of
+ pre-eclampsia and chronic hypertension]
+ Heilmann L, Schmid-Schonbein H.
+
+
+ Zentralbl Gynakol. 1986;108(7):393-402.
+ [Changes in flow properties of the blood in pregnancy] Heilmann L.
+
+
+ Eur J Vasc Surg. 1992 Jan;6(1):36-40. Claudication induces systemic capillary endothelial
+ swelling. Hickey NC, Hudlicka O, Simms MH.
+
+
+ Blood. 2001 Mar 15;97(6):1697-702.
+ Serotonin induces the expression of tissue factor and plasminogen activator inhibitor-1 in cultured rat
+ aortic endothelial cells. Kawano H, Tsuji H, Nishimura H, Kimura S, Yano S, Ukimura N, Kunieda
+ Y, Yoshizumi M, Sugano T, Nakagawa K, Masuda H, Sawada S, Nakagawa M.
+
+
+
+ Br Med J (Clin Res Ed). 1984 Nov 24;289(6456):1405-8.
+ Increases in platelet and red cell counts, blood viscosity, and arterial pressure during mild surface
+ cooling: factors in mortality from coronary and cerebral thrombosis in winter. Keatinge WR,
+ Coleshaw SR, Cotter F, Mattock M, Murphy M, Chelliah R.
+ "Six hours of mild surface cooling in moving air at 24 degrees C with little fall in core temperature
+ (0.4 degree C) increased the packed cell volume by 7% and increased the platelet count and usually the
+ mean platelet volume to produce a 15% increase in the fraction of plasma volume occupied by platelets.
+ Little of these increases occurred in the first hour. Whole blood viscosity increased by 21%; plasma
+ viscosity usually increased, and arterial pressure rose on average from 126/69 to 138/87 mm
+ Hg."
+
+
+ Acta Chir Scand. 1976;142(1):20-5. Induction of endogenous fibrinolysis inhibition in the dog.
+ Effect of intravascular coagulation and release of free fatty acids. Lindquist O, Bagge L,
+ Saldeen T. "In all groups subjected to infusion of thrombin an increase in plasma free fatty acids (FFA) was
+ observed. The role of this increase for the development of fibrinolysis inhibition was tested by
+ infusion of norepinephrine alone and in combination with nicotinic acid. Norepinephrine caused an
+ increase of FFA after 2 hours and in urokinase inhibitor activity after 24-48 hours.
+
+ Both of these were diminished by high doses of nicotinic acid, indicating that the release of FFA rather
+ than intravascular coagulation might be the principal mechanism underlying the occurrence of fibrinolysis
+ inhibition following trauma."
+
+
+ Matrix Biol. 2002 Jan;21(1):31-7. Inhibitors of the hyaluronidases. Mio K, Stern R.
+ "Because of increased interest in hyaluronidases and their hyaluronan substrate, a study of these inhibitors
+ was undertaken recently. The predominant serum inhibitor is magnesium-dependent...."
+
+
+ Vopr Onkol. 1991;37(9-10):992-7. [Blood coagulation disorders and tumor growth][Article in
+ Russian] Mkrtchian LN, Shukurian SG, Sarkisian OM, Magakian AG, Khachaturova TS, Ambartsumian AM.
+
+
+ Usp Fiziol Nauk. 1989 Oct-Dec;20(4):94-109. [The physiologic coagulation fibrinolytic system of the
+ body and
+
+ thrombohemorrhagic theory in oncology] [Article in Russian] Nadiradze ISh,
+ Machabeli MS.
+
+
+
+ Arch Gynecol Obstet. 2002 Nov;267(1):7-10. Sex hormones, hemostasis and early pregnancy
+ loss. Nelson DB, Ness RB, Grisso JA, Cushman M. "This study was designed to determine the
+ association between coagulation factors and spontaneous abortion adjusting for sex steroids and to examine
+ the influence of sex hormones on coagulation factors early in pregnancy." "The relationship between
+ coagulation factors and spontaneous abortion was reduced after adjustment for progesterone suggesting that
+ progesterone mediates the relationship between low levels of coagulation factors and spontaneous
+ abortion. Progesterone seems to be the primary marker for a spontaneous abortion among women seeking
+ emergent care."
+
+
+ Toxicol Pathol. 1992;20(1):71-80.
+ Pathogenesis of blood-filled cavities in estrogen-induced anterior pituitary tumors in male
+ Sprague-Dawley rats. van Nesselrooij JH, Hendriksen GJ, Feron VJ, Bosland MC.
+
+
+ Arch Int Physiol Biochim. 1983 Jul;91(2):81-5. Effects of the administration of progesterone and
+ adrenal medullectomy on the plasma fibrinogen levels in rats with surgical injury (laparotomy).
+ Palma JA, Gavotto AC, Villagra SB.
+
+
+
+ Pediatr Crit Care Med. 2000 Jul;1(1):65-71. Administration of autologous fetal membranes: Effects on
+ the coagulation in pregnant mini-pigs.
+ Petroianu GA, Toomes LM, Maleck WM, Friedberg C, Bergler WF, Rufer R. "A hallmark of the so-called
+ amniotic fluid embolism is the induction of coagulation defects. Entry of meconium-free autologous
+ amniotic fluid into the circulation, however, is innocuous." "Animals received 2 g FM [fetal
+ membranes] (shredded and suspended in lactated Ringer's solution) via an ear vein.
+ However, the full clinical picture of amniotic fluid embolism and disseminated intravascular coagulation
+ could not be elicited despite the high dose of FM used."
+
+
+ Am J Physiol. 1976 Apr;230(4):996-1002. Free fatty acids and albumin as mediators of
+ thrombin-stimulated fibrinogen synthesis.
+
+ Pickart LR, Thaler MM. "Mobilization of FFA in mice, triggered with an injection of thrombin, was followed
+ within 24 h by a 2.5-fold increase in fibrinogen synthesis and a 30% increase in plasma fibrinogen
+ concentration." "Injection of exogenous defatted albumin into mice before thrombin injection prevented the
+ FFA-associated rise in fibrinogen synthesis and plasma concentration." "These studies indicate that the
+ FFA/ALBUMIN RATIO MAY PLAY A MAJOR ROLE IN THE REPLENISHMENT OF FIBRINOGEN AFTER PERIODS OF RAPID
+ DEFIBRINOGENATION."
+
+
+ Thromb Haemost. 1995 Jul;74(1):391-5. Tissue factor expression in human leukocytes and tumor
+ cells. Rickles FR, Hair GA, Zeff RA, Lee E, Bona RD. "Tissue factor (TF) exists in a
+ cryptic form [i.e. without procoagulant activity (PCA)] in peripheral blood monocytes and quiescent
+ tissue macrophages but is expressed constitutively in most human tumor cells." "The regulation
+ of TF synthesis in cells is complex and new information from transfection studies suggests that changes in
+ cellular glycosylation pathways impair cell surface expression of functional TF." "The importance of
+ carbohydrate modification of TF is reviewed."
+
+
+ Nature 138: 32 (1936). Selye, H. A Syndrome produced by diverse nocuous agents.
+
+
+
+ Int J Microcirc Clin Exp. 1996 Sep-Oct;16(5):266-70. Hyperventilation enhances transcapillary
+ diffusion of sodium fluorescein. Steurer J, Schiesser D, Stey C, Vetter W, Elzi MV, Barras JP,
+ Franzeck UK.
+
+
+ Lancet. 1991 Jul 6;338(8758):9-13. Seasonal variations in fibrinogen concentrations among elderly
+ people. Stout RW, Crawford V. "Mortality and morbidity in elderly people are higher in winter
+ than in summer months, with seasonal variations in rates of both fatal and non-fatal myocardial infarction
+ and stroke." "Significant seasonal effects were found for fibrinogen, plasma viscosity, and HDL cholesterol
+ (p less than 0.003, Bonferroni adjustment). Plasma fibrinogen concentrations showed the greatest seasonal
+ change and were 23% higher in the coldest six months compared with summer months. Fibrinogen was
+ significantly (p less than 0.05) and negatively related to core body temperature and all measures of
+ environmental temperature." "Those living in institutions had greater changes in plasma fibrinogen than
+ those living in the community. The seasonal variation in plasma fibrinogen concentration is large enough to
+ increase the risk of both myocardial infarction and stroke in winter."
+
+
+ Akush Ginekol (Mosk). 1989 Jan;(1):43-6. [Coagulative activity of the amniotic fluid]
+ [Article in Russian] Tersenov OA, Mikhaleva IV, Usol'tseva VA, Byshevskii Ash. "An
+ ultracentrifugation study has shown thromboplastin to be the only blood coagulating agent, present in the
+ amniotic fluid (AF).
+ Its AF level shows no correlation to the rate of intrapartum or early postpartum thrombohemorrhagic
+ complications...."
+
+
+ Metabolism. 1989 May;38(5):471-8.
+ Effects of hypothyroidism on vascular 125I-albumin permeation and blood flow in Rats. Tilton
+ RG, Pugliese G, Chang K, Speedy A, Province MA, Kilo C, Williamson JR. "Effects of hypothyroidism on
+ vascular 125I-albumin permeation and on blood flow were assessed in multiple tissues of male Sprague-Dawley
+ rats rendered hypothyroid by dietary supplementation with 0.5% (wt/wt) 2-thiouracil or by thyroidectomy."
+ "After 10 to 12 weeks of thiouracil treatment, 125I-albumin permeation was increased significantly
+ in the kidney, aorta, eye (anterior uvea, choroid, retina), skin, and new granulation tissue...."
+
+
+ Clin Nutr. 2001 Aug;20(4):351-9. Effect of eicosapentaenoic acid (EPA) on tight junction
+ permeability in intestinal monolayer cells. Usami M, Muraki K, Iwamoto M, Ohata A, Matsushita
+ E, Miki A.
+
+
+
+ Carcinogenesis. 2003 Jun;24(6):1009-13. Epub 2003 Mar 28. Tissue factor signal
+
+ transduction in angiogenesis. Versteeg HH, Peppelenbosch MP, Spek CA. Tissue factor
+ (TF), a 47-kDa transmembrane glycoprotein, is a principal regulator of oncogenic neoangiogenesis and
+ controls therefore the cancerous process.
+
+ Although originally identified as a component of the coagulation cascade, it has become clear that TF
+ functions as a cytokine-like receptor and this notion was confirmed by the discovery of
+ coagulation-independent actions of TF (which include regulation of tumour growth, embryonic and oncogenic
+ blood vessel formation as well as regulation of inflammation and sepsis). In accordance, TF-mediated signal
+ transduction events are readily detected and the elucidation of the underlying molecular mechanisms has
+ recently seen spectacular progress and it is now understood that the role of TF in angiogenesis is both
+ coagulation-dependent and independent. The recent evidence for this emerging insight will be the subject of
+ this review.
+
+
+ Semin Thromb Hemost. 2003 Jun;29(3):317-20. Occurrence of components of fibrinolytic pathways in
+ situ in laryngeal cancer.
+ Wojtukiewicz MZ, Sierko E, Zacharski LR, Rozanska-Kudelska M, Zimnoch L.
+
+
+ Semin Thromb Hemost. 2003 Jun;29(3):239-46. Malignancy as a solid-phase coagulopathy: implications
+ for the etiology, pathogenesis, and treatment of cancer. Zacharski LR.
+
+
+
+ Thromb Res. 2003 Jun 1;110(4):213-4. Heparin treatment of malignancy: the case for clinical trials
+ in colon cancer. Zacharski LR.
+
+
+ Anticancer Res. 2003 May-Jun;23(3C):2789-93. Low-molecular-weight heparin in oncology.
+ Zacharski LR, Loynes JT.
+
+
+ Cancer Lett. 2002 Dec 1;186(1):1-9.
+ Anticoagulants in cancer treatment: malignancy as a solid phase coagulopathy. Zacharski LR.
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Bone Density: First Do No Harm
+
+
+ Bone Density: First Do No Harm
+
+
+
+
+ No topic can be understood in isolation. People frequently ask me what they should do about their
+ diagnosed osteoporosis/osteopenia, and when they mention “computer controlled” and “dual photon x-ray”
+ bone density tests, my attention tends to jump past their bones, their diet, and their hormones, to the
+ way they must perceive themselves and their place in the world. Are they aware that this is an x-ray
+ that’s powerful enough to differentiate very opaque bones from less opaque bones? The soft tissues
+ aren’t being studied, so they are allowed to be “overexposed” until they appear black on the film. If a
+ thick area like the thigh or hip is to be measured, are they aware that the x-ray dose received at the
+ surface where the radiation enters might be 20 times more intense than the radiation that reaches the
+ film, and that the 90 or 95% of the missing energy has been absorbed by the person’s cells? If I limited
+ my response to answering the question they thought they had asked me, I would feel that I had joined a
+ conspiracy against them. My answer has to assume that they are really asking about their health, rather
+ than about a particular medical diagnosis.
+
+
+ Neurologists are famous for making exquisitely erudite diagnoses of problems that they can’t do anything
+ to remedy. The owners of expensive dual photon x-ray absorptiometer diagnostic machines are in a very
+ different position. The remedies for osteoporosis are things that everyone should be doing, anyway, so
+ diagnosis makes no difference in what the physician should recommend to the patient.
+
+
+ Most often, estrogen is prescribed for osteoporosis, and if the doctors didn’t have their bone density
+ tests, they would probably prescribe estrogen anyway, “to protect the heart,” or “to prevent Alzheimer’s
+ disease.” Since I have already written about estrogen and those problems, there’s no need to say more
+ about it here, except that estrogen is the cause of a variety of tissue atrophies, including the
+ suppression of bone formation.[1]
+
+
+ General Electric, a major advocate of x-ray screening for osteoporosis and breast cancer, has advertised
+ that 91% of breast cancers could be cured if everyone used their technology. Breast cancer has not
+ decreased despite the massive application of the technology, though the US government and others (using
+ crudely deceptive statistis) claim that the War on Cancer is being won. Similarly, during the last
+ decades when the “high technology” x-ray machines have been more widely used, the age-specific incidence
+ of osteoporosis has increased tremendously. This apparently includes a higher rate of shortening of
+ stature with aging than in earlier generations.[2]
+
+
+ I think there are several reasons for avoiding x-ray tests of bone density, besides the simple one that
+ everyone should eat a bone-protective diet, regardless of the present density of their bones.
+
+
+ Even seemingly identical x-ray machines, or the same machine at a different time, can give very
+ different estimates of bone density.[3-10] Radiologists evaluating the same images often reach very
+ different conclusions.[11] Changes in the tissue water and fat content can make large differences in
+ apparent bone density,[12] and estrogen, which affects those, could appear to cause improved bone
+ density, when it is merely causing a generalized inflammatory condition, with edema. A machine that is
+ accurate when measuring an aluminum model, won’t necessarily give meaningful results when the
+ composition of the tissue, including the bone marrow, has changed. Calcification of soft tissues can
+ create the impression of increased bone density.[13] Studies of large groups of people show such small
+ annual losses of bone density (around 1%), especially in the neck of the femur (which is important in
+ hip fractures) that the common technical errors of measurement in an individual seem very large.
+
+
+ Ultrasound devices can do an extremely good job of evaluating both bone density and strength [14-16],
+ rather than just density.
+
+ Ultrasound stimulates bone repair.
+ X-rays accelerate the rate of bone loss.
+ X-rays do their harm at any dose; there is no threshold at which the harm begins.
+
+ X-ray damage is not limited to the area being investigated. Deflected x-rays affect adjacent areas, and
+ toxins produced by irradiated cells travel in the bloodstream, causing systemic effects. Dental x-rays
+ cause thyroid cancer and eye cancer. Recent experiments have shown that low doses of radiation cause
+ delayed death of brain cells. The action of x-rays produces tissue inflammation, and diseases as
+ different as Alzheimer’s disease and heart disease result from prolonged inflammatory processes.
+
+
+ I have never known a physician who knew, or cared, what dose of radiation his patients were receiving. I
+ have never known a patient who could get that information from their doctors.
+
+
+ The radiation exposure used to measure bone density may be higher (especially when the thigh and hip are
+ x-rayed) than the exposure in dental x-rays, but dental x-rays are known to increase the incidence of
+ cancer. Often, dentists have their receptionists do the x-rays, which probably doesn’t matter, since the
+ dentist is usually no more concerned than the receptionist about understanding, and minimizing, the
+ dose. Even radiological specialists seldom are interested in the doses they use diagnostically.
+
+
+ It was only after a multitude of dentists had a finger amputated that it became standard practice to ask
+ the patient to hold the film, while the dentist stood safely back away from the rays.
+
+
+ Just after the beginning of the century, Thomas Edison was helping to popularize x-rays, but the
+ horrible death of his chief technician turned Edison into an enemy of the technology. By the 1940s, the
+ dangers of radiation were coming to be understood by the general public, and it was only the
+ intervention of the US government, to popularize atomic bombs and nuclear power, that was able to
+ reverse the trend.
+
+
+ In 1956 and 1957, Linus Pauling was the only well known scientist who opposed the government’s policies.
+ The government took away his passport, and his opportunities to write and speak were limited by a
+ boycott imposed by a variety of institutions, but instigated by the nuclear industry and its agent, the
+ Atomic Energy Commission. The government which considered Pauling a threat to national security, had
+ placed thousands of German and Hungarian “ex”-Nazis in high positions in industry and government
+ agencies, after protecting them from prosecution as war criminals. The official government policy,
+ directed by the financier Admiral Strauss who controlled the Atomic Energy Commision, was to tell the
+ public that radiation was good. Their extreme secrecy regarding their radiation experiments on
+ Americans, however, indicated that they were aware of the malignant nature of their activities; many of the records were simply destroyed, so that no one could ever know what had been
+ done. Scientists who worked for the government, Willard Libby, John Goffman, and many others, were
+ working to convince the public that they shouldn’t worry. Of the multitude of scientists who served the
+ government during that time, only a few ever came to oppose those policies, and those who did were
+ unable to keep their jobs or research grants. Gofman has become the leader in the movement to protect
+ the public against radiation, especially, since 1971, through the Committee for Nuclear Responsibility,
+ PO Box 421993, San Francisco, CA 94132..
+
+
+ Gofman has said: "I was stupid in those days. In 1955, '56, people like Linus Pauling were
+ saying that the bomb fallout would cause all this trouble. I thought, 'We're not sure. If you're not
+ sure, don't stand in the way of progress.' I could not have thought anything more stupid in my life.
+
+
+
+
+ "The big moment in my life happened while I was giving a health lecture to nuclear engineers. In the
+ middle of my talk it hit me! What the hell am I saying? If you don't know whether low doses are safe
+ or not, going ahead is exactly wrong. At that moment, I changed my position entirely."[17]
+
+
+
+
+ In 1979, Gofman said: "There is no way I can justify my failure to help sound an alarm over these
+ activities many years sooner than I did. I feel that at least several hundred scientists trained in
+ the biomedical aspect of atomic energy - myself definitely included - are candidates for
+ Nuremburg-type trials for crimes against humanity for our gross negligence and irresponsibility. Now
+ that we know the hazard of low-dose radiation, the crime is not experimentation - it's murder." [18]
+
+
+
+ Many ordinary people were making exactly that argument in the 1950s, but government censorship kept the
+ most incriminating evidence from the public. The climate of intimidation spread throughout the culture,
+ so that teachers who spoke about the dangers of radiation were called disloyal, and were fired. Now,
+ people who don’t want x-rays are treated as crackpots. Probably because of this cultural situation,
+ Gofman’s recommendations are very mild--simply for doctors to use good technology and to know what they
+ are doing, which could lead to ten-fold or even hundred-fold dose reduction. Even with such mild
+ restraint in the use of diagnostic x-rays, Gofman’s well founded estimate is that 250,000 deaths caused
+ by radiation could be prevented annually. I believe many more deaths would be prevented if ultrasound
+ and MRI were used consistently instead of x-rays. Using Gofman’s estimate, I think we can blame at least
+ ten million deaths on just the medical x-rays that have been used inappropriately because of the
+ policies of the U.S. government in the last half century. That wouldn’t include the deaths caused by
+ radioactive fallout from bomb tests and leaks from nuclear power plants, or the vast numbers of people
+ mentally impaired by all sorts of toxic radiation.
+
+
+ Although nearly all the people who committed the radiation crimes of the 1950s and 1960s have
+ died or retired, the culture they created remains in the mass media and scientific journals, and in
+ the medical and academic professions.
+
+
+
+ Medical journals describe ways to minimize diagnostic x-ray exposure, and they advocate many seemingly
+ effective treatments for osteoporosis, giving an impression that progress is being made in “managing”
+ osteoporosis, but the real situation is very different. Fractures resulting from osteoporosis are
+ increasing, and osteoporosis is affecting younger and younger people. I think it would be reasonable to
+ say that a woman with osteoporosis is usually better off when it’s not diagnosed, because of the
+ dangerous things prescribed for it. Estrogen has become the main “treatment” for osteoporosis, but many
+ of the other ways of “managing” osteoporosis are both ineffective and unsafe.
+
+
+ Many women are told to stop taking a thyroid supplement when osteoporosis is diagnosed, but
+ hypothyroidism often leads to hyperprolactinema and hypercortisolemia, which are two of the most clearly
+ established causes of osteoporosis. Calcitonin, vitamin D-active metabolite, and estrogen-”HRT”
+ treaments can cause respiratory alkalosis (relative hyperventilation),[19-24] and hypothyroidism
+ produces a predisposition to hyperventilation.[25] Hyperventilation tends to cause calcium loss. In
+ respiratory alkalolis, CO2 (and sometimes bicarbonate) are decreased, impairing calcium retention, and
+ in “metabolic alkalosis,” with increased
+ bicarbonate, calcium is retained more efficiently and bone formation is stimulated, and its dissolution
+ is suppressed.
+
+
+ Other women are told to reduce their protein consumption, or to take fluoride or whatever drug has been
+ most recently promoted. A protein deficiency is a clear cause of osteoporosis, and bone density
+ corresponds to the amount of protein consumed. Milk protein, especially, protects against osteoporosis,
+ independently of milk’s other important nutrients. Too much fluoride clearly increases the risk of bone
+ fractures,[26] and the side effects of other drugs haven’t been properly studied in humans, while they
+ often have dangerous effects in animals.
+
+
+ Calcium, magnesium, vitamin A, vitamin B6- , vitamin K, and vitamin D are important for the development
+ and maintenance of bones. For example, a vitamin A deficiency limits the synthesis of progesterone and
+ proteins. In calcium deficiency, parathyroid hormone is increased, and tends to cause the typical
+ changes of aging, shifting calcium from hard tissues to soft, and decreasing the ratio of extracellular
+ to intracellular (excitatory) calcium.
+
+
+ Polyunsaturated fats are converted to prostaglandins (especially under the influence of estrogen), and
+ several prostaglandins have toxic effects on bone. Those fats also suppress the formation of thyroid
+ hormone and progesterone. The increased use of the unsaturated oils has coincided with the increase of
+ osteoporosis.
+
+
+ The oxidation of proteins caused by free radicals is increased with aging and by the use of unsaturated
+ fats, and it contributes to tissue atrophy, including the age-related shrinkage of the bones. In animal
+ studies, “adequate” dietary protein, 13.8% of the diet (equivalent to about 80 grams per day for a
+ person) is associated with more oxidative damage to tissue proteins than the very high protein diets,
+ 25.7% or 51.3%, that would be equivalent to about 150 or 300 grams of protein daily for a person.[27]
+ Yet, many physicians recommend a low protein diet to protect against osteoporosis.
+
+
+ Avoiding fluoridated water and the polyunsaturated oils, and drinking two quarts of milk daily (which
+ will provide only 66 grams of protein), and using some other nutrient-rich foods such as eggs and
+ fruits, are probably the basic things to protect the bones. For vitamins, especially K, occasional liver
+ can be helpful. Meats, fruits, leaves, and coffee are rich in magnesium.
+
+
+ Some people have argued that the acidity of urine produced by eating meat causes calcium loss. However,
+ a high protein diet also improves the absorption of calcium by the intestine. Another overlooked
+ function of dietary protein is that it stimulates insulin secretion, and insulin is anabolic for
+ bone.[28]
+
+
+ The same diet that protects against osteoporosis, i.e., plenty of protein and calcium, etc., also
+ protects against kidney stones and other abnormal calcificatons.
+
+
+ REFERENCES
+
+ 1. Proc Assoc Am Physicians 1996 Mar;108(2):155-64 Potential mechanism of estrogen-mediated
+ decrease in bone formation: estrogen increases production of inhibitory insulin-like growth
+ factor-binding protein-4. Kassem M, Okazaki R, De Leon D, Harris SA, Robinson JA, Spelsberg
+ TC, Conover CA, Riggs BL.
+
+
+ 2. Am J Phys Anthropol 1990 Dec;83(4):467-76. Stature loss among an older
+ United States population and its relation to bone mineral status. Galloway A, Stini WA, Fox
+ SC, Stein P. “With advancing age there is a gradual decrease in height apparently beginning in the
+ mid-40s. Thereafter, there is a relatively rapid decrease in measured height. This contrasts to
+ the much slower rates predicted from earlier populations (Trotter and Gleser: American Journal of
+ Physical Anthropology 9:311-324, 1951).
+ The rate of stature loss is associated with diminution of bone mineral density as well as with
+ maximum height. Since there are suggestions of a secular trend toward greater reductions in bone mineral
+ density, this study suggests there may be a secular trend toward an increase in statural loss with age.”
+
+
+ 3. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1994 Mar;160(3):260-5. [The quantitative determination of bone mineral content--a system comparison of similarly built
+ computed tomographs]. [Article in German] Andresen R, Radmer S, Banzer D, Felsenberg D,
+ Wolf KJ Klinik fur Radiologie, Universitatsklinikum Steglitz der FU Berlin. An intercomparison of 4 CT
+ scanners of the same manufacturer was performed. The bone mineral content of 11 lumbar vertebral columns
+ removed directly post mortem was determined in a specially constructed lucite-water phantom. Even
+ devices of the same construction were shown to yield a variation in the quantitative evaluation markedly
+ exceeding the annual physiological mineral loss. As long as scanner adjustment by physical calibration
+ phantoms has not yet been established, a course assessment and therapy control of bone mineral content
+ should always be carried out on the same QCT scanner.
+
+
+ 4. Osteoporos Int 1990 Oct;1(1):23-9. Vertebral bone mineral density measured
+ laterally by dual-energy X-ray absorptiometry. Slosman DO, Rizzoli R, Donath A, Bonjour JP.
+ “The bone mineral density (BMD) of lumbar vertebrae in the anteroposterior (AP) view may be
+ overestimated in osteoarthritis or with aortic calcification, which are common in elderly.” “Then, we
+ compared the capability of BMD LAT and BMD AP scans for monitoring bone loss related to age and for
+ discriminating the BMD of postmenopausal women with nontraumatic vertebral fractures from that of young
+ subjects. In vitro, when a spine phantom was placed in lateral position in the middle of 26 cm of water
+ in order to simulate both soft-tissue thickness and X-ray source remoteness, the coefficient of
+ variation (CV) of six repeated determinations of BMD was 1.0%. In vivo, the CV of paired BMD LAT
+ measurements obtained in 20 healthy volunteers after repositioning was 2.8%.”
+
+
+ 5. Eur J Nucl Med 1990;17(1-2):3-9.
+ Comparative study of the performances of X-ray and gadolinium 153 bone densitometers at the level of
+ the spine, femoral neck and femoral shaft. Slosman DO, Rizzoli R, Buchs B, Piana F, Donath
+ A, Bonjour JP. “In vivo, at the spine level, with DPA, mean
+ CV of BMD measured 6 times after repositioning in 6 healthy volunteers was 3.8% +/- 1.9% and 2.1%
+ +/- 0.7% . . . .”
+
+
+
+
+ 6. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1995 Apr;162(4):269-73. [Experimental studies of the visualization of the vertebral body spongiosa by high-resolution computed
+ tomography]. Henschel MG, Freyschmidt J, Holland BR. “The measured lower limit of
+ visualisation of cancellous bone structures is clearly worse than expected from the measurements of
+ spatial resolution with standard phantoms used for HR-CT (0.6 versus 0.4 mm). True and exact imaging
+ of normal cancellous bone cannot be achieved even by modern HR-CT. Noise creates structures
+ mimicking cancellous bone.”
+
+
+
+ 7. J Comput Tomogr 1984 Apr;8(2):91-7. Quantitative computed tomography assessment of spinal
+ trabecular bone. I. Age-related regression in normal men and women. Firooznia H, Golimbu C,
+ Rafii M, Schwartz MS, Alterman ER. “Computed tomography, utilized in conjunction with a
+ calibrated phantom containing a set of reference densities (K2HPO4 and water), is capable
+ of determining the mineral content of the trabecular bone of the spine with an
+ accuracy of about 6% of the ash weight of the vertebrae scanned (specimen studies).”
+
+
+ 8. Calcif Tissue Int 1991 Sep;49(3):174-8. Precision and stability of dual-energy X-ray
+ absorptiometry measurements.
+
+
+
+
+ 9. J Comput Assist Tomogr 1993 Nov-Dec;17(6):945-51. Influence of temperature
+ on QCT: implications for mineral densitometry. Whitehouse RW, Economou G, Adams JE.
+ “Inaccuracies in quantitative CT (QCT) for vertebral bone mineral measurements may result from
+ differences between the temperature of the vertebrae and the calibration standards.” “In the computer
+ simulation, the
+ fat error associated with single energy QCT for trabecular bone mineral densitometry was 20% less
+ for specimens at room temperature than at body temperature.” “The fat error of
+ single
+ energy QCT for mineral densitometry may have been underestimated in previous in vitro studies using
+ vertebral specimens scanned at room temperature.”
+
+
+ 10. Phys Med Biol 1986 Jan;31(1):55-63. Quantitative CT measurements: the
+ effect of scatter acceptance and filter characteristics on the EMI 7070. Merritt RB,
+ Chenery SG “Non-linearities in projection values on computed tomography (CT) scanners cause
+ corresponding errors in derived Hounsfield unit attenuation measurements. Existing commercial
+ machines have been refined for clinical usefulness but not necessarily for quantitative
+ accuracy.”
+ “It is concluded that, irrespective of any quality assurance protocol, interpatient and
+ interslice errors can be expected to range from 3 to 10% for water-equivalent materials and the
+ intraslice positional dependence of the CT number can vary up to 5% for dense bone-like materials in
+ a uniform phantom.”
+
+
+ 11. Skeletal Radiol 1986;15(5):347-9. Observer variation in the detection of
+ osteopenia. Epstein DM, Dalinka MK, Kaplan FS, Aronchick JM, Marinelli DL, Kundel HL. In
+ order to determine observer variation in the detection of osteopenia, 15 pairs of lateral chest
+ radiographs obtained within two weeks of each other were reviewed separately by two radiologists and one
+ orthopedist on three separate occasions. Intra- and interobserver variations were calculated for each
+ individual film and film pairs using Kappa values. The individual observers were not able to
+ give consistent readings on the same film on different days
+
+ additional factors of repeat films
+
+ or separate observers
+
+ agreement was even worse.
+ The identification of osteopenia from the lateral view of the thoracic spine is highly
+ subjective and variable from film to film and observer to observer.
+
+
+ 12. P. Schneider and C. Reiners, Letter, JAMA 277(1), 23, Jan. 1, 1997. "The
+ influence of fat distribution on bone mass measurements with DEXA can be of considerable magnitude
+ and ranges up to 10% error per 2 cm of fat."
+
+
+ 13. Calcif Tissue Int 1990 Apr;46(4):280-1. Effect of radiographic
+ abnormalities on rate of bone loss from the spine. Dawson-Hughes B, Dallal GE. “Spurious rates of loss of spine BMD are likely to be found in subjects with calcification of the
+ aorta, osteophytes or other abnormalities in the spine scan field. This should be kept in mind when
+ serial spine scans are being considered in these subjects.”
+
+
+
+ 14. Przegl Lek 2000;57(2):93-9. [No title available]. Jaworski M, Lorenc RS. “. . .Dual Energy X-ray Absorptiometry (DEXA) method is a reference method to diagnose
+ osteoporosis. This method allows to measure bone density and bone mass, however bone quality can
+ not be estimated. Quantitative ultrasound (QUS)
+ method provides information about bone structure.”
+
+
+ 15. Osteoporos Int 2000;11(4):354-60.
+ Assessment of a new quantitative ultrasound calcaneus measurement: precision and discrimination of
+ hip fractures in elderly women compared with dual X-ray absorptiometry. He YQ, Fan B, Hans
+ D, Li J, Wu CY, Njeh CF, Zhao S, Lu Y, Tsuda-Futami E, Fuerst T, Genant HK.
+
+
+ 16. Cas Lek Cesk 2000 Apr 26;139(8):231-6 [X-ray densitometry and
+ ultrasonography of the heel bone--sensitivity and comparison with densitometry of the axial
+ skeleton]. [Article in Czech] Michalska D, Zikan V, Stepan J, Weichetova M, Kubova V,
+ Krenkova J, Masatova A. “The DXA of the heel underestimates the prevalence of osteoporosis. The results
+ of the heel QUS (Stiffness) appear to be better correlated to femoral BMD than heel BMD.”
+
+
+ 17. John Gofman, M.D. (biographical chapter. pages 401-412.) In Studs Terkel's book
+ Coming of Age. The Story of our Century by Those Who Lived It. The New Press.
+ NY. 1995.
+
+
+ 18. Gofman, J.W. An irreverent, illustrated view of nuclear power.
+ Committee for Nuclear Responsibility. San Francisco, CA. pp. 227-228, 1979.
+
+
+ 19. Kidney Int 1992 Sep;42(3):727-34. Chronic respiratory alkalosis induces
+ renal PTH-resistance, hyperphosphatemia and hypocalcemia in humans. Krapf R, Jaeger P,
+ Hulter HN Department of Medicine, Insel University Hospital, Berne, Switzerland. “The effects of
+ chronic respiratory alkalosis on divalent ion homeostasis have not been reported in any
+ species.” “Chronic respiratory alkalosis (delta PaCO2, -8.4 mm Hg, delta[H+] -3.2
+ nmol/liter) resulted in a sustained decrement in plasma ionized calcium concentration (delta[IoCa++]p,
+ -0.10 mmol/liter, P less than 0.05) and a sustained increment in plasma phosphate concentration
+ (delta[PO4]p, +0.14 mmol/liter, P less than 0.005) associated with increased fractional
+ excretion of Ca++ . . .”
+
+
+
+ 20. J Clin Endocrinol Metab 1999 Jun;84(6):1997-2001 Hormone replacement
+ therapy causes a respiratory alkalosis in normal postmenopausal women.
+
+ partial pressure of carbon dioxide. . . .”
+ “Accompanying changes in blood pH were apparent in the estrogen plus MPA group, where there was
+ an upward trend at 1 week
+
+
+
+ 21. Wien Klin Wochenschr 1979 Apr 27;91(9):304-7 [Investigations on the
+ pathogenesis of distal renal tubular acidosis]. Schabel F, Zieglauer H. “Bicarbonate loading is followed by a lowering of calcium excretion to within the normal range and a
+ decrease in the uncharacteristic renal hyperaminoaciduria.”
+
+
+
+ 22. Calcif Tissue Int 1984 Sep;36(5):604-7. Respiratory alkalosis and reduced
+ plasmatic concentration of ionized calcium in rats treated with 1,25
+ dihydroxycholecalciferol. Locatto ME, Fernandez MC, Caferra DA, Gimenez MC, Vidal MC, Puche
+ RC. “The daily administration of supraphysiological doses of 1,25 dihydroxycholecalciferol (0.1-2.5
+ micrograms/d/100 g body weight) to rats, produced respiratory alkalosis. With the doses of 0.1-0.2
+ micrograms/d/100 g and feeding a diet with 0.7% of calcium, calcemias did not exceed 2.75 mM, and
+ significantly reduced plasma ionized calcium levels were measured. The latter
+ phenomenon was found associated with increased urinary excretion of cAMP, soft tissue calcium
+ content, and polyuria with hypostenuria, all known effects of parathyroid hormone.”
+
+
+ 23. Am J Physiol 1996 Jul;271(1 Pt 2):F216-22. Metabolic alkalosis decreases
+ bone calcium efflux by suppressing osteoclasts and stimulating osteoblasts. Bushinsky
+ DA.
+ “In vivo and in vitro evidence indicates that metabolic acidosis, which may occur prior to complete
+ excretion of end products of metabolism, increases urinary calcium excretion.
+ The additional urinary calcium is almost certainly derived from bone mineral.” “To
+ determine whether metabolic alkalosis alters net calcium efflux (JCa+) from bone and bone cell function,
+ we cultured neonatal mouse calvariae for 48 h in either control medium (pH approximately equal to
+ 7.4, [HCO3-] approximately equal to 24), medium simulating mild alkalosis (pH
+ approximately equal to 7.5, [HCO3-] approximately equal to 31), or severe alkalosis (pH approximately
+ equal to 7.6, [HCO3-] approximately equal to 39) and measured JCa+ and the release of
+ osteoclastic beta-glucuronidase and osteoblastic collagen synthesis. Compared with control, metabolic
+ alkalosis caused a progressive decrease in JCa+, which was correlated inversely with
+ initial medium pH (pHi). Alkalosis caused a decrease in osteoclastic beta-glucuronidase
+ release, which was correlated inversely with pHi and directly with JCa+. Alkalosis also
+ caused an increase in osteoblastic collagen synthesis, which was correlated directly with pHi and
+ inversely with JCa+. There was a strong inverse correlation between the effects alkalosis on
+ osteoclastic beta-glucuronidase release and osteoblastic collagen synthesis. Thus metabolic alkalosis
+ decreases JCa+ from bone, at least in part, by decreasing osteoclastic resorption and increasing
+ osteoblastic formation. These results suggest that the provision of base to neutralize endogenous acid
+ production may improve bone mineral accretion.”
+
+
+ 24. Am J Physiol 1997 Nov;273(5 Pt 2):F698-705 The effects of respiratory
+ alkalosis and acidosis on net bicarbonate flux along the rat loop of Henle in vivo. Unwin
+ R, Stidwell R, Taylor S, Capasso G.
+
+
+ 25. Can J Anaesth 1999 Feb;46(2):185-9. Acute respiratory alkalosis associated
+ with low minute ventilation in a patient with severe hypothyroidism. Lee HT, Levine M.
+ “His profoundly lowered basal metabolic rate and decreased CO2 production, resulting probably
+ from severe hypothyroidism, may have resulted in development of acute respiratory alkalosis in spite
+ of concurrently diminished minute ventilation.”
+
+
+ 26. Am J Epidemiol 1991 Apr 1;133(7):649-60.
+ A prospective study of bone mineral content and fracture in communities with differential fluoride
+ exposure. Sowers MF, Clark MK, Jannausch ML, Wallace RB. “Residence in the higher-fluoride
+ community was associated with a significantly lower radial bone mass in premenopausal
+ and postmenopausal women, an increased rate of radial bone mass loss in premenopausal women, and
+ significantly more fractures among postmenopausal women. There was no difference in the 5-year relative
+ risk of any fracture in the higher-calcium community versus the control community; however, the
+ relative risk was 2.1 (95% confidence interval (CI) 1.0-4.4) in women in the higher-fluoride
+ community compared with women in the control community.
+ There was no difference in the 5-year risk of wrist, spine, or hip fracture in the
+ higher-calcium community versus the control community; however, the 5-year relative risk for women
+ in the higher-fluoride community, compared with women in the control community, was 2.2 (95% CI
+ 1.1-4.7). Estimates of risk were adjusted for age and body size.”
+
+
+ 27. J Nutr 2000 Dec;130(12):2889-96.
+ Long-term high protein intake does not increase oxidative stress in rats. Petzke KJ, Elsner
+ A, Proll J, Thielecke F, Metges CC.
+
+
+ 28. Med Hypotheses 1995 Sep;45(3):241-6.
+ Anabolic effects of insulin on bone suggest a role for chromium picolinate in preservation of bone
+ density. McCarty MF. “Physiological levels of insulin reduce the ability of PTH to activate
+ protein kinase C in osteoblasts, suggesting that insulin may be a physiological antagonist of bone
+ resorption. In addition, insulin is known to promote collagen production by osteoblasts.” [I
+ think chromium is too toxic to use as a supplement.]
+
+
+
+ 29: Anesthesiology 1998 Dec;89(6):1389-400. Effects of hyperventilation and
+ hypocapnic/normocapnic hypoxemia on renal function and lithium clearance in humans.
+ Vidiendal Olsen N, Christensen H, Klausen T, Fogh-Andersen N, Plum I, Kanstrup IL, Hansen JM Department
+ of Neuroanaesthesia, Copenhagen University Hospital, Denmark. NVO@DADLNET.DK BACKGROUND: Using the renal
+ clearance of lithium as an index of proximal tubular outflow, this study tested the hypothesis that
+ acute hypocapnic hypoxemia decreases proximal tubular reabsorption to the same extent as hypocapnic
+ normoxemia (hyperventilation) and that this response is blunted during normocapnic hypoxemia. METHODS:
+ Eight persons were studied on five occasions: (1) during inhalation of 10% oxygen (hypocapnic
+ hypoxemia), (2) during hyperventilation of room air leading to carbon dioxide values similar to those
+ with hypocapnic hypoxemia, (3) during inhalation of 10% oxygen with the addition of carbon dioxide to
+ produce normocapnia, (4) during normal breathing of room air through the same tight-fitting face mask as
+ used on the other study days, and (5) during breathing of room air without the face mask. RESULTS:
+ Hypocapnic and normocapnic hypoxemia and hyperventilation increased cardiac output, respiratory minute
+ volume, and effective renal plasma flow. Glomerular filtration rate remained unchanged on all study
+ days. Calculated proximal tubular reabsorption decreased during hypocapnic hypoxemia and
+ hyperventilation but remained unchanged with normocapnic hypoxemia. Sodium clearance increasedslightly during hypocapnic and normocapnic hypoxemia, hyperventilation, and normocapnic
+ normoxemia with but not without the face mask. CONCLUSIONS:The results indicate
+ that
+ (1) respiratory alkalosis with or without hypoxemia decreases proximal tubular reabsorption and that
+ this effect, but not renal vasodilation or natriuresis, can be abolished by adding carbon dioxide to
+ the hypoxic gas; (2) the increases in the effective renal plasma flow were caused by
+ increased ventilation rather than by changes in arterial oxygen and carbon dioxide levels; and (3) the
+ natriuresis may be secondary to increased renal perfusion, but application of a face mask also may
+ increase sodium excretion.
+
+
+ 31: Wien Klin Wochenschr 1979 Apr 27;91(9):304-7. [Investigations on the pathogenesis of distal
+ renal tubular acidosis]. [Article in German] Schabel F, Zieglauer H In distal (type 1) RTA,
+ renal acid excretion is impaired by the inability to establish adequate pH gradients between plasma and
+ distal tubular fluid at any level of acidosis. Main clinical signs in infancy are anorexia, vomiting and
+ failure to thrive. Despite low serum bicarbonate levels the renal threshold of bicarbonate is normal,
+ while urinary pH levels are high even with values below the threshold. Under conditions of
+ bicarbonate-induced systemic alkalosis urinary the pCO2 exceeds blood pCO2 in normal
+ subjects. by contrast, the urinary pCO2 tension is not significantly greater in distal RTA,
+ indicating a failure of the cells of the distal nephron to secrete hydrogen ions even without a
+ gradient. Red cell carbonic anhydrase is within the normal range, whilst the inhibition of carbonic
+ anhydrase activity has no effect on distal tubular function. Until now no histological or enzymatic
+ defect could be detected to explain the ineffective acidification. Bicarbonate loading is
+ followed by a lowering of calcium excretion to within the normal range and a decrease in
+ the uncharacteristic renal hyperaminoaciduria.
+
+
+
+
+
+
+
diff --git a/raypeat-articles/processed/breastcancer.html b/raypeat-articles/processed/breastcancer.html
new file mode 100644
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--- /dev/null
+++ b/raypeat-articles/processed/breastcancer.html
@@ -0,0 +1,585 @@
+
+ Breast Cancer
+
+
+ Breast Cancer
+
+
+
+
+ It’s important to know the realities of cancer in the population, the death rate from cancer, and the
+ effects of its aggressive diagnosis and treatment. Appreciating those, I think the need for a new
+ attitude toward cancer can be seen.
+
+
+ Official US data for the years 1990 to 1993 showed 505,300 cancer deaths in 1990, and 529,900 cancer
+ deaths in 1993. This was an increase of roughly 1.3% per year (which was faster than the population
+ growth) during the time in which Rodu and Cole (1996) and agencies of the U.S. government claimed the
+ death rate was decreasing one half percent (0.5%) per year.
+
+
+ This increase happened despite the abnormal population bulge in the number of people between the ages of
+ 35 and 50, resulting from the postwar baby boom. Cancer incidence is about ten times higher among the
+ older population than in this younger age range, so in this abnormally structured population, the death
+ rate from cancer is much lower than it would be if the population composition were the same as before
+ the war, and it is lower than it will be in ten or twenty years, when the population bulge reaches the
+ prime cancer years.
+
+
+ In 1994, total cancer deaths increased to 536,900 (an increase of 1.32% over 1993). The crude death rate
+ per 100,000 population was 203.2 in 1990, in 1993 it was 205.6, in 1994 it had increased to 206. This, despite the population distortion caused by the baby boom, causing a scarcity of people
+ in the age groups with the highest rates of cancer mortality.
+
+
+ In the U.S. in 1994 there were altogether 2,286,000 deaths. In a population of about 260 million, this
+ was a death rate of less than 1% per year (about 0.88%). The chance of dying that year for any person
+ was less than one in a hundred. That doesn’t mean that life expectancy is over 100 years, but that would
+ be implied if we ignored the population bulge of the baby boomers, as the cancer statisticians are
+ doing.
+
+
+ When the U.S. Department of Health and Human Services, and every major medical journal in the United
+ States lies about the simple statistics of cancer death rates, it’s clear that very powerful and
+ dangerous social forces are operating. Anyone who knows about the baby boom that started right after the
+ second world war must also realize that in 1940, at the end of the great depression, when infant and
+ childhood mortality was very high and people postponed having children, the population had a
+ disproportionate number of old people, and that it would be outrageous to use the rate of cancer in the
+ pre-war population to evaluate the rate of cancer in the post-war population. But that is what is being
+ done, and the mass media are helping to prevent the public from questioning the official story about
+ cancer.
+
+
+ If the health of the population in 1940 is to be compared to that of a very differently constituted
+ later population, the appropriate method is to compare the rate of death among people of a certain age.
+ The death rate from leukemia, especially among children, was greatly increased in the post-war years,
+ when people were being exposed to radiation from atomic bomb tests. The death rates among adults of
+ various ages, from breast cancer, prostate cancer, and melanoma have steadily increased. Rodu and Cole,
+ who declared victory in the war against cancer, said the decline in total cancer mortality began in
+ 1991. (Cole and Rodu, 1996) If lung cancer is excluded, they say mortality from other cancers
+ has been declining since 1950! (“The fifty-year decline of cancer in America,” Rodu and
+ Cole, 2001.) The first time I saw this bizarre use of “age restandardization” was when Professor Bruce
+ Ames was on a lecture tour for the American Cancer Society, and was speaking to the biology department
+ at the University of Oregon. He showed a graph indicating that the mortality curves for most types of
+ cancer in the U.S. had begun their downward curve in the late 1940s just after the A.C.S. came onto the
+ scene. Even though I think the A.C.S. probably initiated the practice of age-standardizing with
+ reference to the 1940 population, they don’t always find that date suitable for their purposes. In
+ fund-raising literature showing their past success in curing childhood leukemia, they restandardized
+ mortality with reference to the postwar year when the leukemia death rate was at its highest, with the
+ result that their cures appeared to be steadily lowering the death rate. But the incidence rate varied
+ according to the intensity of the radioactive intensity that pregnant women were exposed to, and so both
+ the incidence and the mortality fell after atmospheric testing was stopped.
+
+
+ Government officials, editors of the big medical journals, professors and broadcasters, have been able
+ to get away with this huge statistical fraud. I suspect that they will soon feel encouraged to simply
+ make up the data that they want, because eventually “age standardization” isn’t going to work to hide
+ the actual increases in mortality. Since people with cancer usually die of something else, such as a
+ stroke or heart failure, it will be no trick at all to make cancer mortality decline to be replaced by
+ other causes of death. The precedent for such fabulizing of data exists in the FDA’s approval of AZT,
+ and other less notorious drugs.
+
+
+ Radiation, estrogen, and a variety of chemical pollutants are known to be the major causes of breast
+ cancer, but the efforts of the cancer establishment have been directed toward denying that these
+ avoidable agents are the cause of the great increase in breast cancer during the last several decades.
+ The cancer industry, including major producers of chemotherapy drugs, subsidizes the American Cancer
+ Society and “Breast Cancer Awareness Week,” and it is in their interest to convince the public that
+ early detection and conventional treatment with surgery, chemotherapy, and radiation are winning the war
+ against cancer. There is always light at the end of the tunnel, in the war against cancer, just as there
+ was in the Vietnam war. Their consistent effort to dissuade the government from acting to reduce the
+ public’s exposure to the known causes of cancer should make it clear that they are in the business of
+ treating cancer, not eliminating it.
+
+
+ In the 1960s I read some articles in a small town newspaper about Leonell Strong’s cancer research, and
+ his treatment by the American Cancer Society and the Salk Institute. Leonell Strong had developed
+ strains of mice for use in cancer research. In some of the strains, 100% of the females developed
+ mammary cancer. Strong had demonstrated that these strains had very high levels of estrogen. He showed
+ me mice that he had treated with simple extracts of liver, that were free of cancer, and whose
+ descendants remained free of cancer for several generations.
+
+
+ Strong had received his PhD in genetics under T. H. Morgan. For a person trained in classical genetics,
+ and who had spent his career developing the supposedly genetically determined cancer trait, the
+ elimination of the trait by a few injections must have been hard to understand, but at least he tried to
+ understand it.
+
+
+ When he had earlier demonstrated the presence of a virus in the milk of cancer-prone mice, and when he
+ showed the role of heredity in cancer, he was popular with the cancer business, but when he showed that
+ “genetic” cancer could be eradicated with a simple treatment, he became the object of official abuse. He
+ said that the Salk institute had offered him a position to induce him to move with his large colony of
+ mice from New York to San Diego, but when he arrived he found that he had no job, and his records of
+ decades of research had been lost. He said that a memo which was discovered in a lawsuit revealed that
+ the institute had just wanted his mice, and never intended to give him the promised job. For the cancer
+ establishment, his discovery of a way to prevent cancer was not welcome.
+
+
+ In 1969, two years before the war against cancer had begun pouring public money into the pockets of the
+ cancer establishment, Harry Rubin gave a lecture that criticized the cancer establishment’s claim that
+ it was curing cancer. He cited a study by a pathologist who had looked for cancer in the tissues of
+ people who had been killed in accidents. He found identifiable cancers in the tissues of everyone over
+ the age of fifty that he examined. If everyone over 50 has histologically detectable cancer, then the use of biopsy specimens as the basis for determining whether a person needs treatment has no
+ scientific basis.
+
+
+ The definition of a disease, and the recognition of its presence, has an important place in medicine,
+ but understanding its cause or causes is essential for both treatment and prevention. The dominant
+ belief in medicine is that diseases are significantly caused by “genes,” including diseases such as
+ cancer, diabetes, psychoses, and neurological diseases. In Israel, ethnic groups that had never had much
+ diabetes before immigrating, within a single generation had diabetes as often as other Israelis. Shortly
+ after insulin became available for the treatment of diabetes, the incidence of the disease in the U.S.
+ began to increase. The simple death rate from diabetes per 100,000 population is now higher than it was
+ in 1920, before insulin treatment became available. Neurological diseases and autoimmune diseases, along
+ with diabetes and cancer, have increased greatly in recent generations. These simply aren’t genetic
+ diseases, and there should be a shift of resources away from useless or harmful treatments toward their
+ prevention.
+
+
+ Even when a disease’s cause isn’t clearly understood, it is essential to use logical thinking in
+ diagnosing its presence. The presence of a certain gene or “genetic marker” is often thought to have
+ great diagnostic significance, which it rarely has. But even gross “signs” of a disease can be used
+ diagnostically only if we know that similar signs aren’t present in perfectly healthy
+ people. When pains are thought to be the result of a herniated intervertebral disk, x-ray
+ pictures may be produced as confirmation of the diagnosis. But when people without pains are just as
+ likely to have herniated disks (about 2/3 of normal people have them), the diagnosis fails to be
+ convincing. When x-rays or MRIs show “plaques” in the head, multiple sclerosis is often “confirmed,” but
+ when normal medical students show just as many brain plaques, the diagnosis must be questioned.
+ Similarly, when mature people who were perfectly healthy until they were killed by an accident are found
+ to always have identifiable cancers, any diagnosis of cancer that is based on a similar histological
+ specimen must be reconsidered.
+
+
+ By diagnosing something that is as common and trivial as dandruff as “cancer,” physicians can get a very
+ high rate of cures, whether they use surgery, radiation, or chemotherapy. Abnormal cellular
+ proliferation is usually harmless, but it has become an important part of a business that makes several
+ billion dollars per year, with no definite benefits except the financial benefits for those in the
+ business.
+
+
+ Before cancer treatment became culturally practically obligatory, and when fewer people died of cancer,
+ some people lived into old age with clearly “malignant” cancers, and died of some other cause. The
+ policy of leaving a cancer alone is now established for prostate cancer in old men. Until there is clear
+ evidence to the contrary, a similar policy might be appropriate for many kinds of cancer.
+
+
+ If every year more people are treated for cancer, and every year more people die of cancer, one simply
+ wonders whether fewer people would die if few were treated.
+
+
+ If the first rule of medicine is to do no harm, then the second rule, growing out of the first, would
+ have to be to give no treatment without knowing what is being treated, and to have a valid basis for
+ believing that the damage done by the treatment is not worse than the damage that the disease would
+ cause. If cancer specialists haven’t demonstrated that their treatments improve their patients’
+ situation, then their professional activities aren’t justified; the statistics suggest that they aren’t.
+
+
+ There simply isn’t a valid base of knowledge about the natural history of cancer development in humans
+ to permit a valid judgment to be made about the meaning of particular signs or indicators or
+ histological structures. The extensive use of mammograms has increased the diagnosis of “ductal
+ carcinoma in situ” by more than 1000% (a 16- or 18-fold increase in some
+ hospitals, and expected to double in the next decade), increasing the number of mastectomies and other
+ treatments, but the increased treatments and early diagnosis haven’t produced any visible
+ change in the death rate.
+
+
+
+ The pathologists talk knowingly of “pre-neoplastic” conditions that indicate an increased risk of
+ malignancy, but instead of data, what they have is an ideology about the nature of cancer. When they say
+ that a growth pattern is premalignant or that a cell has a malignant structure, they might as well be
+ talking about goblins, because the scientific basis for what they are saying is nothing but a belief in
+ the ideology that cancer is “clonal,” that a particular cancer derives from a single defective
+ cell. They are so self-assured, and have so many sources to cite about the “clonal nature
+ of cancer,” that it seems impolite to suggest that they might simply be misusing language and logic.
+
+
+ Isn’t a person derived from a single cell, and so, in that sense, “clonal”? As organs differentiate in
+ the development of the organism, can’t organs be traced back to the cells from which they developed?
+ Isn’t every tissue “a clone” in that sense? What is it that makes the “clonal” nature of cancer tissue
+ so special? Isn’t it just that a nasty, mean, malignant tissue is, mentally, traced back to a
+ “malignant” cell, by analogy with the way good tissues are traced back to good cells? If the tumor is
+ odious, it must derive from an odious cell, and what could make that cell so hateful if it is
+ genetically identical to the good cells? Therefore, the goblin reasoning goes, a genetic mutation must
+ have produced the evil cell.
+
+
+ The actual evidence is that there are broad changes in tissues preceding the appearance of cancer. The
+ goblin theory explains this by saying that a multitude of “precancerous” mutations occurred before the
+ mutant cancer cell appeared. Harry Rubin has carefully shown experimentally and logically that cancer
+ precedes the genetic changes that occur in tumors. But the ideology that cancer is the result of a
+ genetic mutation forces its devotees to say that the genetic changes that can be found in a mature tumor
+ must have occurred in one cell that was previously not malignant. An effect is identified as a cause.
+
+
+ The clonal-goblin theory of cancer leads logically to the conclusion that the cancer clone must be
+ exorcised by surgery, chemotherapy, and/or radiation.
+
+
+ The biological theory of cancer, on the other hand, is inclined to view the normal and abnormal
+ development of cells in terms of the cells’ responses to conditions.
+
+
+ Estrogen and ionizing radiation are the most clearly documented causes of breast cancer. Their
+ excitatory effects lead to inflammation, edema, fibrosis, and interruption of intercellular regulatory
+ processes. Radiation is estrogenic, and increased estrogenic stimulation produces growth and temporary
+ loss of differentiated functions. Estrogen and radiation aren’t the only things that can cause these
+ systematic changes in the structure of tissues--for example, vitamin A deficiencies, hypothyroidism,
+ chlorinated hydrocarbons, irritation, and lack of oxygen can cause similar changes--but estrogen and
+ irradiation have been studied enough to give us a fairly distinct picture of the real processes involved
+ in the development of cancer.
+
+
+ Polyunsaturated fats are another clearly identified cause of cancer, especially breast cancer. These
+ fats synergize with estrogen, and sensitize to radiation. Their effects on the mother can be seen in the
+ offspring, as an increased tendency to develop breast or prostate cancer.
+
+
+ An individual’s hormone balance can be disrupted by exposure to radiation, estrogens, or unsaturated
+ fats. The hormonal balance of the parent is imprinted upon the offspring, acting on the chromosomes, the
+ liver, brain, genitals, pituitary, bones--in fact, the prenatal imprint can probably be found everywhere
+ in the offspring.
+
+
+ It’s easy to reduce our exposure to radiation, by avoiding mammograms, bone density scans, and
+ other x-rays of all sorts. Ultrasound and MRI can produce good images of any tissue without the
+ deadly effects of ionizing radiation.
+
+
+
+ Polyunsaturated fats can be reduced by careful selection of foods, but the food industry is finding ways
+ to contaminate traditionally safe foods, such as beef and milk, by using new kinds of animal feed.
+ Still, milk, cheese, beef, and lamb are safe, considering their high nutritional content, and the
+ remarkable purification that occurs in the rumen of cows, sheep, and goats. Some studies suggest a
+ protective effect from saturated fat (Chajes, et al., 1999.)
+
+
+ Estrogenic influences can be significantly reduced by avoiding foods such as soy products and
+ unsaturated fats, by eating enough protein to optimize the liver’s elimination of estrogen, and by using
+ things such as bulk-forming foods (raw carrots, potatoes, and milk, for example) that stimulate bowel
+ action and prevent reabsorption of estrogens from the intestine. Avoiding hypothyroidism is essential
+ for preventing chronic retention or formation of too much estrogen.
+
+
+ Some studies show that dietary starch, rather than fat, is associated with breast cancer. Starch
+ strongly stimulates insulin secretion, and insulin stimulates the formation of estrogen.
+
+
+ Estrogen is formed in fat cells under the influence of cortisol, and this formation is suppressed by
+ progesterone and thyroid. Postmenopausal obesity is associated with increased estrogen and breast
+ cancer. The prevention of weight gain, and supplementation with thyroid and progesterone if necessary,
+ should be protective against many types of cancer, especially breast, kidney, and uterine cancer.
+
+
+ Prenatal or early life exposure to estrogens, including phytoestrogens, or to irradiation, or to
+ polyunsaturated oils, increases the incidence of mammary cancers in adulthood.
+
+
+ Protein deficiency prenatally or early in life causes a life-long excess of serotonin. Feeding an excess
+ of tryptophan, the precursor of serotonin, during pregnancy produces pituitary and mammary tumors in the
+ offspring. Serotonin, besides being closely associated with the effects of estrogen (e.g., mediating its
+ stimulation of prolactin secretion) and polyunsaturated fats, can be metabolized into carcinogens.
+
+
+ Prenatal protein deficiency and excess unsaturated oils predispose to a developmental pattern involving
+ hypothyroidism and hyperestrogenism; puberty occurs at an earlier age, along with a
+ tendency to gain weight. Inflammatory processes (e.g., “autoimmune diseases”) are usually intensified
+ under those conditions. Inflammation itself increases the effects of estrogen and serotonin.
+
+
+ Both preventively and therapeutically, the use of the antiinflammatory and antioxidative substances such
+ as aspirin, caffeine, progesterone, and thyroid hormone would seem appropriate. Aspirin is coming to be
+ widely accepted as an anticancer agent, and at moderate doses can cause cancer cells to die. It, like
+ progesterone and thyroid, has a wide variety of anti-estrogenic effects. Especially when a tumor is
+ painfully inflamed, aspirin’s effects can be quick and dramatic. However, people aren’t likely to be
+ pleased if their cancer doctor tells them to “take aspirin and call me in six months.” Aspirin’s
+ reputation for causing stomach bleeding causes people to avoid it, even when the alternative is
+ something that’s seriously toxic to other organs, and it might just seem too ordinary to be considered
+ as a powerful anticancer drug.
+
+
+ Because of the toxic (carcinogenic, and anti-respiratory) effects of the “essential fatty acids,” which
+ are usually stored in the tissues in very large quantities, it’s important to avoid the stresses or
+ hunger that would release the fats into the blood stream. Estrogens and adrenalin and serotonin and
+ growth hormone, and prolonged darkness, increase the release of the free fatty acids. Frequent meals,
+ including some saturated fats such as coconut oil, and a balance of protein, sugars, and salts, will
+ minimize the release of stored fats.
+
+
+ The population trends toward greater obesity and earlier puberty, both of which are associated with a
+ higher risk of breast cancer, suggest that the war against cancer is far from over. In the 19th century
+ when the incidence of breast cancer was much lower than it is now, puberty usually occurred around the
+ age of 17. In countries with a low incidence of breast cancer, puberty still occurs in the middle to
+ late teens. People who are now 100 generally had puberty years later than girls do now. The biological
+ changes now seen in children in the U.S. suggest that the incidence of degenerative diseases of all
+ sorts is likely to increase as these children grow up.
+
+
+ A metabolic approach to the prevention and treatment of cancer would have many beneficial side effects,
+ such as producing generally healthier, happier and brighter babies.
+
+
+ REFERENCES
+
+ Radiat Res 1998 Sep;150(3):330-48 Mortality in beagles irradiated during prenatal and postnatal
+ development. II. Contribution of benign and malignant neoplasia. Benjamin SA, Lee AC,
+ Angleton GM, Saunders WJ, Keefe TJ, Mallinckrodt CH. To evaluate the lifetime carcinogenic hazards of
+ exposure to ionizing radiation during development, 1,680 beagles received whole-body exposures to 60Co
+ gamma rays or sham exposures. Eight groups of 120 dogs each received mean doses of 15.6-17.5 or
+ 80.8-88.3 cGy in early, mid- or late gestation, at 8, 28 or 55 days postcoitus or at 2 days after birth.
+ Another group of 120 dogs received a mean dose of 82.6 cGy as 70-day-old juveniles and one group of 240
+ dogs received a mean dose of 81.2 cGy as 365-day-old young adults. Sham irradiations were given to 360
+ controls. Sexes were equally represented. In 1,343 dogs allowed to live out their life span, neoplasia
+ was a major disease, contributing to mortality in 40% of the dogs. There was a significant increase in
+ benign and malignant neoplasms occurring in young dogs (<4 years old), including fatal malignancies,
+ after irradiation in the perinatal (late fetal and neonatal) periods. The lifetime incidence of fatal
+ neoplasms was also increased in dogs irradiated perinatally. Three malignancies-lymphomas,
+ hemangiosarcomas and mammary carcinomas-accounted for 51% of all fatal tumors. There was an apparent
+ lifetime increase and earlier onset of lymphomas in dogs exposed as fetuses. Fatal hemangiosarcomas were
+ increased in dogs irradiated early and late in gestation. Fatal mammary carcinomas were not increased by
+ irradiation, although non-fatal carcinomas were increased after perinatal exposure. Myeloproliferative
+ disorders and central nervous system astrocytomas appeared to be increased in perinatally irradiated
+ dogs. These data suggest that irradiation in both the fetal and neonatal periods is associated with
+ increased early onset and lifetime cancer risk.
+
+
+ Int J Cancer 1999 Nov 26;83(5):585-90. Fatty-acid composition in serum phospholipids and risk of
+ breast cancer: an incident case-control study in Sweden. Chajes V, Hulten K, Van Kappel AL,
+ Winkvist A, Kaaks R, Hallmans G, Lenner P, Riboli E. “. . . women in the
”
+
+
+ Tumori 2000 Jan-Feb;86(1):12-6 Factors of risk for breast cancer influencing post-menopausal
+ long-term hormone replacement therapy. Chiechi LM, Secreto G. “. . . growing
+ evidence points to increased breast cancer risk in HRT long-term users, and the adverse effect
+ would, obviously, overwhelm any other benefit. At present, the risk/benefit ratio of HRT is an
+ object of hot debate . . . .”
+ “We conclude that some biologic and clinical markers, namely android obesity, bone density,
+ mammographic density, androgen and estrogen circulating levels, alcohol consumption, benign breast
+ disease, and familiarity, should be carefully considered before prescribing long-term HRT. Our
+ analysis suggests that HRT could increase the risk of breast cancer and useless in preventing
+ coronary heart disease and osteoporotic fractures when administered in women with
+ positivity for one or more of these markers.”
+
+
+ Cancer 1996 Nov 15;78(10):2045-8. Declining cancer mortality in the United States. Cole
+ P, Rodu B.
+
+
+ Preventing Breast Cancer:
+ The story of a Major, Proven, Preventable Cause of This Disease. John W.
+ Gofman, M.D., Ph.D. 1996. “This book uncovers the major cause of the recent breast-cancer incidence in
+ the USA. The author shows that past exposure to ionizing radiation --- primarily medical x-rays --- is
+ responsible for about 75 percent of the breast-cancer problem in the United States. The good news: Since
+ the radiation dosage given today by medical procedures can be significantly reduced without interfering
+ with a single useful procedure, numerous future cases of breast-cancer can be prevented. The author
+ recommends specific actions to start breast-cancer prevention now, not ten years from now.”
+
+
+ Am J Public Health 1998 Mar;88(3):458-60. Geographic variations in breast cancer mortality: do
+ higher rates imply elevated incidence or poorer survival? Goodwin JS, Freeman JL, Freeman
+ D, Nattinger AB. “Mortality rates from breast cancer are approximately 25% higher for women in
+ the northeastern United States than for women in the South or West. This study examined the
+ hypothesis that the elevation is due to decreased survival rather than increased incidence.” “The
+ elevated mortality in the Northeast is apparent only in older women. For women aged 65
CONCLUSIONS: Those seeking to explain the excess breast cancer mortality in the Northeast
+ should assess survival and should examine differences in cancer control practices that affect survival.”
+
+
+ Nutrition 1999 May;15(5):392-401 The influence of maternal diet on breast cancer risk among
+ female offspring. Hilakivi-Clarke L, Clarke R, Lippman M. The induction of breast cancer is
+ a long process, containing a series of biological events that drive a normal mammary cell towards
+ malignant growth. However, it is not known when the initiation of breast cancer occurs. One hypothesis
+ is that a high estrogenic environment during the perinatal period increases subsequent breast cancer
+ risk. There are many sources of extragonadal estrogens, particularly in the diet. The purpose of this
+ paper is to review the evidence that a high maternal intake of dietary fats increases serum estrogens
+ during pregnancy and increases breast cancer risk in daughters. Our animal
+ studies show that a high maternal consumption of corn oil consisting mainly of linoleic acid
+ (omega-6 polyunsaturated fatty acid, PUFA), increases both circulating estradiol (E2) levels during
+ pregnancy and the risk of developing carcinogen-induced mammary tumors among the female rat
+ offspring. A similar increase in breast cancer risk occurs in female offspring exposed to injections of
+ E2 through their pregnant mother. Our data suggest that the mechanisms by which an early exposure to
+ dietary fat and/or estrogens increases breast cancer risk is related to reduced differentiation of the
+ mammary epithelial tree and increased number of mammary epithelial cell structures that are known to the
+ sites of neoplastic transformation. These findings may reflect our data of the reduced estrogen receptor
+ protein levels and protein kinase C activity in the developing mammary glands of female rats exposed to
+ a high-fat diet in utero. In summary, a high dietary linoleic acid intake can elevate pregnancy estrogen
+ levels and this, possibly by altering mammary gland morphology and expression of fat- and/or
+ estrogen-regulated genes, can increase breast cancer risk in the offspring. If true for women, breast
+ cancer prevention in daughters may include modulating the mother's pregnancy intake of some dietary
+ fats.
+
+
+ Mol Cell Biochem 1998 Nov;188(1-2):5-12 Timing of dietary fat exposure and mammary
+ tumorigenesis: role of estrogen receptor and protein kinase C activity. Hilakivi-Clarke L,
+ Clarke R. The possible association between a high fat diet and increased breast cancer risk has remained
+ controversial. This largely reflects the conflicting data obtained from migrant, case control and animal
+ studies, which generally support this association, and cohort studies which often fail to show a link
+ between fat and breast cancer. The mammary gland is particularly sensitive to estrogens during fetal
+ development, leading us to hypothesize that dietary fat levels during this period may significantly
+ influence breast cancer risk. Using chemically-induced mammary tumors in rats as our experimental model,
+ we have demonstrated the ability of a maternal diet, high in the polyunsaturated fatty acid
+ (PUFA) linoleic acid, to alter mammary gland differentiation, accelerate the onset of sexual
+ maturation, and increase breast cancer risk. The mammary glands of female rats exposed to a
+ high-fat diet in utero have more of the undifferentiated structures (terminal end buds) and fewer of the
+ differentiated structures (alveolar buds) than the glands of rats exposed to a low-fat diet in utero.
+ Furthermore, these mammary glands contain lower levels of total estrogen receptors and have reduced
+ total protein kinase C activity. These effects appear to be mediated by an increase in the serum
+ estradiol levels of pregnancy, which are elevated at least 30% in pregnant dams fed a high-fat
+ diet. Furthermore, the administration of estradiol to pregnant dams produces effects on
+ mammary gland development, onset of puberty and sensitivity to chemical carcinogenesis comparable to
+ those seen in the offspring of rats fed a high fat diet during pregnancy. Our results, thus, support the
+ hypothesis based on epidemiological
+ data that high maternal estrogen levels increase daughters' breast cancer risk. The results also
+ suggest that a high-fat diet may be an important factor in increasing pregnancy estrogenic activity.
+
+
+
+ Proc Natl Acad Sci U S A 1997 Aug 19;94(17):9372-7. A maternal diet high in n - 6
+ polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among
+ female rat offspring. Hilakivi-Clarke L, Clarke R, Onojafe I, Raygada M, Cho E, Lippman M.
+ We hypothesized that feeding pregnant rats with a high-fat diet would increase both circulating
+ 17beta-estradiol (E2) levels in the dams and the risk of developing carcinogen-induced mammary
+ tumors among their female offspring. Pregnant rats were fed isocaloric diets containing 12% or 16%
+ (low fat) or 43% or 46% (high fat) of calories from corn oil, which primarily contains the
+ n - 6 polyunsaturated fatty acid (PUFA) linoleic acid, throughout pregnancy. The
+ plasma concentrations of E2 were significantly higher in pregnant females fed a high n - 6 PUFA
+ diet. The female offspring of these rats were fed with a laboratory chow from birth onward, and when
+ exposed to7,12-dimethylbenz(a)anthracene had a significantly higher mammary tumor incidence
+ (60% vs. 30%) and shorter latency for tumor appearance (11.4 +/- 0.5 weeks vs. 14.2 +/- 0.6 weeks) than
+ the offspring of the low-fat mothers. The high-fat offspring also had puberty onset at a younger age,
+ and their mammary glands contained significantly higher numbers of the epithelial structures that are
+ the targets for malignant transformation. Comparable changes in puberty onset, mammary gland morphology,
+ and tumor incidence were observed in the offspring of rats treated daily with 20 ng of E2 during
+ pregnancy. These data,
+ if extrapolated to humans, may explain the link among diet, early puberty onset, mammary parenchymal
+ patterns, and breast cancer risk, and indicate that an in utero exposure to a diet high in n - 6
+ PUFA and/or estrogenic stimuli may be critical for affecting breast cancer risk.
+
+
+
+ Oncol Rep 1998 May-Jun;5(3):609-16 Maternal genistein exposure mimics the effects of estrogen on
+ mammary gland development in female mouse offspring. Hilakivi-Clarke L, Cho E, Clarke R.
+ Human and animal data indicate that a high maternal estrogen exposure during pregnancy increases breast
+ cancer risk among daughters. This may reflect an increase in the epithelial structures that are the
+ sites for malignant transformation, i.e., terminal end buds (TEBs), and a reduction in epithelial
+ differentiation in the mammary gland. Some phytoestrogens, such as genistein which is a major component
+ in soy-based foods, and zearalenone, a mycotoxin found in agricultural products, have estrogenic effects
+ on the reproductive system, breast and brain. The present study examined whether in utero exposure to
+ genistein or zearalenone influences mammary gland development. Pregnant mice were injected daily with i)
+ 20 ng estradiol (E2); ii) 20 microg genistein; iii) 2 microg zearalenone; iv) 2 microg tamoxifen (TAM),
+ a partial estrogen receptor agonist; or v) oil-vehicle between days 15 and 20 of gestation. E2,
+ genistein, zearalenone, and tamoxifen all increased the density of TEBs in the mammary glands. Genistein
+ reduced, and zearalenone increased, epithelial differentiation. Zearalenone also increased epithelial
+ density, when compared with the vehicle-controls. None of the treatments had permanent effects on
+ circulating E2 levels. Maternal exposure to E2 accelerated body weight gain, physical maturation (eyelid
+ opening), and puberty onset (vaginal opening) in the female offspring. Genistein and tamoxifen had
+ similar effects on puberty onset than E2. Zearalenone caused persistent cornification of the estrus
+ smears. These findings indicate that maternal exposure to physiological doses of genistein mimics the
+ effects of E2 on the mammary gland and reproductive systems in the offspring. Thus, our results suggest
+ that genistein acts as an estrogen in utero, and may increase the incidence of mammary tumors if given
+ through a pregnant mother. The estrogenic effects of zearalenone on the mammary gland, in contrast, are
+ probably counteracted by the permanent changes in estrus cycling.
+
+
+ Am J Public Health 1991 Apr;81(4):462-5 Does increased detection account for the rising
+ incidence of breast cancer? Liff JM, Sung JF, Chow WH, Greenberg RS, Flanders WD. “The
+ incidence of breast cancer has been increasing over time in the United States.” “To determine the role
+ of screening in this increase, trends in the incidence of in situ and invasive carcinoma of the breast
+ were evaluated using records of the metropolitan Atlanta SEER program between 1979 and 1986.” “The
+ average annual age-adjusted incidence of invasive disease rose 29 percent among Whites and 41 percent
+ among Blacks. Incidence increased in all age groups.” “Asymptomatic tumors accounted for only 40 percent
+ of the increased incidence among whites and 25 percent of the increased incidence among blacks, with
+ mammography as the principal contributing procedure.” “These data suggest that increased detection
+ accounts for some but not all of the rising incidence of breast cancer in the United States.”
+
+
+ J Clin Oncol 2001 Jan 1;19(1):239-41. The fifty-year decline of cancer in america. Rodu
+ B, Cole P. Department of Pathology, School of Medicine, and the Department of Epidemiology, School of
+ Public Health, University of Alabama at Birmingham, Birmingham, AL. PURPOSE: From 1950 to 1990, the
+ overall cancer mortality rate increased steadily in the United States, a trend which ran counter to
+ declining mortality from other major diseases. The purpose of this study was to assess the impact of
+ lung cancer on all-cancer mortality over the past 50 years. METHODS: Data from the National Centers for
+ Health Statistics were used to develop mortality rates for all forms of cancer combined, lung cancer,
+ and other-cancer (all-cancer minus lung cancer) from 1950 to 1998. RESULTS: When lung cancer is
+ excluded, mortality from all other forms of cancer combined declined continuously from 1950 to 1998,
+ dropping 25% during this period. The decline in other-cancer mortality was approximately 0.4%
+ annually from 1950 to 1990 but accelerated to 0.9% per year from 1990 to 1996 and to 2.2% per year
+ from 1996 to 1998.
+ CONCLUSION: The long-term decline is likely due primarily to improvements in medical care,
+ including screening, diagnosis, and treatment.
+
+
+
+ J Mammary Gland Biol Neoplasia 1998 Jan;3(1):49-61 Role of hormones in mammary cancer initiation
+ and progression. Russo IH, Russo J. “Administration of carcinogen to pregnant, parous or
+ hormonally treated virgin rats, on the other hand, fails to elicit a tumorigenic response, a phenomenon
+ attributed to the higher degree of differentiation of the mammary gland induced by the hormonal
+ stimulation of pregnancy. In women a majority of breast cancers that are initially hormone dependent are
+ manifested during the postmenopausal period. Estradiol plays a crucial role in their development and
+ evolution.”
+
+
+
+ Hum Reprod 1999 Aug;14(8):2155-61
+ Tryptophan ingestion by pregnant rats induces pituitary and mammary tumours in the adult female
+ offspring.
+ Santana C, Martin L, Valladares F, Diaz-Flores L, Santana-Herrera C, Milena A, Rodriguez Diaz M
+ “. . . maternal ingestion of tryptophan induced a marked rise in 665-day-old offspring in the incidence
+ of both pituitary prolactinomas (62%) and mammary adenomas (49%). Present data suggest that tryptophan
+ regulates serotonergic differentiation during early development. A transitory modification of the
+ tryptophan concentration in the fetal brain induces a permanent increase in hypothalamic serotonin level
+ and, in addition to modifying the release of prolactin, increases the incidence of tumours in the
+ hypophysis and mammary gland.”
+
+
+
+ JAMA 1977 Feb 21;237(8):789-90. Breast cancer induced by radiation. Relation to mammography and
+ treatment of acne. Simon N.This communication reports cases of 16 women in
+ whom cancer of the breast developed after radiation therapy for acne or hirsutism, suggesting another
+ group at higher risk than is generally expected for cancer of the breast.
+ It is prudent to regard the carcinogenic effect of radiation on the breast as proportional to dose
+ without a threshold. Mammography in young women should be ordered only selectively, not for
+ screening.
+
+
+
+ Rev Interam Radiol 1977 Oct;2(4):199-203. Cancer of the breast--induction by radiation and role
+ of mammography. Simon N.
+
+
+
+ Eur J Clin Nutr 1999 Feb;53(2):83-7. Western nutrition and the insulin resistance syndrome: a
+ link to breast cancer. Stoll BA. “The incidence of breast cancer in the Western world runs
+ parallel to that of the major components of the insulin resistance syndrome--hyperinsulinaemia,
+ dyslipidaemia, hypertension and atherosclerosis. Evidence is reviewed that the growth of breast cancer
+ is favoured by specific dietary fatty acids, visceral fat accumulation and inadequate physical exercise,
+ all of which are thought to interact in favouring the development of the insulin resistance syndrome.”
+ “Experimental evidence suggests that hyperinsulinaemia and its concomitants can increase the promotion
+ of mammary carcinogenesis and the mechanism is likely to involve increased bioactivity of insulin-like
+ growth factor 1 (IGF-1). Case-control and cohort studies have shown that higher serum levels of IGF-1
+ are associated with increased breast cancer risk.” “Nutritional and lifestyle modifications that improve
+ insulin sensitivity may not only decrease a tendency to atherosclerosis but also reduce breast cancer
+ risk in women.”
+
+
+
+ Strong, Leonell C, Biological Aspects of Cancer and Aging, Oxford, Pergamon
+ Press, 1968.
+
+
+
+ Ethn Dis 1999 Spring-Summer;9(2):181-9. Secular trend of earlier onset of menarche with
+ increasing obesity in black and white girls: the Bogalusa Heart Study.
+
+ in black girls (11.4+/-1.3 vs 12.3+/-1.4 years) and white girls (11.5+/-1.3 vs 12.3+/-1.3
+ years). Furthermore, twice as many girls in the second cohort had reached menarche by ages younger
+ than 12 years (P<0.001).” “Since increases in body fatness and related early
+ onset of menarche are risk factors for disorders in adult life including cardiovascular disease and
+ breast cancer, the secular trend in the increasing incidence of obesity throughout the United States
+ is becoming a major public health problem.”
+
+
+
+
+
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+
+ Caffeine: A vitamin-like nutrient, or adaptogen
+
+
+ Caffeine: A vitamin-like nutrient, or adaptogen
+
+
+
+ Questions about tea and coffee, cancer and other degenerative diseases, and the hormones.
+
+
+
+ There is a popular health-culture that circulates mistaken ideas about nutrition, and coffee drinking has
+ been a perennial target of this culture. It is commonly said that coffee is a drug, not a food, and that its
+ drug action is harmful, and that this harm is not compensated by any nutritional benefit. Most physicians
+ subscribe to most of these "common sense" ideas about coffee, and form an authoritative barrier against the
+ assimilation of scientific information about coffee.
+
+
+ I think it would be good to reconsider coffee"s place in the diet and in health care.
+
+
+ Coffee drinkers have a lower incidence of thyroid disease, including cancer,
+ thannon-drinkers.
+
+
+ Caffeine protects the liver from alcohol and acetaminophen (Tylenol) and other toxins, and coffee
+ drinkers are less likely than people who don"t use coffee to have elevated serum enzymes and other
+ indications of liver damage.
+
+
+ Caffeine protects against cancer caused by radiation, chemical carcinogens, viruses, and
+ estrogens.
+
+
+ Caffeine synergizes with progesterone, and increases its concentration in blood and tissues.
+
+
+
+ Cystic breast disease is not caused by caffeine, in fact caffeine"s effects are likely to be
+ protective; a variety of studies show that coffee, tea, and caffeine are protective against breast
+ cancer.
+
+
+ Coffee provides very significant quantities of magnesium, as well as other nutrients including
+ vitamin B1.
+
+ Caffeine "improves efficiency of fuel use" and performance: JC Wagner 1989.
+ Coffee drinkers have a low incidence of suicide.
+ Caffeine supports serotonin uptake in nerves, and inhibits blood platelet aggregation.
+
+ Coffee drinkers have been found to have lower cadmium in tissues; coffee making removes heavy metals
+ from water.
+
+
+ Coffee inhibits iron absorption if taken with meals, helping to prevent iron overload.
+
+ Caffeine, like niacin, inhibits apoptosis, protecting against stress-induced cell death, without
+ interfering with normal cell turnover.
+
+ Caffeine can prevent nerve cell death.
+ Coffee (or caffeine) prevents Parkinson"s Disease (Ross, et al., 2000).
+
+ The prenatal growth retardation that can be caused by feeding large amounts of caffeine is prevented
+ by supplementing the diet with sugar.
+
+
+ Caffeine stops production of free radicals by inhibiting xanthine oxidase, an important factor in
+ tissue stress.
+
+
+
+
+ Caffeine lowers serum potassium following exercise; stabilizes platelets, reducing thromboxane
+ production.
+
+
+ One definition of a vitamin is that it is an organic chemical found in foods, the lack of which causes a specific disease,
+ or group of diseases. A variety of substances that have been proposed to be vitamins haven"t been recognized
+ as being essential, and some substances that aren"t essential are sometimes called vitamins. Sometimes these
+ issues haven"t had enough scientific investigation, but often nonscientific forces regulate nutritional
+ ideas.
+
+
+ The definition of "a disease" isn"t as clear as text-book writers have implied, and "causality" in biology
+ is always more complex than we like to believe.
+
+
+ Nutrition is one of the most important sciences, and should certainly be as prestigious and well financed as
+ astrophysics and nuclear physics, but while people say "it doesn"t take a brain surgeon to figure that out,"
+ no one says "it doesn"t take a nutritionist to understand that." Partly, that"s because medicine treated
+ scientific nutrition as an illegitimate step-child, and refused throughout the 20th century to recognize
+ that it is a central part of scientific health care. In the 1970s, physicians and dietitians were still
+ ridiculing the idea that vitamin E could prevent or cure diseases of the circulatory system, and babies as
+ well as older people were given "total intravenous nutrition" which lacked nutrients that are essential to
+ life, growth, immunity, and healing. Medicine and science are powerfully institutionalized, but no
+ institution or profession has existed for the purpose of encouraging people to act reasonably.
+
+
+
+ In this environment, most people have felt that subtleties of definition, logic and evidence weren"t
+ important for nutrition, and a great amount of energy has gone into deciding whether there were "four food
+ groups" or "seven food groups" or a "nutritional pyramid." The motives behind governmental and
+ quasi-governmental nutrition policies usually represent something besides a simple scientific concern for
+ good health, as when health care institutions say that Mexican babies should begin eating beans when they
+ reach the age of six months, or that non-whites don"t need milk after they are weaned. In a culture that
+ discourages prolonged breast feeding, the effects of these doctrines can be serious.
+
+
+ After a century of scientific nutrition, public nutritional policies are doing approximately as much harm as
+ good, and they are getting worse faster than they are getting better..
+
+
+ In this culture, what we desperately need is a recognition of the complexity of life, and of the
+ political-ecological situation we find ourselves in. Any thinking which isn"t "system thinking" should be
+ treated with caution, and most contemporary thinking about health neglects to consider relevant parts of the
+ problem-system. "Official" recommendations about salt, cholesterol, iron, unsaturated and saturated fats,
+ and soybeans have generally been inappropriate, unscientific, and strongly motivated by business interests
+ rather than by biological knowledge.
+
+
+ Definitions have rarely distinguished clearly between nutrients and drugs, and new commercial motives are
+ helping to further blur the distinctions.
+
+
+ Essential nutrients, defensive (detoxifying, antistress) nutrients, hormone-modulating nutrients,
+ self-actualization nutrients, growth regulating nutrients, structure modifiers, life extension agents,
+ transgenerationally active (imprinting)
+ nutrients--the line between nutrients and biological modifiers often depends on the
+ situation. Vitamins D and A clearly have hormone-like properties, and vitamin E"s effects, and those of many
+ terpenoids and steroids and bioflavonoids found in foods, include hormone-like actions as well as
+ antioxidant and pro-oxidant functions. The concept of "adaptogen" can include things that act like both
+ drugs and nutrients.
+
+
+
+ Some studies have suggested that trace amounts of nutrients could be passed on for a few generations, but
+ the evidence now indicates that these transgenerational effects are caused by phenomena such as
+ "imprinting." But the hereditary effects of nutrients are so complex that their recognition would force
+ nutrition to be recognized as one of the most complex sciences, interwoven with the complexities of growth
+ and development.
+
+
+ The idea that poor nutrition stunts growth has led to the idea that good nutrition can be defined in terms
+ of the rate of growth and the size ultimately reached. In medicine, it is common to refer to an obese
+ specimen as "well nourished," as if quantity of food and quantity of tissue were necessarily good things.
+ But poisons can stimulate growth ("hormesis"), and food restriction can extend longevity. We still
+ have to determine basic things such as the optimal rate of growth, and the optimal size.
+
+
+ Nutrition textbooks flatly describe caffeine as a drug, not a nutrient, as if it were obvious that nutrients
+ can"t be drugs. Any of the essential nutrients, if used in isolation, can be used as a drug, for a specific
+ effect on the organism that it wouldn"t normally have when eaten as a component of ordinary food. And
+ natural foods contain thousands of chemicals, other than the essential nutrients. Many of these are called
+ nonessential nutrients, but their importance is being recognized increasingly. The truth is that we aren"t
+ sure what they "aren"t essential" for. Until we have more definite knowledge about the organism I don"t
+ think we should categorize things so absolutely as drugs or nutrients.
+
+
+ The bad effects ascribed to coffee usually involve administering large doses in a short period of time.
+ While caffeine is commonly said to raise blood pressure, this effect is slight, and may not occur during the
+ normal use of coffee. Experimenters typically ignore essential factors. Drinking plain water can cause an
+ extreme rise in blood pressure, especially in old people, and eating a meal (containing carbohydrate) lowers
+ blood pressure. The increased metabolic rate caffeine produces increases the cellular consumption of
+ glucose, so experiments that study the effects of coffee taken on an empty stomach are measuring the effects
+ of increased temperature and metabolic rate, combined with increased adrenaline (resulting from the decrease
+ of glucose), and so confuse the issue of caffeine"s intrinsic effects.
+
+
+ In one study (Krasil"nikov, 1975), the drugs were introduced directly into the carotid artery to study the
+ effects on the blood vessels in the brain. Caffeine increased the blood volume in the brain, while
+ decreasing the resistance of the vessels, and this effect is what would be expected from its stimulation of
+ brain metabolism and the consequent increase in carbon dioxide, which dilates blood vessels.
+
+
+
+ In the whole body, increased carbon dioxide also decreases vascular resistance, and this allows circulation
+ to increase, while the heart"s work is decreased, relative to the amount of blood pumped. But when the whole
+ body"s metabolism is increased, adequate nutrition is crucial.
+
+
+ In animal experiments that have been used to argue that pregnant women shouldn"t drink coffee, large doses
+ of caffeine given to pregnant animals retarded the growth of the fetuses. But simply giving more sucrose
+ prevented the growth retardation. Since caffeine tends to correct some of the metabolic problems that could
+ interfere with pregnancy, it is possible that rationally constructed experiments could show benefits to the
+ fetus from the mother"s use of coffee, for example by lowering bilirubin and serotonin, preventing
+ hypoglycemia, increasing uterine perfusion and progesterone synthesis, synergizing with thyroid and cortisol
+ to promote lung maturation, and providing additional nutrients.
+
+
+ One of the most popular misconceptions about caffeine is that it causes fibrocystic breast disease. Several
+ groups demonstrated pretty clearly that it doesn"t, but there was no reason that they should have had to
+ bother, except for an amazingly incompetent, but highly publicized, series of articles--classics of their
+ kind--by J. P. Minton, of Ohio State University. Minton neglected to notice that the healthy breast contains
+ a high percentage of fat, and that the inflamed and diseased breast has an increased proportion of glandular
+ material Fat cells have a low level of cyclic AMP, a regulatory substance that is associated with normal
+ cellular differentiation and function, and is involved in mediating caffeine"s ability to inhibit cancer
+ cell multiplication. Minton argued that cAMP increases progressively with the degree of breast disease, up
+ to cancer, and that cAMP is increased by caffeine. A variety of substances other than caffeine that inhibit
+ the growth of cancer cells (as well as normal breast cells) act by increasing the amount of cyclic
+ AMP, while estrogen lowers the amount of cAMP and increases cell growth. Minton"s argument should have been
+ to use more caffeine, in proportion to the degree of breast disease, if he were arguing logically from his
+ evidence. Caffeine"s effect on the breast resembles that of progesterone, opposing estrogen"s effects.
+
+
+ Many studies over the last 30 years have shown caffeine to be highly protective against all kinds of
+ carcinogenesis, including estrogen"s carcinogenic effects on the breast. Caffeine is now being used along
+ with some of the standard cancer treatments, to improve their effects or to reduce their side effects. There
+ are substances in the coffee berry besides caffeine that protect against mutations and cancer, and that have
+ shown strong therapeutic effects against cancer. Although many plant substances are protective against
+ mutations and cancer, I don"t know of any that is as free of side effects as coffee.
+
+
+ To talk about caffeine, it"s necessary to talk about uric acid.
+ Uric acid, synthesized in the body, is both a stimulant and a very important antioxidant, and its
+ structure is very similar to that of caffeine.
+
+ A deficiency of uric acid is a serious problem. Caffeine and uric acid are in the group of chemicals called
+ purines.
+
+
+ Purines (along with pyrimidines) are components of the nucleic acids, DNA and RNA, but they have many other
+ functions. In general, substances related to purines are stimulants, and substances related to pyrimidines
+ are sedatives.
+
+
+ When the basic purine structure is oxidized, it becomes in turn hypoxanthine, xanthine, and uric acid, by
+ the addition of oxygen atoms. When methyl groups (CH3) are added to nitrogens in the purine ring,
+ the molecule becomes less water soluble. Xanthine (an intermediate in purine metabolism) has two oxygen
+ atoms, and when three methyl groups are added, it becomes trimethyl xanthine, or caffeine. With two methyl
+ groups, it is theophylline, which is named for its presence in tea. We have enzyme systems which can add and
+ subtract methyl groups; for example, when babies are given theophylline, they can convert
+ it into caffeine.
+
+
+
+ We have enzymes that can modify all of the methyl groups and oxygen atoms of caffeine and the other purine
+ derivatives. Caffeine is usually excreted in a modified form, for example as a methylated uric acid.
+
+
+ One of the ways in which uric acid functions as an "antioxidant" is by modifying the activity of the enzyme
+ xanthine oxidase, which in stress can become a dangerous source of free radicals. Caffeine also restrains
+ this enzyme. There are several other ways in which uric acid and caffeine (and a variety of intermediate
+ xanthines) protect against oxidative damage. Coffee drinkers, for example, have been found to have lower
+ levels of cadmium in their kidneys than people who don"t use coffee, and coffee is known to inhibit the
+ absorption of iron by the intestine, helping to prevent iron overload.
+
+
+ Toxins and stressors often kill cells, for example in the brain, liver, and immune system, by causing the
+ cells to expend energy faster than it can be replaced. There is an enzyme system that repairs genetic
+ damage, called "PARP." The activation of this enzyme is a major energy drain, and substances that inhibit it
+ can prevent the death of the cell. Niacin and caffeine can inhibit this enzyme sufficiently to prevent this
+ characteristic kind of cell death, without preventing the normal cellular turnover; that
+ is, they don"t produce tumors by preventing the death of cells that aren"t needed.
+
+
+ The purines are important in a great variety of regulatory processes, and caffeine fits into this complex
+ system in other ways that are often protective against stress. For example, it has been proposed that tea
+ can protect against circulatory disease by preventing abnormal clotting, and the mechanism seems to be that
+ caffeine (or theophylline) tends to restrain stress-induced platelet aggregaton.
+
+
+ When platelets clump, they release various factors that contribute to the development of a clot. Serotonin
+ is one of these, and is released by other kinds of cell, including mast cells and basophils and nerve cells.
+ Serotonin produces vascular spasms and increased blood pressure, blood vessel leakiness and inflammation,
+ and the release of many other stress mediators. Caffeine, besides inhibiting the platelet aggregation, also
+ tends to inhibit the release of serotonin, or to promote its uptake and binding.
+
+
+
+ J. W. Davis, et al., 1996, found that high uric acid levels seem to protect against the development of
+ Parkinson"s disease. They ascribed this effect to uric acid"s antioxidant function. Coffee drinking, which
+ lowers uric acid levels, nevertheless appeared to be much more strongly protective against
+ Parkinson"s disease than uric acid.
+
+
+ Possibly more important than coffee"s ability to protect the health is the way it does it. The studies that
+ have tried to gather evidence to show that coffee is harmful, and found the opposite, have provided insight
+ into several diseases. For example, coffee"s effects on serotonin are very similar to carbon dioxide"s, and
+ the thyroid hormone"s. Noticing that coffee drinking is associated with a low incidence of Parkinson"s
+ disease could focus attention on the ways that thyroid and carbon dioxide and serotonin, estrogen, mast
+ cells, histamine and blood clotting interact to produce nerve cell death.
+
+
+ Thinking about how caffeine can be beneficial across such a broad spectrum of problems can give us a
+ perspective on the similarities of their underlying physiology and biochemistry, expanding the implications
+ of stress, biological energy, and adaptability.
+
+
+ The observation that coffee drinkers have a low incidence of suicide, for example, might be physiologically
+ related to the large increase in suicide rate among people who use the newer antidepressants called
+ "serotonin reuptake inhibitors." Serotonin excess causes several of the features of depression, such as
+ learned helplessness and reduced metabolic rate, while coffee stimulates the uptake (inactivation
+ or storage) of serotonin, increases metabolic energy, and tends to improve mood. In animal studies, it
+ reverses the state of helplessness or despair, often more effectively than so-called antidepressants.
+
+
+ The research on caffeine"s effects on blood pressure, and on the use of fuel by the more actively
+ metabolizing cells, hasn"t clarified its effects on respiration and nutrition, but some of these experiments
+ confirm things that coffee drinkers usually learn for themselves.
+
+
+ Often, a woman who thinks that she has symptoms of hypoglycemia says that drinking even the smallest amount
+ of coffee makes her anxious and shaky. Sometimes, I have suggested that they try drinking about two ounces
+ of coffee with cream or milk along with a meal. It"s common for them to find that this reduces their
+ symptoms of hypoglycemia, and allows them to be symptom-free between meals. Although we don"t know exactly
+ why caffeine improves an athlete"s endurance, I think the same processes are involved when coffee increases
+ a person"s "endurance" in ordinary activities.
+
+
+ Caffeine has remarkable parallels to thyroid and progesterone, and the use of coffee or tea can help to
+ maintain their production, or compensate for their deficiency. Women spontaneously drink more coffee
+ premenstrually, and since caffeine is known to increase the concentration of progesterone in the blood and
+ in the brain, this is obviously a spontaneous and rational form of self-medication, though medical editors
+ like to see things causally reversed, and blame the coffee drinking for the symptoms it is actually
+ alleviating. Some women have noticed that the effect of a progesterone supplement is stronger when they take
+ it with coffee. This is similar to the synergy between thyroid and progesterone, which is probably involved,
+ since caffeine tends to locally activate thyroid secretion by a variety of mechanisms, increasing
+ cyclic AMP and decreasing serotonin in thyroid cells, for example, and also by lowering the systemic stress
+ mediators.
+
+
+ Medical editors like to publish articles that reinforce important prejudices, even if, scientifically, they
+ are trash. The momentum of a bad idea can probably be measured by the tons of glossy paper that have gone
+ into its development. Just for the sake of the environment, it would be nice if editors would try to think
+ in terms of evidence and biological mechanisms, rather than stereotypes.
+
+
+ REFERENCES
+
+
+ Fiziol Zh SSSR Im I M Sechenova 1975 Oct;61(10):1531-8. [Changes in the resistance and capacity of
+ the cerebral vascular bed under the influence of vasoactive substances]. [Article in Russian]
+ Krasil'nikov, V.G. Effects of intracarotid injections of vasoactive agents on cerebrovascular resistance
+ (CVR) and cerebral blood volume (CBV) were studied in hemodynamically isolated brain of cats. Perfusion
+ pressure shifts at a constant blood volume perfusion reflected CVR changes, and changes of venous outflow -
+ CBV alterations. Administration of adrenaline, serotonin, and angiotensine was followed mainly by an
+ increase of CVR and a decrease of CBV. The CVR
+
+ could be reduced by isopropilnoradrenaline, acetylcholine, histamine, and caffeine.
+ CBV was decreased after isopropilnoradrenaline, acetycholine, histamine injections and increased by
+ caffeine.
+ The possible role of the active changes of cerebral capacitance vessels in the transcapillary fluid
+ exchange is discussed. Capacitance vessels active responses are supposed to entail wrong results when using
+ certain techniques for measurement of cerebral blood flow and metabolism.
+
+
+
+ Proc Soc Exp Biol Med 1999 Apr;220(4):244-8. The prevention of lung cancer induced by a
+ tobacco-specific carcinogen in rodents by green and black Tea. Chung FL "The oxidation products
+ found in black tea, thearubigins and theaflavins, also possess antioxidant activity, suggesting that black
+ tea may also inhibit NNK-induced lung tumorigenesis. Indeed, bioassays in A/J mice have shown that black tea
+ given as drinking water retarded the development of lung cancer caused by NNK." "We conducted a 2-year
+ lifetime bioassay in F344 rats to determine whether black tea and caffeine are protective against
+ lung tumorigenesis induced by NNK. Our studies in both mice and rats have generated important new data
+ that support green and black tea and
+
+ caffeine as potential preventive agents against lung cancer, suggesting that a closer examination of the
+ roles of tea and caffeine on lung cancer
+ in smokers may be warranted."
+
+
+ Pharmacol Biochem Behav 2000 May;66(1):39-45. Caffeine-induced increases in the brain and plasma
+ concentrations of neuroactive steroids in the rat. Concas A, Porcu P, Sogliano C, Serra M,
+ Purdy RH, Biggio G. "A single intraperitoneal injection of caffeine induced dose- and time-dependent
+ increases in the concentrations of pregnenolone, progesterone, and 3alpha-hydroxy-5alpha-pregnan-20-one
+ (allopregnanolone) in the cerebral cortex." "Caffeine also increased the plasma
+ concentrations of pregnenolone and progesterone with a dose-response relation similar to that observed
+ in the brain . . ."
+
+
+ "Moreover, the brain and plasma concentrations of pregnenolone, progesterone, and allopregnanolone were not
+ affected by caffeine in adrenalectomized-orchiectomized rats."
+
+
+ Cancer Res 1998 Sep 15;58(18):4096-101. Inhibition of
+ lung carcinogenesis by black tea in Fischer rats treated with a tobacco-specific carcinogen:
+ caffeine as an important constituent. Chung FL, Wang M, Rivenson A, Iatropoulos MJ, Reinhardt
+ JC, Pittman B, Ho CT, Amin SG. "The NNK-treated group, given 2% black tea, showed a significant reduction of
+ the total lung tumor (adenomas, adenocarcinomas, and adenosquamous carcinomas) incidence from 47% to
+ 19%, whereas the group given 1% and 0.5% black tea showed no change. The 2% tea also reduced liver tumor
+ incidence induced by NNK from 34% in the group given only deionized water to 12%." "The
+ most unexpected finding was the remarkable reduction of the lung tumor incidence, from 47% to 10%, in
+ the group treated with 680 ppm caffeine, a concentration equivalent to that found in the 2% tea. This
+ incidence is comparable to background levels seen in the control group. This study demonstrated
+ for the first time in a 2-year lifetime bioassay that black tea protects against lung tumorigenesis in F344
+ rats, and this effect appears to be attributed, to a significant extent, to caffeine as an active
+ ingredient of tea."
+
+
+
+ Cancer Lett 1991 Mar;56(3):245-50.
+ Inhibition by caffeine of ovarian hormone-induced mammary gland tumorigenesis in female GR mice. VanderPloeg LC, Welsch CW. "Hormone treatment induced mammary tumors in 95-100% of the mice. Caffeine
+ treatment significantly (P less than 0.05) reduced the mean number of mammary tumors per mouse and
+ significantly (P less than 0.05) increased the mean latency period of mammary tumor appearance."
+
+
+ Breast Cancer Res Treat 1991 Nov;19(3):269-75.
+ Caffeine inhibits development of benign mammary gland tumors in carcinogen-treated female Sprague-Dawley
+ rats. Wolfrom DM, Rao AR, Welsch CW.
+
+
+ Cancer 1985 Oct 15;56(8):1977-81.
+ The inhibitory effect of caffeine on hormone-induced rat breast cancer. Petrek JA, Sandberg WA,
+ Cole MN, Silberman MS, Collins DC. "The current investigation examines the effect of two caffeine doses in
+ ACI rats with and without diethylstilbestrol (DES). Without DES, cancer did not develop in any of the rats
+ receiving either of the two caffeine dosages. With DES, increasing caffeine dosage lengthened the time to
+ first cancer, decreased the number of rats that developed cancers, and decreased the number of cancers
+ overall." "In conclusion, chronic caffeine ingestion inhibits rat breast cancer, neither by interfering with
+ the high prolactin levels--a necessary step in murine tumor development--nor by causing hypocaloric intake."
+
+
+
+ Nutr Cancer 1998;30(1):21-4.
+ Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex
+ hormone-binding globulin in premenopausal Japanese women. Nagata C, Kabuto M, Shimizu H.
+ "Although the effect of caffeine cannot be distinguished from effects of coffee and green tea,
+ consumption of caffeine-containing beverages appeared to favorably alter hormone levels associated with
+ the risk of developing breast cancer."
+
+
+ J Environ Pathol Toxicol Oncol 1992; 11(3):177-89.
+ Caffeine, theophylline, theobromine, and developmental growth of the mouse mammary gland.
+ VanderPloeg LC, Wolfrom DM, Rao AR, Braselton WE, Welsch CW. "These data demonstrate that certain
+ methylxanthines (e.g., caffeine and theophylline) but not others (e.g., theobromine) can significantly
+ enhance mammotrophic hormone-induced mammary lobulo-alveolar differentiation
+
+
+ in female Balb/c mice, an effect that appears not to be manifested via a direct action of the
+ methylxanthines on the mammary gland."
+
+
+ J Environ Pathol Toxicol Oncol 1994;13(2):81-8.
+ Enhancement by caffeine of mammary gland lobulo-alveolar development in mice: a function of increased
+ corticosterone. Welsch CW, VanderPloeg LC. Previously we have reported that the stimulatory
+ effect of caffeine on
+ lobulo-alveolar development
+ in the mammary glands of female Balb/c mice is not due to a direct action of the drug on the
+ mammary gland but appears to be due to a caffeine-induced alteration of a yet to be defined systemic
+ physiological process (VanderPloeg et al., J Environ Pathol Toxicol Oncol 11:177-189, 1992). "In the present
+ study, we administered caffeine (via the drinking water, 500 mg/L) to ovariectomized, estrogen- and
+ progesterone-treated Balb/c mice. After 30 days of caffeine treatment, a significant (p < 0.001)
+ enhancement of lobulo-alveolar development in the mammary glands of the hormone-treated mice, compared with
+ hormone treated control mice, was observed."
+
+
+ Am J Clin Nutr 1997 Jun;65(6):1826-30. Dietary caffeine intake and bone status of postmenopausal
+ women. Lloyd T, Rollings N, Eggli DF, Kieselhorst K, Chinchilli VM.
+
+
+
+ Eur J Epidemiol 1993 May;9(3):293-7. Unexpected effects of coffee consumption on liver
+ enzymes. Casiglia E, Spolaore P, Ginocchio G, Ambrosio GB. Istituto di Medicina Clinica,
+ Universita di Padova, Italy. The effects of regular daily coffee consumption on liver enzymes were studied
+ in a large number of subjects from the general population. In coffee drinkers, liver enzymes (gamma-glutamyl
+ transferase, alanine-amino transferase, and alkaline phosphatase) and serum bilirubin were lower than in
+ non-coffee-drinking subjects or in those consuming less than 3 cups daily. The hypothesis proposed is that
+ liver enzymes are a target for caffeine contained in coffee.
+
+
+ Anticancer Res 1996 Jan-Feb;16(1):151-3
+ Suppression by coffee cherry of the growth of spontaneous mammary tumours in SHN mice. Nagasawa
+ H, Yasuda M, Sakamoto S, Inatomi H Experimental Animal Research Laboratory, Meiji University, Kanagawa,
+ Japan. We previously found that coffee cherry (CC), residue after removal of coffee beans, significantly
+ suppressed the development of spontaneous mammary tumours of mice. In this paper, the effects of CC on the
+ growth of the palpable size of this type of tumour was examined. Free access as drinking
+ water of 0.5% solution of the hot water extract of CC for 10 days resulted in a marked inhibition of the
+ tumour growth: The percent changes of tumour sizes were 53.8 +/- 11.7% and 13.8 +/- 10.9% in the
+
+ control and the experimental groups, respectively. Associated with this, thymidylate synthetase activity in
+ the mammary tumours was significantly lower in the experimental group than in the control. Normal and
+ preneoplastic mammary gland growth, body weight change and weights and structures of endocrine organs were
+ only slightly affected by the treatment. The findings indicate that CC is promising as an antitumour agent.
+
+
+ Yakugaku Zasshi 1997 Jul;117(7):448-54. [Effect of tea extracts, catechin and caffeine against
+ type-I allergic reaction]. [Article in Japanese] Shiozaki T, Sugiyama K, Nakazato K, Takeo
+ T.
+ "Caffeine also showed a inhibitory effect on the PCA reaction. These results indicate that tea could
+ provide a significant protection against the type-I allergic reaction. These findings also suggest that
+ tea catechins and caffeine play an important role in having an inhibitory effect on the type-I allergic
+ reaction."
+
+
+
+
+ Acta Chir Scand 1989 Jun-Jul;155(6-7):317-20. Does coffee consumption protect against thyroid
+ disease? Linos A, Linos DA, Vgotza N, Souvatzoglou A, Koutras DA
+
+
+ Br J Nutr 1999 Aug;82(2):125-30.
+ Inverse association between coffee drinking and serum uric acid concentrations in middle-aged Japanese
+ males. Kiyohara C, Kono S, Honjo S, Todoroki I, Sakurai Y, Nishiwaki M, Hamada H, Nishikawa H,
+ Koga H, Ogawa S, Nakagawa K
+
+
+ Cancer Res 1997 Jul 1;57(13):2623-9. Effects of tea, decaffeinated tea, and caffeine on UVB
+ light-induced complete carcinogenesis in SKH-1 mice: demonstration of caffeine as a biologically
+ important constituent of tea. Huang MT, Xie JG, Wang ZY, Ho CT, Lou YR, Wang CX, Hard GC,
+ Conney A.H.
+
+
+
+ Mutat Res 1981 Jun;89(2):161-77. Non-mutagenicity of urine from coffee drinkers compared with that
+ from cigarette smokers. Aeschbacher HU, Chappuis C.
+
+
+ Biol Neonate 1981;40(3-4):196-8. The effects of maternal carbohydrate (sucrose) supplementation on
+ the growth of offspring of pregnancies with habitual caffeine consumption. Dunlop M, Court JM,
+ Larkins RG. "When maternal caffeine (10 mg/kg/day) was consumed together with supplementary sucrose (7
+ g/kg/day) the expected offspring growth reduction attributed to caffeine did not occur."
+
+
+ Biochim Biophys Acta 1992 Dec 15;1175(1):114-22. Caffeine promotes survival of cultured sympathetic
+ neurons deprived of nerve growth factor through a cAMP-dependent mechanism. Tanaka S, Koike T.
+
+
+
+ JAMA 2000 May 24-31;283(20):2674-9. Association of coffee and caffeine intake with the risk of
+ Parkinson disease. Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, Tanner
+ CM, Masaki KH, Blanchette PL, Curb JD, Popper JS, White LR.
+
+
+ Farmakol Toksikol 1983 Sep-Oct;46(5):107-11 [Use of the swimming test for demonstrating
+ antidepressive activity of drugs during single and repeated administration]. [Article in
+ Russian] Rusakov DIu, Val'dman AV.
+ "The use of the "swimming test" made it possible to identify the activity of tricyclic (desipramine,
+ chlorimipramine, amitryptyline) and atypical antidepressants (befuralin, zimelidine, trazodon), that of
+ pyrazidol (type A MAO inhibitor) and of a number of new compounds--derivatives of benzofuran
+ and morpholine upon single and chronic administration. To define the method specificity, use was made of the
+ neuroleptic haloperidol, the tranquilizer diazepam, and of nembutal, which did not exhibit any activity in
+ the test in question.
+ Psychostimulants (amphetamine, caffeine) dramatically increased the time of active swimming. The effect
+ lasted throughout all the 30 minutes of testing, which is not characteristic for
+ antidepressants."
+
+
+ Gen Pharmacol 1996 Jan;27(1):167-70 The influence of antagonists of poly(ADP-ribose) metabolism on
+ acetaminophen hepatotoxicity. Kroger H, Ehrlich W, Klewer M, Gratz R, Dietrich A, Miesel R.
+
+
+ Ann Clin Lab Sci 1977 Jan-Feb;7(1):68-72. Effects of drugs on platelet function. Morse EE.
+
+
+ Thromb Haemost 1982 Apr 30;47(2):90-5. Effect of cAMP phosphodiesterase inhibitors on ADP-induced
+ shape change, cAMP and nucleoside diphosphokinase activity of rabbit platelets.
+
+
+ Lam SC, Guccione MA, Packham MA, Mustard JF.
+
+
+ Carcinogenesis 1998 Aug;19(8):1369-75.
+ The coffee-specific diterpenes cafestol and kahweol protect against aflatoxin B1-induced genotoxicity
+ through a dual mechanism. Cavin C, Holzhauser D, Constable A, Huggett AC, Schilter B.
+
+
+ Am J Epidemiol 1994 Apr 1;139(7):723-7.
+ Coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan.
+ Kono S, Shinchi K, Imanishi K, Todoroki I, Hatsuse K.
+
+
+ Carcinogenesis 1996 Nov;17(11):2377-84
+ Placental glutathione S-transferase (GST-P) induction as a potential mechanism for the anti-carcinogenic
+ effect of the coffee-specific components cafestol and kahweol. Schilter B, Perrin I, Cavin C,
+ Huggett AC
+
+
+
+ J Nutr 1999 Jul;129(7):1361-7.
+ Teas and other beverages suppress D-galactosamine-induced liver injury in rats. Sugiyama K, He
+ P, Wada S, Saeki S
+
+
+ Nutr Cancer 1999;33(2):146-53.
+ Effects of oral administration of tea,
+ decaffeinated tea, and caffeine on the formation and growth of tumors in high-risk SKH-1 mice
+ previously treated with ultraviolet B light. Lou YR, Lu YP, Xie JG, Huang MT, Conney AH.
+
+
+ Ind Health 2000 Jan;38(1):99-102. Effects of coffee consumption against the development of liver
+ dysfunction: a 4-year follow-up study of middle-aged Japanese male office workers.
+ Nakanishi N, Nakamura K, Suzuki K, Tatara K.
+
+
+
+ Ind Health 2000 Jan;38(1):99-102. Effects of coffee consumption against the development of liver
+ dysfunction: a 4-year follow-up study of middle-aged Japanese male office workers.
+ Nakanishi N, Nakamura K, Suzuki K, Tatara K. .
+
+
+ Biochim Biophys Acta 1992 Dec 15; 1175(1):114-22. Caffeine promotes survival of cultured sympathetic
+ neurons deprived of nerve growth factor through a cAMP-dependent mechanism. Tanaka S, Koike T.
+
+
+ Int J Epidemiol 1998 Jun;27(3):438-43. Coffee consumption and decreased serum
+ gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers. Tanaka
+ K, Tokunaga S, Kono S, Tokudome S, Akamatsu T, Moriyama T, Zakouji H.
+ ". . . recent epidemiological studies have suggested unexpected, possibly beneficial effects of coffee
+ against the occurrence of alcoholic liver cirrhosis and upon serum liver enzyme levels."
+ "Increased coffee consumption was strongly and independently associated with decreased GGT activity among
+ males (P trend < 0.0001); the inverse association between coffee and serum GGT was more evident among
+ heavier alcohol consumers (P < 0.0001), and was absent among non-alcohol drinkers." "Similar inverse
+ associations with coffee and interactions between coffee and alcohol intake were observed for serum
+ aspartate aminotransferase and alanine aminotransferase. Intake of green tea, another popular source of
+ caffeine in Japan, did not materially influence the liver enzyme levels. CONCLUSIONS: Our results suggest
+ that coffee may inhibit the induction of GGT in the liver by alcohol consumption, and may possibly protect
+ against liver cell damage due to alcohol."
+
+
+ Am J Hosp Pharm 1989 Oct;46(10):2059-67. Abuse of drugs used to enhance athletic performance.
+ Wagner JC.
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
+
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+
+
+ Calcium and Disease: Hypertension, organ calcification, & shock, vs. respiratory energy
+
+
+
+ Calcium and Disease: Hypertension, organ calcification, & shock, vs. respiratory energy
+
+
+
+
+ SOME CONTEXTS In biology and biochemistry, calcium is the substance most often studied, so it is
+ significant that researchers still speak of a calcium paradox. There are several such paradoxes: As
+ bones lose calcium, the soft tissues calcify; when less calcium is eaten, blood calcium may increase,
+ along with calcium in many organs and tissues; if an organ such as the heart is deprived of calcium for
+ a short time, its cells lose their ability to respond normally to calcium, and instead they take up a
+ large, toxic amount of calcium. Magnesium deficiency and calcium deficiency have some similar symptoms
+ (such as cramping), but magnesium is antagonistic to calcium in many systems. It is the basic protective
+ calcium blocker. Inflammation leads to excessive uptake of calcium by cells, and is a factor in obesity,
+ depression, and the degenerative diseases. Protein deficiency is an important cause of deranged calcium
+ metabolism. Vitamins K, E, and A are important in regulating calcium metabolism, and preventing
+ osteoporosis. Aspirin (with antiestrogenic and vitamin E-like actions) is protective against bone
+ resorption and hypercalcemia.
+
+
+ It is extremely important to realize that calcium deposits in soft tissues become worse when the diet is low in calcium. Persons suffering from arthritis, bursitis, scleroderma, hardening of the arteries and
+ any abnormality where calcium deposits or spurs may cause pain are often afraid to eat foods rich in
+ calcium. Actually they can never improve until their calcium and magnesium intakes are adequate. Not
+ infrequently physicians tell individuals with kidney stones to avoid all milk, thereby causing stones to
+ form even more rapidly. Such calcium deposits can also occur when vitamin E is undersupplied. After
+ open-heart surgery, when both magnesium and vitamin E are drastically needed and could easily be given, the
+ calcification of heart muscles often becomes so severe that it can cause death within a few days. Pages
+ 171-172,
+ Lets Eat Right to Keep Fit, Adelle Davis, Signet, 1970.
+
+
+
+ Almost all biologists think of the organism as a machine, regulated by information according to innate
+ programs. When it comes down to the details, their explanations sometimes make Rube Goldbergs imaginary
+ contraptions seem elegant. At their best, they usually rely on some mysterious things called ionic pumps,
+ that perform active transport, powered by little motors, under instructions from molecules that act on their
+ specific receptors. When things get unmanageable, the biologists speak of paradoxes. Calcium is the most
+ studied of all regulatory molecules, so it isnt surprising that there is more than one calcium paradox. But
+ there are ways of looking at the organism, focusing on energy metabolism, that dont involve the ad
+ hoc theory of calcium pumps, and that make it easy to keep things in context. Ionized atoms and
+ molecules behave in orderly ways, in relation to their size and their electrical charge. Organic material,
+ even when its dead, selectively binds certain metal ions, and excludes others. The living organism produces
+ a stream of metabolic products, such as carbon dioxide or lactic acid, which interact specifically with each
+ other and with the metal ions, modifying their concentrations inside cells and in the body fluids. This
+ movement of ions can be called active transport, without invoking the mysterious machinery of membrane
+ pumps. Chemical changes produced inside cells, for example by respiration, create different electrical
+ charges in different compartments (inside and outside of capillaries, for example) which affect the
+ movements of water and ions, by simple physical processes, not by molecular pumps. The result of these
+ passive and active processes is that each kind of ion has a characteristic concentration in each
+ compartment, according to the metabolic energy state of the organism. Magnesium and potassium are mainly
+ intracellular ions, sodium and calcium are mainly extracellular ions. When cells are excited, stressed, or
+ de-energized, they lose magnesium and potassium, and take up sodium and calcium. The mitochondria can bind a
+ certain amount of calcium during stress, but accumulating calcium can reach a point at which it inactivates
+ the mitochondria, forcing cells to increase their inefficient glycolytic energy production, producing an
+ excess of lactic acid. Abnormal calcification begins in the mitochondria. When cells are stressed or dying,
+ they take up calcium, which tends to excite the cells at the same time that it inhibits their energy
+ production, intensifying their stress. A cramp or a seizure is an example of uncontrolled cellular
+ excitation. Prolonged excitation and stress contribute to tissue inflammation and fibrosis. Gross
+ calcification generally follows the fibrosis that is produced by inflammation. Arteries, kidneys, and other
+ organs calcify during aging. At the age of 90, the amount of calcium in the elastic layer of an artery is
+ about 35 times greater than at the age of 20. Nearly every type of tissue, including the brain, is
+ susceptible to the inflammatory process that leads through fibrosis to calcification. The exception is the
+ skeleton, which loses its calcium as the soft tissues absorb calcium. These observations lead to some
+ simplifying ideas about the nature of aging and disease. Some people who know about the involvement of
+ calcium in aging, stress, and degeneration suggest eating a low calcium diet, but since we all have
+ skeletons, dietary calcium restriction cant protect our cells, and in fact, it usually intensifies the
+ process of calcification of the soft tissues. Statistics from several countries have clearly shown that the
+ mortality rate (especially from arteriosclerotic heart disease, but also from some other diseases, including
+ cancer) is lower than average in regions that have hard water, which often contains a very large amount of
+ either calcium or magnesium. Many studies have shown that dietary calcium (or vitamin D, which increases
+ calcium absorption) can have very important antiinflammatory effects. About 25 years ago, David McCarron
+ noticed that the governments data on diet and hypertension showed that the people who ate the most salt had
+ the lowest blood pressure, and those who ate the least salt had the highest pressure. He showed that a
+ calcium deficiency, rather than a sodium excess, was the most likely nutritional explanation for
+ hypertension. Hans Selye found that some steroids contribute to inflammation and calcification. Animals
+ could be sensitized to develop calciphylaxis, an intense, localized interaction of inflammation and
+ calcification. In the 1970s, Constance Martin pointed out that, up to that time, estrogen was known to
+ increase soft tissue calcium, but hadnt been shown to improve bone calcification and strength. Oxygen
+ deprivation, cyanide poisoning, x-irradiation, and all other sorts of injury also increase the calcium
+ content of soft tissues. One of Selyes colleagues, G. Jasmin, showed that magnesium deficiency causes
+ inflammation. A deficiency of either calcium or magnesium can stimulate the parathyroid glands to produce
+ more hormone (parathyroid hormone, PTH), which increases calcium absorption, but also removes calcium from
+ the bones. This hormone, responding to a dietary calcium or magnesium deficiency, is an important factor in
+ causing cells to take up too much calcium, and its excess is associated with many inflammatory and
+ degenerative diseases. Interleukin-6 (IL-6), an inflammatory cytokine which increases with aging, is
+ commonly considered to have an important role in the multiple processes of atrophy in old age. One of the
+ things which can increase the production of IL-6 is the parathyroid hormone (PTH), which increases the
+ amount of calcium circulating in the blood, partly by causing it to be removed from the bones; IL-6
+ stimulates the process of calcium removal from bones. Some of the interactions of hormones and other
+ regulatory chemicals are interesting, even though they are normally treated as if they were parts of a
+ machine that operates according to a hidden program written in the genes. Prolactin, which is increased
+ under the influence of estrogen or serotonin, causes the body to lose calcium (drawing it from the bones),
+ and it stimulates the secretion of PTH, which compensates for the calcium loss by increasing its
+ mobilization from bones. Prolactins action on bone is at least partly by increasing IL-6 formation; IL-6
+ stimulates the release of prolactin. Serotonin and IL-6 stimulate each others secretion, and PTH and
+ serotonin each stimulate the others release.. PTH (like estrogen and serotonin) inhibits cellular
+ respiration and activates glycolysis, lowering the ATP level and shifting the cells metabolism toward the
+ production of lactic acid rather than carbon dioxide. PTH also causes bicarbonate to be lost in the urine.
+ Since the formation of carbon dioxide lowers the intracellular pH, and the formation of lactic acid raises
+ it (through the reaction of NADH with pyruvate), the proteins in the cell become more strongly negatively
+ charged under the influence of oxygen deprivation, or under the influence of these hormones. In the cell
+ with high pH and increased negative electrical charge, the positively charged calcium ion is absorbed into
+ the cytoplasm. The calcium can enter from the relatively concentrated external fluid, but it can also be
+ released from acidic intracellular stores, the way serotonin is released by a disturbance of pH. There are
+ several other pro-inflammatory substances, such as the cytokines, that have a similar effect on cellular
+ energy systems. The antimetabolic actions of PTH mimic those seen in aging and diabetes, and surgical
+ removal of the parathyroid glands has been known to eliminate diabetes. PTH can cause diuresis, leading to
+ loss of blood volume and dehydration, hypertension, paralysis, increased rate of cell division, and growth
+ of cartilage, bone, and other tissues. Simply eating an adequate amount of calcium and magnesium can
+ alleviate many problems related to stress and aging that are considered serious, such as heart arrhythmia,
+ pancreatitis, and tissue calcification. The antiinflammatory, anti-allergy actions of calcium and magnesium
+ are well established, and there is clear evidence that obesity and various emotional disturbances can result
+ from their deficiency. Chronically high PTH can produce anemia, by a variety of mechanisms. Since a very low
+ sodium diet increases the loss of magnesium, by increasing aldosterone synthesis, simply increasing the
+ amount of sodium in the diet can help some people to balance their minerals and minimize stress. During
+ fasting and other intense stress, the kidneys destroy a large amount of protein to form ammonia to maintain
+ their ability to excrete acids, so using a large amount of the alkaline minerals can reduce the protein
+ catabolism. A diet of milk and fruit, or milk and meat, provides a nutritional balance with generous amounts
+ of calcium and magnesium. Leafy vegetables are a very rich source of magnesium, but they are also a
+ potential source of large amounts of lead and other toxins. In 1960, many people, including the
+ U.S.government, were advocating the use of a largely vegetarian diet for children, because of the amount of
+ radioactive strontium in milk. I compared the amount of strontium in a diet of vegetables that would provide
+ the necessary quantity of calcium and protein, and it was clear that vegetables were the worst source of
+ radioactive strontium, because their ratio of strontium to calcium was much higher than the ratio in milk.
+ The cows were concentrating calcium and protein from the contaminated plant foods, eliminating much of the
+ strontium. This principle still applies to the toxins that are currently found in the U.S. food supply. Milk
+ has many protective effects besides providing calcium. Many babies are being given milk substitutes (health
+ food drinks) made from soy or rice, with terrible consequences. The same products used by adults have less
+ disastrous effects in the short term, but are still likely to contribute to degeneration and dementia. Much
+ of the intracellular magnesium is complexed with ATP, and helps to stabilize that molecule. If cellular
+ energy production is low, as in hypothyroidism, cells tend to lose their magnesium very easily, shifting the
+ balance toward the lower energy molecule, ADP, with the release of phosphate. ADP complexes with calcium,
+ rather than magnesium, increasing the cells calcium content. Increased intracellular calcium, in association
+ with excess nitric oxide and excitatory amino acids, is involved in several neurodegenerative diseases,
+ including ALS, Alzheimers disease, Parkinsons disease, Huntingtons chorea, and epilepsy. Magnesium,
+ nicotine, progesterone, and many other substances are known to protect against excitotoxic calcium overload,
+ but there is no coherent effort in the health professions to make rational use of the available knowledge.
+ Respiration and carbon dioxide are the basic antagonists of the PTH. At birth, a baby has practically no
+ PTH, probably because of the high intrauterine concentration of carbon dioxide, but within a few days the
+ PTH rises. Increased carbon dioxide favors bone formation, and decreased bicarbonate favors the loss of
+ calcium from bone (Canzanello, et al., 1995; Bushinsky, et al, 2001). The use of sodium bicarbonate can
+ stimulate bone formation. A low protein diet, similar to that eaten by a large proportion of women (0.8 g/kg
+ of body weight) increases PTH, and so probably contributes to the development of osteoporosis and the
+ diseases of calcification. In an extreme protein deficiency, there is a shift towards inflammation,
+ serotonin excess, and excessive clotting, which might be related to the effect of the milder, more common
+ protein deficiency. Many people advocate a low protein diet, specifically to prevent or treat osteoporosis,
+ but the cultures that traditionally have had extremely high protein diets, such as the Masai, are very
+ healthy. Recent studies (see Bell and Whiting, 2002) are emphasizing the importance of animal protein in
+ preventing osteoporosis. Traditional meat-eating cultures efficiently use the whole animal, including blood,
+ skin, bones, and the various organs, rather than just the muscles. That diet is favorable for calcium
+ regulation, because it provides more vitamin A, D, E, and K, calcium, and gelatin, and less of the
+ pro-inflammatory amino acids, tryptophan and cysteine. Most loss of calcium from bones occurs during the
+ night. PTH tends to cycle with prolactin, which increases during the night, along with cortisol and the
+ other stress hormones. These nocturnal hormones probably account for the morning stiffness seen in many
+ rheumatic conditions, connective tissue diseases, and in aging. Progesterone, which increases the carbon
+ dioxide content of the tissues, is remarkably able to inhibit the actions of most of the inflammatory and
+ catabolic mediators, and to protect against degenerative calcification and osteoporosis. It also protects
+ against abnormal clotting. PTH increases platelet calcium concentration, and under some conditions can
+ produce inappropriate coagulation. Aspirin inhibits the actions of PTH, helping to prevent the calcification
+ of inflamed tissues, and it inhibits the loss of calcium from bones. Aspirin decreases the release of IL-6.
+ A protein called the PTH-related protein (PTHrP) has the same functions as PTH, but can be produced in any
+ tissue. It is responsible for the hypercalcemia of cancer, and is apparently involved in the frequent
+ metastasis of breast cancer to the bones. With only a small change in the theory of the nature of a living
+ organism, recognizing the importance of the interactions of metabolites and structural substances,
+ controlled by energetic metabolism, real progress could be made in understanding disease and health. The
+ most important calcium paradox is that medical journals (e.g.,
+ International J. of Cardiology,
+ Dec., 2002) are still promoting the idea that eating too much calcium causes hardening of the arteries and
+ other diseases of calcification.
+
+ REFERENCES
+
+
+
+ J Am Soc Nephrol 1994 Apr;4(10):1814-9. A role of parathyroid hormone for the activation of cardiac
+ fibroblasts in Uremia. Amann K, Ritz E, Wiest G, Klaus G, Mall G. Thus, PTX abolished and PTH
+ restored intermyocardiocytic changes of experimental uremia. These observations argue for a permissive role
+ of PTH for fibroblast activation and the genesis of the cardiac fibrosis of uremia.
+
+
+ Clin Endocrinol (Oxf) 1976 May;5(3):291-3. Recurrent hormone dependent chorea: effects of oestrogens and
+ progestogens. Barber PV, Arnold AG, Evans G.
+
+
+ Biochem Biophys Res Commun 2001 Feb 23;281(2):277-81. 17 beta-estradiol increases Ca(2+) influx and
+ down regulates interleukin-2 receptor in mouse thymocytes. Azenabor AA, Hoffman-Goetz L.
+
+
+
+ Nutr Rev 2002 Oct;60(10 Pt 1):337-41. Elderly women need dietary protein to maintain bone mass. Bell J,
+ Whiting SJ. Researchers who conducted a recent prospective study of older adults reported that animal
+ protein had a protective role for bone, especially in elderly women, whereas plant protein was negatively
+ associated with bone mineral density. Other studies confirm the beneficial effect of increasing dietary
+ protein intake in older women to reduce bone mineral density loss and risk of fracture, suggesting that
+ emphasis should be placed on promoting adequate protein intake in elderly women.
+
+
+ Am J Physiol Renal Physiol 2001 Dec;281(6):F1058-66. Metabolic, but not respiratory, acidosis increases bone
+ PGE(2) levels and calcium release. Bushinsky DA, Parker WR, Alexander KM, Krieger NS. A decrease in blood pH
+ may be due to either a reduction in bicarbonate concentration ([HCO(3)(-)]; metabolic acidosis) or to an
+ increase in PCO(2) (respiratory acidosis). In mammals, metabolic, but not respiratory, acidosis increases
+ urine calcium excretion without altering intestinal calcium absorption, indicating that the additional
+ urinary calcium is derived from bone. In cultured bone, chronic metabolic, but not respiratory, acidosis
+ increases net calcium efflux (J(Ca)), decreases osteoblastic collagen synthesis, and increases osteoclastic
+ bone resorption. Metabolic acidosis increases bone PGE(2) production, which is correlated with J(Ca), and
+ inhibition of PGE(2) production inhibits this acid-induced J(Ca). Thus metabolic, but not respiratory,
+ acidosis induces the release of bone PGE(2), which mediates J(Ca) from bone.
+
+
+ J Clin Endocrinol Metab 1991 Jan;72(1):69-76. Circadian variation in ionized calcium and intact parathyroid
+ hormone: evidence for sex differences in calcium homeostasis. Calvo MS, Eastell R, Offord KP, Bergstralh EJ,
+ Burritt MF. Serum intact PTH levels showed a significant circadian pattern in both sexes (P less than or
+ equal to 0.001).
+
+
+ J Lab Clin Med 1995 Jul;126(1):81-7. Effect of chronic respiratory acidosis on calcium metabolism in the
+ rat. Canzanello VJ, Kraut JA, Holick MF, Johns C, Liu CC, Madias NE. Chronic metabolic acidosis typically
+ results in hypercalciuria and negative calcium balance. The impact of chronic respiratory acidosis on
+ calcium metabolism has been less well studied. To address this issue, metabolic balance and static bone
+ histomorphometric data were obtained during a 14-day exposure of rats to 10% CO2 (blood pH 7.33, PaCO2 83 mm
+ Hg) and were compared with pair-fed controls. All rats were fed a 0.8% calcium diet. Urinary calcium
+ excretion (mg/period, mean +/- SEM) was increased during both week 1 and week 2 (16 +/- 3 vs 9 +/- 1 and 16
+ +/- 2 vs 9 +/- 1, CO2 group vs controls, respectively [p < 0.05]). Net intestinal calcium absorption
+ (intake minus fecal excretion) was increased throughout the period of hypercapnia (week 1, 213 +/- 19 mg vs
+ 135 +/- 15 mg; week 2, 135 +/- 16 mg vs 43 +/- 14 mg; and cumulatively, 344 +/- 27 mg vs 178 +/- 20 mg, CO2
+ group vs controls [p < 0.01]). As a consequence of the marked increment in intestinal calcium absorption
+ during hypercapnia, mean net calcium balance was more positive than that of controls throughout the study
+ (week 1, 197 +/- 18 mg vs 126 +/- 15 mg; week 2, 120 +/- 15 mg vs 34 +/- 15 mg; and cumulatively, 317 +/- 25
+ mg vs 159 +/- 20 mg, CO2 group vs controls, respectively [p < 0.01]). There were no significant
+ differences in calcium intake, plasma total calcium, immunoreactive parathyroid hormone, 25-hydroxyvitamin
+ D, or creatinine clearance between the two groups.
+
+
+
+ Mov Disord 1991;6(4):355-7. An unusual cause of recurrent chorea. Caviness JN, Muenter MD. Lee Silverman
+
+
+ Bone 2000 Jan;26(1):79-85.
+ Correlation of estradiol, parathyroid hormone, interleukin-6, and soluble interleukin-6 receptor during
+ the normal menstrual cycle. Chiu KM, Arnaud CD, Ju J, Mayes D, Bacchetti P, Weitz S, Keller ET.
+
+
+ These data demonstrate that IL-6 and PTH fluctuate with E2, and serum II-6 is associated with PTH
+ levels during the menstrual cycle.
+
+
+
+ J Cell Sci 2002 Feb 1;115(Pt 3):599-607. pH-dependent regulation of lysosomal calcium in macrophages.
+ Christensen KA, Myers JT, Swanson JA. Average free calcium concentration in macrophage lysosomes was
+ 4-6x10(-4) M, less than half of the extracellular calcium concentration, but much higher than cytosolic
+ calcium levels. pH-dependent reductions of lysosomal calcium concentrations appeared to result from calcium
+ movement out of lysosomes into cytoplasm, since increases in cytosolic calcium levels could be detected upon
+ lysosome alkalinization.
+
+
+ Adv Neurol 1979;26:123-33. Ovarian steroid hormones and cerebral function. Cogen PH, Zimmerman EA.
+
+
+ J Bone Miner Res 1996 Oct;11(10):1419-29. Stimulation of neonatal mouse calvarial bone resorption by the
+ glucocorticoids hydrocortisone and dexamethasone. Conaway HH, Grigorie D, Lerner UH. In vitro stimulation of
+ bone resorption was observed with the glucocorticoids hydrocortisone and dexamethasone. The 45Ca release
+ stimulated by 1 microM hydrocortisone and 0.1 microM dexamethasone was also inhibited by 10 microM
+ progesterone in a competitive manner and by 1 microM of the antiglucocorticoid RU38486, both of which are
+ modulators of glucocorticoid binding.
+
+
+ J Physiol 2002 Mar 15;539(Pt 3):791-803. MgATP counteracts intracellular proton inhibition of the
+ sodium-calcium exchanger in dialysed squid axons. DiPolo R, Beauge L. The increase in Ca(2+)(i) affinity
+ induced by ATP at acid pH (6.9) can be mimicked by a rise in pH(i) from 6.9 to 7.3 in the absence of the
+ nucleotide.
+
+
+ J Maine Med Assoc 1977 Oct;68(10):370-1 Quadriparesis as an unusual manifestation of hypercalcemia. Dyro FM.
+
+
+
+
+ Hypertension 1986 Jun;8(6):497-505. Effects of calcium infusion on blood pressure in hypertensive and
+ normotensive humans. Ellison DH, Shneidman R, Morris C, McCarron DA. Together, these data provide evidence
+ for interactions between dietary sodium intake and the cardiovascular response to calcium. They confirm that
+ hypertensive subjects exhibit enhanced parathyroid gland function even when dietary factors are controlled,
+ and they suggest that these subjects are more sensitive to the cardiovascular effects of short-term calcium
+ infusion.
+
+
+ Yale J Biol Med 1996 Sep-Dec;68(5-6):215-7. Diplopia associated with hyperparathyroidism: report of a case.
+ Forman BH, Ciardiello K, Landau SJ, Freedman JK. A patient with hypercalcemia due to primary
+ hyperparathyroidism presented with diplopia that resolved with surgical removal of his parathyroid adenoma
+ and normalization of his serum calcium values. No previous report of this feature of hyperparathyroidism has
+ been reported.
+
+
+ J Nutr Sci Vitaminol (Tokyo) 1985 Dec;31 Suppl:S15-9. Aging and calcium as an environmental
+ factor.
+ Fujita T Calcium deficiency is a constant menace to land-abiding animals, including mammals. Humans enjoying
+ exceptional longevity on earth are especially susceptible to calcium deficiency in old age. Low calcium and
+ vitamin D intake, short solar exposure, decreased intestinal absorption, and falling renal function with
+ insufficient 1,25(OH)2 vitamin D biosynthesis all contribute to calcium deficiency, secondary
+ hyperparathyroidism, bone loss and possibly calcium shift from the bone to soft tissue, and from the
+ extracellular to the intracellular compartment, blunting the sharp concentration gap between these
+ compartments. The consequences of calcium deficiency might thus include not only osteoporosis, but also
+ arteriosclerosis and hypertension due to the increase of calcium in the vascular wall, amyotrophic
+ lateral sclerosis and senile dementia due to calcium deposition
+ in the central nervous system, and a decrease in cellular function, because of blunting of
+ the difference in extracellular-intracellular calcium, leading to diabetes mellitus, immune deficiency
+ and others (Fig. 6)
+
+
+
+ Ann N Y Acad Sci 1990;587:371-5. Cytokines and osteoporosis. Fujita T, Matsui T, Nakao Y, Shiozawa S, Imai
+ Y. Conditions associated with immune dysfunction such as aging, corticosteroid therapy, and rheumatoid
+ arthritis are associated with osteoporosis, which is also more common in females than in males, like most of
+ the autoimmune-collagen diseases. Peripheral lymphocyte subsets CD4/CD8 were higher in patients with senile
+ osteoporosis than in the age-matched controls, and returned to normal after 1 month of 1 alpha(OH)vitamin D3
+ treatment. Plasma interferon reflecting macrophage function decreased with advance in age and increased in
+ response to 1 alpha(OH)D3 treatment. As one of the immunoregulators, vitamin D tends to stimulate the
+ macrophage-natural killer system and suppress the lymphocyte system, stimulating TGF beta and TNF alpha
+ activity. Senile osteoporosis of low turnover thus appears to be associated with vitamin D deficiency, low
+ macrophage function, high CD4 lymphocyte proportion, low IL-1 and high IL-2 activity, low IFN alpha and high
+ IFN gamma activity, and low TGF beta and TNF alpha activity.
+
+
+
+ Contrib Nephrol 1991;90:206-11.
+ Calcium, parathyroids and aging.
+
+ Fujita T Calcium is unique in its distribution in living organisms with an extremely high hard and soft
+ tissue and extra- intracellular concentration gradient. Calcium
+ deficiency through stimulating parathyroid hormone secretion tends to blunt such a difference by
+ paradoxically increasing the calcium concentration in the soft tissue and intracellular compartment.
+ Since aging is associated with the progressive aggravation of calcium deficiency, such blunting
+ also progresses with aging. The dysfunction, damage and death of cells occurring in all diseases
+ is always associated with a blunting of the extra- and intracellular calcium components. Calcium
+ supplement especially with highly biologically available active absorbable calcium, was associated with
+ the suppression of parathyroid
+ hormone secretion and the normalization of a such blunting of intercompartmental distribution of
+ calcium examples in hypertension and diabetes mellitus with evident improvement of clinical
+ manifestations and laboratory tests.
+
+
+
+ Presse Med 2001 Apr 7;30(13):653-8. [Hypovitaminosis D: a major worldwide public health problem]
+ Gannage-Yared MH, Tohme A, Halaby G. Mild to moderate hypovitaminosis D causes secondary hyperparathyroidism
+ increasing the risk of fracture, particularly femoral neck fracture. Vitamin D would also have an
+ antiinflammatory and anticancer effect. Hypovitaminosis D is frequently observed in Europe in the elderly,
+ particularly in the institutionalized population, but is also seen in otherwise healthy younger adults. An
+ estimated 40% of the young European population has some degree of hypovitaminosis D. Finally, the beneficial
+ effect of moderate sun exposure on cutaneous vitamin D synthesis (and psychological well-being) must not be
+ overlooked.
+
+
+ Mol Med 1996 Mar;2(2):204-10.
+ Parathyroid hormone-related protein is induced during lethal endotoxemia and contributes to
+ endotoxin-induced mortality in rodents. Funk JL, Moser AH, Strewler GJ, Feingold KR, Grunfeld
+ C. Parathyroid hormone-related protein (PTHrP) is a ubiquitous and highly conserved vasoactive peptide whose
+ role and regulation in normal physiology remain an enigma. Recently, we demonstrated that low-dose endotoxin
+ (LPS) induces intrasplenic, but not systemic, levels of PTHrP; and that tumor necrosis factor, a
+ pro-inflammatory cytokine, is the major mediator of this effect. We have therefore hypothesized that, with
+ higher, lethal doses of endotoxin, PTHrP could be induced in multiple tissues to such a degree that it could
+ contribute to the lethality of septic shock. In response to a near-lethal dose of endotoxin, PTHrP mRNA
+ levels increased acutely in every vital organ examined (spleen, lung, heart, kidney, and liver). Circulating
+ levels of PTHrP also increased, peaking 2 hr after administration of high-dose endotoxin. These
+ results suggest that PTHrP belongs to the cascade of pro-inflammatory cytokines induced during lethal
+ endotoxemia that is responsible for the toxic effects of LPS.
+
+
+
+ Calcif Tissue Int 1990 May;46(5):294-9. Effective therapy of glucocorticoid-induced osteoporosis with
+ medroxyprogesterone acetate. Grecu EO, Weinshelbaum A, Simmons R. The results lend support to the hypothesis
+ of a progesterone-glucocorticoid competitive antagonism at the bone level, though other possibilities can be
+ entertained, and suggest MPA as an effective therapy for glucocorticoid-induced osteoporosis in men.
+
+
+
+ Proc Soc Exp Biol Med 1986 Mar;181(3):438-42. Forskolin-induced bone resorption in neonatal mouse
+ calvaria in vitro. Gunasekaran S, Hall GE, Kenny AD Lactic acid release was increased
+ during the 96 hr of incubation in proportion to the calcium release in the media.
+
+ J Endocrinol 2000 Feb;164(2):129-38. Estrogen mediates the sex difference in post-burn
+ immunosuppression. Gregory MS, Duffner LA, Faunce DE, Kovacs EJ. Previous studies in our
+ laboratory have demonstrated that cell-mediated immune function was suppressed in female, but not male, mice
+ at 10 days after burn injury and was mediated,
+ in part, by increased production of interleukin-6 (IL-6).
+
+ Increased circulating
+ concentrations of E(2) corresponded with suppressed delayed-type hypersensitivity (DTH) and
+ splenocyte-proliferative responses, and increased circulating concentrations of IL-6 in female mice
+ after burn. Ovariectomy
+ restored the suppressed DTH response and decreased IL-6 concentrations, and administration of
+ exogenous E(2) to both ovariectomized females and intact male mice resulted in a suppressed DTH response. In
+ addition, in vitro treatment with E(2) suppressed splenocyte proliferation in a macrophage-dependent
+ manner and enhanced macrophage production of IL-6.
+
+
+
+ Calcif Tissue Int 1990 May;46(5):294-9. Effective therapy of glucocorticoid-induced osteoporosis with
+ medroxyprogesterone acetate. Grecu EO, Weinshelbaum A, Simmons R.
+
+
+ Nephron 1982;30(3):237-9. Elevated thrombocyte calcium content in uremia and its correction by 1 alpha(OH)
+ vitamin D treatment. Gura V, Creter D, Levi J.
+
+
+ Fortschr Med 1985 Mar 28;103(12):328-30.
+ [Antiallergic effect of oral calcium. A clinico-experimental study] [Article in German] Haas
+ PJ. Randomized Controlled Trial
+
+
+ Acta Univ Carol Med Monogr 1972;53:427-32. The possible role of platelets as trigger in intravascular
+ coagulation associated with acute hyperparathyroidism. Hilgard P, Hohage R, Schmitt W, Minne H, Ziegler R.
+
+
+
+ Sci Total Environ 1986 Oct;54:207-16. Chemical qualities of water that contribute to human health in a
+ positive way. Hopps HC, Feder GL. The chemical substances in water that make positive contributions to human
+ health act mainly in two ways: (i) nutritionally, by supplying essential macro and micro elements that the
+ diet (excluding water) may not provide in adequate amounts (for example, Mg, I and Zn); and (ii) by
+ providing macro and micro elements that inhibit the absorbtion and/or effects of toxic elements such as Hg,
+ Pb and Cd. In this context, the inverse relationship between hard water and cardiovascular disease will be
+ discussed. Specific data relating hardness and Mg and Ca content of potable waters to specific geographic
+ regions of the U.S.A. will be presented. These data show a strong positive correlation between low Mg
+ content and decreased longevity, and between high Ca and Mg content and increased longevity. In the regions
+ considered, increased longevity correlates strongly with decreased cardiovascular mortality, and the
+ decreased longevity with increased cardiovascular mortality.
+
+
+ Calcif Tissue Res 1977 Oct 20;23(3):241-4.
+ Proliferation of osteoclasts in rat bone following bleeding and femoral fractures. Johnell O,
+ Hulth A This rise in the osteoclast population might be due to an increased parathyroid activity released by
+ the trauma, but other factors may be involved. Both bleedings and fractures in rats are followed by
+ hypercalcemia. Brain Behav Immun 2000 Mar;14(1):49-61. Modulation of IL-6 production during the
+ menstrual cycle in vivo and in vitro. Konecna L, Yan MS, Miller LE, Scholmerich J, Falk W,
+ Straub RH. Premenopausal female patients with chronic inflammatory diseases demonstrate changes in disease
+ activity during the MC.
+
+
+ Kidney Int Suppl 1983 Dec;16:S204-7. Pathogenesis of the anemia of uremia: role of secondary
+ hyperparathyroidism. Massry SG PTH may participate in the genesis of the anemia of uremia
+ through at least
+ three pathways. These include inhibition of erythropoiesis, shortening survival of RBCs and inducing
+ fibrosis of bone marrow cavity.
+
+
+
+ Braz J Med Biol Res 2002 Feb;35(2):229-36. Parathyroid hormone secretion in chronic human endogenous
+ hypercortisolism. Lanna CM, Paula FJ, Montenegro RM Jr, Moreira AC, Foss MC. Osteoporosis is a common
+ manifestation of Cushing's syndrome, but the mechanisms responsible for this abnormality have not been
+ defined. Patients with CH showed an increased PTH response to the hypocalcemic stimulus compared to
+ controls.
+
+
+ Am J Clin Nutr 2000 Jul;72(1):168-73.
+ A threshold for low-protein-diet-induced elevations in parathyroid hormone.
+
+ Kerstetter JE, Svastisalee CM, Caseria DM, Mitnick ME, Insogna KL.
+ Elevations in PTH developed by day 4 of the diets containing 0.7 and 0.8 g protein/kg but not during the
+ diets containing 0.9 or 1.0 g protein/kg.
+ Our data suggest that in young healthy women consuming a well-balanced diet, the current recommended dietary
+ allowance for protein (0.8 g/kg) results in short-term perturbations in calcium homeostasis.
+
+
+ J Endocrinol 1995 Sep;146(3):421-9. Effect of oral calcium supplementation on intracellular calcium and
+ plasma renin in men. Lijnen P, Petrov V. Oral calcium supplementation in these men was also accompanied by a
+ reduction in the plasma concentration of intact parathyroid hormone and 1,25-dihydroxyvitamin D3, an
+ increase in 24-h urinary calcium excretion but no change in the plasma total Ca2+ concentration, serum
+ ionized Ca2+ level and plasma phosphate or 25-hydroxyvitamin D3.
+
+
+ Clin Sci (Lond) 1996 Sep;91(3):313-8. Effects of mineral composition of drinking water on risk for stone
+ formation and bone metabolism in idiopathic calcium nephrolithiasis. Marangella M, Vitale C, Petrarulo M,
+ Rovera L, Dutto F. The increase in overall calcium intake due to different drinking water induced modest
+ increases in calcium excretion, whereas oxalate excretion tended to decrease. The changes in oxalate
+ excretion during any one study period compared with another were significantly related to those in calcium
+ intake. Citrate excretion was significantly higher with the high-calcium, alkaline water. 4. Parathyroid
+ hormone, calcitriol and markers of bone resorption increased when patients were changed from the
+ high-calcium, alkaline to the low-calcium drinking water. 5. We suggest that overall calcium intake may be
+ tailored by supplying calcium in drinking water. Adverse effects on bone turnover with low-calcium diets can
+ be prevented by giving high-calcium, alkaline drinking water, and the stone-forming risk can be decreased as
+ effectively as with low-calcium drinking water.
+
+
+ J Endocrinol 1998 Feb;156(2):231-5. Calcium blood level modulates endogenous nitric oxide action: effects of
+ parathroidectomy in patients with hyperparathyroidism. Martina V, Bruno GA, Brancaleoni V, Zumpano E,
+ Tagliabue M, Fornengo R, Gasparri G, Pescarmona GP. In primary hyperparathyroidism (H-PTH) an increase in
+ platelet free calcium levels is present. After surgery, together with the normalization of calcium levels,
+ NO production also returned to normal values.
+
+
+
+ Hypertension 1980 Mar-Apr;2(2):162-8. Enhanced parathyroid function in essential hypertension: a homeostatic
+ response to a urinary calcium leak. McCarron DA, Pingree PA, Rubin RJ, Gaucher SM, Molitch M, Krutzik S.
+ Recent reports . . . suggest that increased parathyroid gland function may be one of the more common
+ endocrine disturbances associated with hypertension. Compared to a second age- and sex-matched normotensive
+ population, the hypertensives demonstrated a significant (p less than 0.005) relative hypercalciuria. For
+ any level of urinary sodium, hypertensives excreted more calcium. These preliminary data suggest that
+ parathyroid gland function may be enhanced in essential hypertension.
+
+
+ Am J Med 1987 Jan 26;82(1B):27-33. The calcium paradox of essential hypertension. McCarron DA, Morris CD,
+ Bukoski R. Three disparate observations--that calcium mediates vascular smooth muscle contraction, that
+ calcium channel blockers lower blood pressure, and that increased dietary calcium intake can also ameliorate
+ hypertension--constitute somewhat of a paradox. This evidence, and the paradoxical therapeutic efficacy of
+ both calcium channel blockers and supplemental dietary calcium, can be integrated into a single theoretic
+ construct.
+
+
+ Am J Hypertens 1995 Oct;8(10 Pt 1):957-64. Regulation of parathyroid hormone and vitamin D in essential
+ hypertension. Young EW, Morris CD, Holcomb S, McMillan G, McCarron DA. The maximal stimulated PTH level was
+ significantly higher in hypertensive than normotensive subjects in the absence of measured differences in
+ serum ionized calcium concentration, serum 1,25(OH)2-vitamin D concentration, and creatinine clearance.
+
+
+ J Clin Invest 1995 Apr;95(4):1933-40.
+ The diurnal rhythm of bone resorption in the rat. Effect of feeding habits and pharmacological
+ inhibitors. Muhlbauer RC, Fleisch H. This paper shows that, in rats, bone mass can be
+ increased by feeding habits per se. . . . we previously found a peak of bone resorption following food
+ administration. We now demonstrate that dividing the solid and liquid intake into portions blunts this
+ peak ....
+
+
+ Whether bone mass in humans is also under the control of dietary habits is not known. If so, an
+ increased meal frequency may be used to prevent osteoporosis.
+ Nephron 2001 Dec;89(4):384-90. Prolonged dietary calcium restriction: a diagnostic approach
+ in idiopathic Hypercalciuria. Muller D, Eggert P.
+
+
+
+
+ J Appl Physiol 2001 Jun;90(6):2094-100. Effects of hypercapnia and hypocapnia on [Ca2+]i mobilization in
+ human pulmonary artery endothelial cells. Nishio K, Suzuki Y, Takeshita K, Aoki T, Kudo H, Sato N, Naoki K,
+ Miyao N, Ishii M, Yamaguchi K. Hypocapnic alkalosis caused a fivefold increase in [Ca2+]i compared with
+ hypercapnic acidosis. The hypocapnia-evoked increase in [Ca2+]i was decreased from 242 +/- 56 to 50 +/- 32
+ nmol/l by the removal of extracellular Ca2+. The main mechanism affecting the hypocapnia-dependent [Ca2+]i
+ increase was thought to be the augmented influx of extracellular Ca2+ mediated by extracellular alkalosis.
+ Hypercapnic acidosis caused little change in PGI2 production, but hypocapnic alkalosis increased it
+ markedly.
+
+
+ Clin Nephrol 2002 Mar;57(3):183-91.. Bone involvement in idiopathic hypercalciuria. Misael da Silva AM, dos
+ Reis LM, Pereira RC, Futata E, Branco-Martins CT, Noronha IL, Wajchemberg BL, Jorgetti V. A negative
+ correlation was observed between IL-6 levels and Z score of the femoral neck. Bone involvement was detected
+ in a young population with nephrolithiasis demonstrating that a strict follow-up is necessary in order to
+ control hypercalciuria.
+
+
+ Am J Physiol Heart Circ Physiol 2002 Jul;283(1):H193-203. CaMKII-dependent reactivation of SR Ca(2+) uptake
+ and contractile recovery during intracellular acidosis. Nomura N, Satoh H, Terada H, Matsunaga M, Watanabe
+ H, Hayashi H. In hearts, intracellular acidosis disturbs contractile performance by decreasing myofibrillar
+ Ca(2+) response, but contraction recovers at prolonged acidosis.
+
+
+ J R Soc Health 1998 Apr;118(2):103-6. Lessons to be learned: a case study approach. Primary
+ hyperparathyroidism simulating an acute severe polyneuritis. Olukoga A. The case is presented of a 65 year
+ old lady with recent onset of neuromuscular manifestations, comprising paraparesis, areflexia and unsteady
+ gait, along with episodes of slurring of speech and diplopia, later confirmed to be due to severe
+ hypercalcaemia--which itself was caused by primary hyperparathyroidism.
+
+
+
+ Nippon Ronen Igakkai Zasshi 1989 May;26(3):216-22. [Calcium and magnesium metabolism in the
+ aged]
+ [Article in Japanese] Ouchi Y, Orimo H Although serum calcium concentration remains constant during ageing,
+ the plasma
+ concentration of calcium regulating hormones has been known to show dramatic change with ageing. The
+ plasma concentration of parathyroid hormone increases with ageing, whereas plasma concentrations of
+ calcitonin and active vitamin D metabolite decrease with ageing. On the other hand, the
+ incidence of soft tissue calcification is known to increase with ageing.
+
+
+
+ J Clin Endocrinol Metab 1978 Sep;47(3):626-32. Calcium-regulating hormones during the menstrual cycle.
+ Pitkin RM, Reynolds WA, Williams GA, Hargis GK. In six subjects with cycle lengths of 27-31 days, PTH levels
+ rose progressively through the follicular phase to a peak at or slightly before the LH surge, then fell
+ progressively through the luteal phase; peak PTH levels were 30-35% above early follicular and late luteal
+ values. One subject experienced a prolonged (44 day) ovulatory cycle characterized by three distinct PTH
+ peaks, each of which coincided with elevations in plasma estradiol level.
+
+
+ Muscle Nerve 1982 Jan;5(1):26-32.
+ Hereditary polymyopathy and cardiomyopathy in the Syrian hamster. II. Development of heart necrotic
+ changes in relation to defective mitochondrial function. Proschek L, Jasmin G Since the
+ mitochondrial respiratory pattern and calcium overload parallel the cardiac degeneration, it is inferred
+ that the cell energy depletion is a functional consequence of an abnormal calcium influx.
+
+ Eur J Endocrinol 1998 Oct;139(4):433-7. Changes in cytochrome oxidase activity in brown adipose
+ tissue during oestrous cycle in the rat.
+ Puerta M, Rocha M, Gonzalez-Covaleda S, McBennett SM, Andrews JF.
+ The involvement of oestradiol in such a cycle is suggested by the fact that oestradiol treatment
+ decreased COX activity to values similar to those found in proestrus.
+
+
+
+ Am J Hypertens 1999 Dec;12(12 Pt 1-2):1217-24. Modification of intracellular calcium and plasma renin by
+ dietary calcium in men. Petrov V, Lijnen P. Our data show that the increase in PARA [plasma renin activity]
+ observed in men during oral calcium supplementation is accompanied by a reduction in the intracellular free
+ and total Ca2+ concentration in platelets and erythrocytes and by a decrease in the plasma concentration of
+ intact parathormone and 1,25-dihydroxyvitamin D3.
+
+
+ Arthritis Rheum 2001 Oct;44(10):2338-41.
+ Association of osteoporosis and cardiovascular disease in women with systemic lupus
+ erythematosus. Ramsey-Goldman R, Manzi S. These results demonstrate an association between
+ decreased BMD and both an increased carotid plaque index and presence of coronary artery calcification in a
+ small cohort of young women with lupus.
+
+
+
+ Am J Hypertens 1994 Dec;7(12):1052-7. Dietary calcium reduces blood pressure, parathyroid hormone, and
+ platelet cytosolic calcium responses in spontaneously hypertensive rats. Rao RM, Yan Y, Wu Y.
+
+
+ J Clin Endocrinol Metab 2002. May;87(5):2008-12 Potassium citrate prevents increased urine calcium excretion
+ and bone resorption induced by a high sodium chloride diet. Sellmeyer DE, Schloetter M, Sebastian A.
+
+
+ J Allergy Clin Immunol 1990 Dec;86(6 Pt 1):881-5 1,25-Dihydroxyvitamin D3 potentiates the decreased
+ response of lymphocytes from atopic subjects to agents that increase intracellular cyclic adenosine
+ monophosphate. Ravid A, Tamir R, Liberman UA, Rotem C, Pick AI, Novogrodsky A, Koren R. Eur J
+ Endocrinol 2002 May;146(5):635-42. Diurnal rhythm of plasma 1,25-dihydroxyvitamin D and vitamin
+ D-binding protein in postmenopausal women: relationship to plasma parathyroid hormone and calcium and
+ phosphate metabolism. Rejnmark L, Lauridsen AL, Vestergaard P, Heickendorff L, Andreasen F,
+ Mosekilde L. With the disclosure of a diurnal rhythm of total plasma 1,25(OH)(2)D, all major
+ hormones and minerals related to calcium homeostasis have now been shown to exhibit diurnal variations.
+
+
+
+
+ Magnes Res 1999 Dec;12(4):257-67. Magnesium deficiency-induced osteoporosis in the rat: uncoupling of bone
+ formation and bone resorption. Rude RK, Kirchen ME, Gruber HE, Meyer MH, Luck JS, Crawford DL. Magnesium
+ (Mg) intake has been linked to bone mass and/or rate of bone loss in humans. Experimental Mg deficiency in
+ animal models has resulted in impaired bone growth, osteopenia, and increased skeletal fragility.
+
+
+ Schweiz Med Wochenschr 1994 Jun 25;124(25):1122-8. [Hypercalcemia] Schmid C. Severe
+ hypercalcemia is mainly caused by inappropriately high concentrations of compounds which promote bone
+ resorption, in particular PTH, PTHrP, or 1,25 (OH)2D3. The major consequences are impaired central
+ nervous system and kidney function (polyuria/dehydration);
+
+ the latter, in turn, aggravate hypercalcemia via decreased fluid intake, mobility, and renal calcium
+ clearance.
+
+
+ J Neurophysiol 2002 May;87(5):2209-24. Intracellular pH response to anoxia in acutely dissociated adult rat
+ hippocampal CA1 neurons. Sheldon C, Church J. During perfusion with HCO/CO(2)- or HEPES-buffered media (pH
+ 7.35) at 37 degrees C, 5- or 10-min anoxic insults were typified by an intracellular acidification on the
+ induction of anoxia, a subsequent rise in pH(i) in the continued absence of O(2), and a further internal
+ alkalinization on the return to normoxia. Reducing extracellular pH from 7.35 to 6.60, or reducing ambient
+ temperature from 37 degrees C to room temperature, also attenuated the increases in steady-state pH(i)
+ observed during and after anoxia and reduced rates of pH(i) recovery from acid loads imposed in the
+ immediate postanoxic period. The results suggest that a Zn(2+)-sensitive acid efflux mechanism, possibly a
+ H(+)-conductive pathway activated by membrane depolarization, contributes to the internal alkalinization
+ observed during anoxia in adult rat CA1 neurons. The rise in pH(i) after anoxia reflects acid extrusion via
+ the H(+)-conductive pathway and also Na(+)/H(+) exchange, activation of the latter being mediated, at least
+ in part, through a cAMP-dependent signaling pathway.
+
+
+ Am J Physiol Heart Circ Physiol 2002 Dec;283(6):H2518-26. pH-induced changes in calcium: functional
+ consequences and mechanisms of action in guinea pig portal vein. Smith RD, Eisner DA, Wray S. The effects of
+ changing extracellular (pH(o)) and intracellular pH (pH(i)) on force and the mechanisms involved in the
+ guinea pig portal vein were investigated to better understand the control of tone in this vessel. When pH(o)
+ was altered, the effects on force and calcium were the same irrespective of whether force had been produced
+ spontaneously by high-K depolarization or by norepinephrine; alkalinization increased tone, and
+ acidification reduced it. Because pH(o) changes also lead to changes in pH(i), we determined whether the
+ effects on force could be explained by these induced pH(i) changes. It was found, however, that only with
+ spontaneous activity did intracellular alkalinization increase force. In depolarized preparations, force was
+ decreased, and, with norepinephrine, force was initially decreased and then increased. Thus the effects of
+ pH(o) cannot be explained solely by changes in pH(i). The role of the sarcoplasmic reticulum (SR) and
+ surface membrane Ca(2+)-ATPase on the mechanism were investigated and shown not to be involved. Therefore,
+ it is concluded that both pH(o) and pH(i) can have powerful modulatory effects on portal vein tone, that
+ these effects are not identical, and that they are likely to be due to effects of pH on ion channels rather
+ than the SR or plasma membrane Ca(2+)-ATPase.
+
+
+
+ Biochem Biophys Res Commun 2002 May 10;293(3):974-8. Arachidonic acid increases intracellular calcium in
+ erythrocytes. Soldati L, Lombardi C, Adamo D, Terranegra A, Bianchin C, Bianchi G, Vezzoli G.. Since
+ arachidonic acid and other polyunsaturated fatty acids influence the activities of most ion channels, we
+ studied their effects on the erythrocyte Ca(2+) influx. AA (5-50 microM) and EPA (20-30 microM) stimulated a
+ concentration-dependent increase in [Ca(2+)](i), deriving from extracellular calcium (1 mM), without
+ affecting the intra- and extracellular pH and membrane voltage. We conclude that AA could activate an
+ erythrocyte voltage-independent Ca(2+) transport via an intermediate product of cyclooxygenase pathway...
+
+
+ BMJ 1991 Mar 30;302(6779):762. Hormone replacement therapy induced chorea. Steiger MJ, Quinn NP. University
+ Department of Clinical Neurology, Institute of Neurology, London.
+
+
+ Nippon Naibunpi Gakkai Zasshi 1991 Dec 20;67(12):1319-38. [Cation metabolism and the effects of circulating
+ factors in pregnancy induced hypertension] Takashima M, Morikawa H, Yamasaki M, Mochizuki M. These data
+ suggest that the increase of p-[Ca2+]i and r-[Na+]i in PIH is important in the initiation and maintenance of
+ hypertension by influencing peripheral vascular resistance, and also various factors in the serum of PIH
+ women may contribute to the accumulation of intracellular ionized calcium in patients with PIH.
+
+
+ Hear Res 2001 Apr;154(1-2):81-7. Effects of gentamicin and pH on [Ca2+]i in apical and basal outer hair
+ cells from guinea pigs. Tan CT, Lee SY, Yao CJ, Liu SH, Lin-Shiau SY. By means of fura-2
+ microspectrofluorimetry, we measured the intracellular calcium concentration ([Ca2+]i) of OHCs bathed in
+ Hanks' balanced salt solution (pH 7.40) during either a resting state or high K+-induced depolarization.
+ While gentamicin and extracellular acidification (pH 7.14) can separately attenuate this increase in [Ca2+]i
+ in both types of OHCs, their suppressive effects are additive in basal OHCs, but not in apical OHCs.
+
+
+
+ Biochem Pharmacol 1983 Jan 15;32(2):355-60. Induction of mast cell secretion by parathormone. Tsakalos ND,
+ Theoharides TC, Kops SK, Askenase PW. The biologically active fragment of human parathormone (PTH) and
+ intact bovine PTH were found to induce secretion of both serotonin and histamine from rat peritoneal mast
+ cells in vitro. Intradermal injection of PTH induced immediate increases in vascular permeability suggesting
+ that PTH could induce mast cell secretion in vivo. These results demonstrate that elevated levels of PTH can
+ induce mast cell secretion in vitro and in vivo and suggest a possible role for mast cells in the
+ pathophysiology of non-allergic disease states.
+
+
+ J Neurol Sci 1989 Feb;89(2-3):189-97. Hyperestrogenemia in neuromuscular diseases. Usuki F, Nakazato O,
+ Osame M, Igata A. The cases, comprising bulbospinal muscular disease of the Kennedy-Alter-Sung type,
+ Kugelberg-Welander disease, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy, were all
+ euthyroid males. The baseline levels of serum estrone were significantly higher in all of the patients than
+ in age-matched normal subjects. Serum baseline testosterone, LH and FSH levels were all essentially normal,
+ except low FSH levels in Duchenne muscular dystrophy.
+
+
+ MMW Munch Med Wochenschr 1976 Oct 22;118(43):1395-8. [Oral application of calcium and vitamin D2 in
+ allergic bronchial asthma] Utz G, Hauck AM. Within 60 minutes after application, a
+ statistically significant reduction of airway resistance (Rt) and intrathoracic gas volume (IGV), as well as
+ an increase of forced exspiratory one second volume (FEV1) and forced inspiratory one second volume (FIV1)
+ was observed, in comparison with placebo. It is concluded that calcium, given orally in combination
+ with calciferol, causes a decrease of airway obstruction in patients with allergic bronchial asthma.
+ J Urol 1994 Oct;152(4):1226-8. Urinary incontinence due to idiopathic hypercalciuria in
+ children.
+ Vachvanichsanong P, Malagon M, Moore ES. In addition to being the most common cause of
+ microhematuria in children, our study demonstrates that idiopathic
+ hypercalciuria is also frequently associated with urinary incontinence of all types.
+ Magnes Trace Elem 1991-92;10(2-4):281-6. Relation of magnesium to osteoporosis and calcium
+ urolithiasis. Wallach S Magnesium influences mineral metabolism in hard and soft tissues
+ indirectly through hormonal and other modulating factors, and by direct effects on the processes of bone
+ formation and resorption and of crystallization (mineralization). Its causative and therapeutic
+ relationships to calcium urolithiasis (CaUr) are controversial despite an association between low urinary Mg
+ and CaUr. Recent studies have also found a tendency to low serum and/or lymphocyte Mg levels in CaUr.
+ Despite earlier studies demonstrating an inhibitory effect of Mg supplementation on experimental CaUr in
+ animals and in spontaneous CaUr in humans, at least two properly controlled clinical trials of Mg
+ supplementation have failed to demonstrate a beneficial effect on CaUr frequency. With regard to the
+ skeleton, experimental studies have shown that Mg depletion causes a decrease in both osteoblast and
+ osteoclast activity with the development of a form of 'aplastic bone disease'. At the same time, bone salt
+ crystallization is enhanced by Mg deficiency. Conversely, Mg excess impairs mineralization with the
+ development of an osteomalacia-like picture, and may also stimulate bone resorption independently of
+ parathyroid hormone. Whether or not Mg depletion may be a causal factor in human osteoporosis is also
+ controversial, and there are conflicting reports as to the Mg content of osteoporotic bone. Small decreases
+ in serum and/or erythrocyte Mg in osteoporotic patients have been reported, and one author has noted
+ improved bone mineral density with a multinutrient supplement rich in Mg. The extant data are sparse and
+ indicate a clear need for more rigorous study.
+
+
+ Semin Dial 2002 May-Jun;15(3):172-86 Calciphylaxis: emerging concepts in prevention, diagnosis, and
+ treatment. Wilmer WA, Magro CM. Several recent reports demonstrate that prolonged hyperphosphatemia and/or
+ elevated calcium x phosphorus products are associated with the syndrome. Protein malnutrition increases the
+ likelihood of calciphylaxis, as does warfarin use and hypercoagulable states, such as protein C and/or
+ protein S deficiency.
+
+
+ J Clin Lab Anal 1998;12(3):145-9. A proposal for standardizing urine collections for bone resorption markers
+ measurement. Zaninotto M, Bernardi D, Ujka F, Bonato P, Plebani M. The findings suggest that nocturnal
+ collection and first morning void samples provide the most reliable data on the rate of bone degradation,
+ possibly showing bone loss not only in osteopenic patients but also in women with a low T-score.
+
+
+
+ Am J Physiol Renal Physiol 2001 Aug;281(2):F366-73. Increased CO(2) stimulates K/Rb reabsorption mediated by
+ H-K-ATPase in CCD of potassium-restricted rabbit. Zhou X, Nakamura S, Xia SL, Wingo CS.
+
+
+ Sci Total Environ 1981 Apr;18:35-45 Water hardness and mortality in the Netherlands. Zielhuis RL, Haring BJ.
+ The hypothesis that the Ca and Mg deficiency in areas with soft drinking water increases the risk of I.H.D.
+ death rate was supported by the finding that food loses more Ca and Mg when it is cooked in soft water as
+ compared to cooking in hard water. However, investigation of a group of 17 municipalities of which mortality
+ and water quality data are known for three periods, 1958-1962, 1965-1970 and 1971-1977, showed that the
+ inverse statistical relation between I.H.D. Mortality and water hardness still existed but with decreasing
+ significance of correlation coefficients.
+
+
+ J Clin Endocrinol Metab 1980 Dec;51(6):1274-8. Serotonin stimulates adenosine 3',5'-monophosphate
+ accumulation in parathyroid adenoma. Zimmerman D, Abboud HE, George LE, Edis AJ, Dousa TP. Since cAMP acts
+ as a mediator of parathyroid hormone (PTH) release, our results suggest that serotonin could be one of the
+ factors regulating PTH secretion and/or contributing to PTH hypersecretion in various forms of primary
+ hyperparathyroidism.
+
+
+ Cas Lek Cesk 1997 Jul 30;136(15):459-63.
+ [New drugs with positive effects on bones]
+
+
+ [Article in Czech] Zofkova I, Kanceva RL. Magnesium influences bone in different ways. It activates
+ osteoblasts, increases bone mineralization, and enhances the sensitivity of target tissues (incl. bone)
+ to PTH and 1,25(OH)2 vitamin D3, Under certain conditions however, magnesium can stimulate bone
+ resorption. A more potent factor than magnesium is stroncium, which not only activates osteoblats but
+ decreases the number of osteoclasts, thus abolishing bone resorption and enhancing formation.
+ Bicarbonates are also favourable for bone. NaHCO3 together with potassium citrate stimulates osteoblasts
+ and enhances bone mineralisation.
+
+ © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
+
+
+
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+
+
+
+
+
+
+
+ © Ray Peat Ph.D. 2014. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Preventing and treating cancer with progesterone.
+
+
+ Preventing and treating cancer with progesterone.
+
+
+ "The energy of the mind is the essence of life." Aristotle
+
+
+ All through the last century, as more and more resources were devoted to solving "the cancer problem," the
+ death rate from cancer increased every year. Something was clearly wrong with the way the problem was being
+ approached.
+
+
+ If you grind up a computer and dissolve it in acid, you can find out exactly what substances it was made of,
+ but you won't learn from that information how the computer worked. Twentieth century biologists became fond
+ of emulsifying cells and studying the soluble parts. By the end of the century, they had identified so many
+ parts that the government was financing projects to use supercomputers to try to understand how the parts
+ interacted.
+
+
+ If some essential information was lost in studying the parts, supercomputation isn't the way to find it.
+ Even with infinite computing capacity, a description of the electrons on carbon and hydrogen atoms on amino
+ acids in protein molecules won't lead to the reality of how those atoms would have functioned in the living
+ state.
+
+
+
+ The image of a cell as a watery solution contained in an elastic membrane bag is still having a radically
+ stupefying effect on biology and medicine. The idea that a cell can be understood by using a computer to
+ model a network of interactions between genes and gene products is nothing more than a technologizing of the
+ primitive understanding of life that was promulgated by the Weismann-Mendel-Morganist school. It was the
+ dogmatic insistence of that genetic determinist school that cancer originated with a genetic mutation.
+
+
+ By the middle of the 20th century, that dogma had excluded the most important parts of biology from the
+ schools and the journals. Ideas of a developmental field, cellular coherence, and holistic cooperativity
+ were denounced as unscientific vitalism. Returning to the idea of a "cancer field" is an essential first
+ step in thinking realistically about preventing and treating cancer, but that idea has hardly progressed
+ since the 1930s.
+
+
+ In the last few years, interest in cloning and stem cells and tissue regeneration has revived interest in
+ studying the factors that contribute to the spatial and temporal ordering of cell growth.
+
+
+ The idea of a developmental field was a fundamental part of embryology in the first half of the 20th
+ century. It was an empirical idea, supported most commonly by evidence that diffusing substances and
+ secreted materials governed the differentiation of cells and tissues, but the form-generating effects of
+ bioelectric fields were also often demonstrated, and there was some evidence that tissue radiations played a
+ role. The extracellular matrix secreted by cells served to transmit information between cells, but its form
+ was regulated by cells, and its structure was a factor governing the cells' differentiation.
+
+
+
+ Experiments in amphibians showed that regeneration of organs had a reciprocal relationship with the
+ development of cancer--a tumor could be turned into a tail, for example, if it was grafted onto the stump
+ following amputation of the tail, but factors that weakened regeneration could cause a tumor to develop. In
+ these experiments, the normal organism's morphogenetic or epimorphic field overrode the disordered
+ developmental field of the tumor.
+
+
+ In the absence of overriding external influences, the disordered system of the tumor, in which cells emitted
+ many products of their disordered metabolism, could interfere with the normal functions of the organism. All
+ of the products of the injured cells, including their altered extracellular matrix, constituted the cancer
+ field.
+
+
+ The recent recognition of the "bystander effect" of radiation exposure, in which cells that haven't been
+ irradiated undergo genetic changes or death when they are exposed to irradiated cells, has provided an
+ opportunity to return to the "field" idea in cancer, because the stress-induced factors emitted by
+ irradiated cells are the same toxic factors emitted by cells undergoing carcinogenesis from other causes,
+ such as over-exposure to estrogen.
+
+
+
+ H. J. Muller, one of T. H. Morgan's students and colleagues, studied the mutagenic effects of x-rays, and
+ the genetic determinists argued that the random changes produced in the genetic material by ionizing
+ radiation provided a model of the evolutionary process. Randomly altered genes and natural selection would
+ explain everything, including cancer. Every time cells divide, their genes supposedly become more
+ susceptible to random changes, so increased replication of cells would increase the risk of producing
+ genetic changes leading to cancer. This idea is so simple and so widely believed that many people focus only
+ on the rate of proliferation, and the random mutations that supposedly occur during proliferation, when they
+ try to explain carcinogenesis. They feel that it's reasonable to discuss cancer without bothering to
+ understand the physiology of the cell or the organism.
+
+
+ The organism can only be understood in its environments, and a cell can't be understood without reference to
+ the tissue and organism in which it lives. Although the geneticists were at first hostile to the idea that
+ nutrition and geography could have anything to do with cancer, they soon tried to dominate those fields,
+ insisting that mutagens and ethnicity would explain everything. But the evidence now makes it very clear
+ that environment and nutrition affect the risk of cancer in ways that are not primarily genetic.
+
+
+ Every tumor, like every person, has a uniqueness, but valid and practical empirical generalizations can be
+ made, if we understand some of their properties and the conditions that govern their development and
+ survival.
+
+
+ Percival Potts' observation of scrotal cancer in chimney sweeps eventually led to the study of soot
+ carcinogenesis, and then to the study of the properties of the polycyclic aromatic hydrocarbons in soot. The
+ similarities of those properties to estrogen's soon became apparent.
+
+
+
+ Over the decades, many studies have confirmed that prolonged, continuous exposure to estrogen is
+ carcinogenic, and that progesterone offsets those effects.
+
+
+ Following the animal studies that showed that carcinogenesis by estrogen could be prevented or reversed by
+ progesterone, studies of the endogenous hormones in women showed that those with a natural excess of
+ estrogen, and/or deficiency of progesterone, were the most likely to develop uterine or breast cancers.
+
+
+ The Morganist school of genetic determinism moved into endocrinology with a doctrine that hormones act only
+ through hormone receptors, proteins which activate certain genes.
+
+
+ Many researchers -- physical chemists, biochemists, cytologists, embryologists, reproductive and
+ developmental biologists, gerontologists, physiologists, neurologists, endocrinologists -- were
+ investigating estrogen's properties and actions, and had made great progress by the 1950s, despite the
+ medical frauds being perpetrated by the estrogen industry (Rothenberg, 2005).
+
+
+ All of this complex and subtle work was of no interest to a small group of people who wanted to impose their
+ genetic views onto biology.
+
+
+ The inventor of the estrogen receptor, Elwood Jensen, has written that the results of certain of his
+ experiments "caused the demise of the transhydrogenation hypothesis and convinced all but the most diehard
+ enzymologists that estradiol binds to a characteristic component of target cells to exert its physiological
+ effect without itself being chemically altered." The hypothesis he referred to was just part of a large
+ fairly systematic international effort.
+
+
+
+ How he did away with the opposition, who were studying the complex metabolic actions of estrogen, was by
+ synthesizing isotope-labeled estradiol and estrone, and claiming to observe that they weren't metabolically
+ altered, as they produced their hormonal effect. Since the experiment was extremely expensive, and required
+ the cooperation of the Atomic Energy Commission, it wasn't easily repeated. However, many experiments have
+ subsequently demonstrated that practically every tissue in the body (and plants and bacteria) metabolize the
+ estrogens, causing estradiol to change into estrone, and estrone, into estradiol. Jensen's decisive and
+ historically crucial experiment was false.
+
+
+ But it served its purpose, and (with help from the pharmaceutical industry and government granting agencies)
+ marginalized the work of those "enzymologists" and everyone else who persisted in studying the complex
+ actions of estrogen.
+
+
+ The enzyme that converts the weaker estrone into the stronger estradiol is an important factor in
+ determining estrogen's effects on a particular tissue. Progesterone is able to regulate the cell's
+ metabolism, so that the oxidative pathway, forming estrone from estradiol, predominates. Estrogen-dominated
+ tissues are likely to have a balance in the direction of reduction rather than oxidation, increasing the
+ amount of the active estradiol.
+
+
+
+ The immediate effects of estrogen and progesterone on cells, that occur long before genes can be activated,
+ were simply ignored or denied by the promoters of the estrogen receptor doctrine. Some of these excitatory
+ or antiexcitatory effects are probably structural changes, that involve the mobilization of calcium inside
+ cells, and the activation or inhibition of reactions involving phosphoric acid. Although they have been
+ known for many years, they are always referred to as "novel" or "non-classical" effects, and are called
+ "membrane effects," because that's the only way the reductionists are able to identify changes that happen
+ immediately throughout the cell.
+
+
+ Cellular excitation involves an increase of intracellular calcium and the activation of phosphorylating
+ enzymes in cells. Some experiments suggest (Improta-Brears, et al., 1999) that the estrogen receptor
+ mediates estrogen's ability to mobilize calcium (leading to the activation of cell division, mitosis).
+ Whether or not it does, the recognition that estrogen activates calcium, leading to activation of the
+ phosphorylation system, should "cause the demise of" the "classical estrogen receptor" doctrine, because the
+ phosphorylation system alters the expression of genes, much as the estrogen receptor was supposed to do by
+ its direct actions. But before it alters the expression of genes, it alters the activities of
+ enzymes. When estrogen activates calcium and phosphorylation independently of the estrogen
+ receptor, the situation is even worse for the Jensen dogma.
+
+
+
+ Progesterone's opposition to those early excitatory effects of estrogen are so basic, that there shouldn't
+ be any difficulty in thinking of it as an antiestrogen, that stops cell division primarily by opposing the
+ excitatory effects of estrogen and other mitogens. Progesterone's opposition to the calcium-activating and
+ phosphorylating effects of estrogen affects everything in the cell, according to the cell's specific nature.
+
+
+ But the reductionists don't like "nongenomic" explanations of anything, even when they are triggered by the
+ estrogen receptor rather than by a membrane-event. So, to argue that progesterone's opposition to estrogen
+ is general, it's necessary to examine each of estrogen's actions, where those actions are clearly known, and
+ to evaluate progesterone's effects on the same events.
+
+
+
+ When a cell is stimulated or slightly stressed, homeostatic mechanisms are activated that help it to return
+ to its normal resting state. The mobilization of calcium and the phosphorylation system is followed by
+ increased synthesis of cholesterol and the formation of glucose from glycogen. Cholesterol itself is
+ protective, and in some cells it is massively converted into progesterone, which is even more effective in
+ restoring homeostasis.
+
+
+ In the ovary, the enzymes that synthesize cholesterol, along with the production of progesterone, are
+ activated by the pituitary hormone, FSH, but also by estrogen. In the liver and uterus and vascular
+ endothelium, which aren't specialized for the production of progesterone, stimulation by estrogen activates
+ the enzymes to increase the formation of cholesterol.
+
+
+ When cells are injured or seriously stressed, instead of being able to directly recover their normal
+ quiescence, they may instead mobilize their systems for growing and replicating, to replace damaged or
+ destroyed cells.
+
+
+ Prolonged exposure to estrogen, that can't be offset by the homeostatic factors, such as progesterone,
+ typically causes cells to enter a growth phase. (But so do other excitatory processes, such as ionizing
+ radiation.)
+
+
+ One of the basic reactions to injury is to shift the cell away from oxidative metabolism to glycolytic
+ metabolism, which is inefficient, but can support cell division. Chemical stains show that during cell
+ division cells are in a reduced state, with abundant sulfhydryl groups including reduced glutathione and
+ protein sulfhydryls. This shift in itself increases the formation of active estradiol from estrone.
+
+
+
+ In the inflamed or estrogen dominated cell, enzymes such as the cyclooxidases (COX), that convert
+ arachidonic acid into prostaglandins, are activated. Beta-glucuronidase and sulfatases are activated, and
+ these cause intracellular estrogen to increase, by removing the water soluble sulfate and glucuronate
+ portions from estrogens that had been inactivated. The detoxifying enzymes that attach those molecules to
+ estrogen are inactivated in the estrogen dominated cell. The prostaglandin formed from arachidonic acid
+ stimulates the formation of the enzyme aromatase or estrogen synthetase, that converts androgens into
+ estrogen.
+
+
+ Those processes, initiated by excitation or injury, increase the amount of estrogen in the cell, which
+ intensifies the excitation.
+
+
+ Progesterone opposes all of those processes, decreasing the amount of estrogen in the cell by modifying the
+ activities of those five types of enzyme.
+
+
+ Although many kinds of protein (including enzymes) bind estrogen, the protein that Jensen called "the
+ estrogen receptor" is largely responsible for the ability of the uterus and breasts to retain high
+ concentrations of estrogen. Various kinds of stimulation or stress (including heat and oxygen deprivation)
+ cause its appearance, and estrogen itself increases the amount of the estrogen receptor in a cell. The
+ estrogen receptor doesn't just "activate genes," as the Jensen dogma claimed. For example, the estrogen
+ receptor directly binds and inactivates the "tumor suppressor" p53 protein, which otherwise would restrain
+ the replication of damaged cells.
+
+
+ Progesterone causes the estrogen receptor to be eliminated. (Batra; Boling and Blandau; Resko, et al.)
+
+
+ Among the cell activating factors, other than estrogen, are proteins that are considered to be "oncogenes,"
+ because of their involvement in cancer. Several of these proteins are activated by estrogen, inhibited by
+ progesterone. The term "oncogene" refers to any gene that contributes to the development of cancer, but it
+ is so burdened by ideology that it shouldn't be used as if it had a simple clear meaning.
+
+
+
+ A variety of proteins promote cell activity and replication, under the influence of estrogen. The "composite
+ transcription factor activating protein 1," AP-1 which integrates the effects of other transcription
+ factors, is important in a variety of cell types, and its activity is increased by estrogen and decreased by
+ progesterone.
+
+
+ When the "progesterone receptor" lacks progesterone, it has the opposite effect of
+ progesterone, and this feature has been used propagandistically, by infecting cells with a virus carrying
+ the progesterone receptor protein, and then suggesting that the disturbed functions of the cell reflect a
+ potential effect of progesterone. The receptor, lacking progesterone, tells the cell that it has a
+ progesterone deficiency, but too many molecular endocrinologists are trying to say that the receptor protein
+ is the same as the progesterone.
+
+
+ The generality of the process of excitation/activation can be clearly seen in the effects of the
+ nerve-inhibiting GABA and the nerve-exciting glutamate or NMDA. In cultured breast cancer cells, GABA
+ inhibits growth, NMDA increases growth. As in the brain, progesterone supports the actions of GABA, and
+ opposes those of NMDA or the excitatory amino acids, while estrogen in general promotes the effects of the
+ excitatory amino acids, and opposes those of GABA.
+
+
+
+ Both the excitatory amino acids and a peptide that promotes inflammation, tumor necrosis factor (TNF),
+ activate the enzyme which makes estrogen, aromatase. Estrogen, by activating NF kappaB, increases the
+ formation of TNF, which in itself can promote the growth and metastasis of cancer. Various antiinflammatory
+ agents, including aspirin, progesterone, testosterone, saturated fats, and glycine, can inhibit the
+ production of NF kappaB.
+
+
+ An enzyme that has been thought of mainly in relation to the brain is catechol-O-methyl transferase, which
+ is inhibited by estrogen (producing effects similar to cocaine), leading to brain excitation.The enzyme
+ detoxifies catecholestrogen (Creveling, 2003), protecting cells from DNA damage (Lavigne, et al., 2001).
+ When the activity of this enzyme is low, there is increased risk of breast cancer (Matsui, et al., 2000).
+ Progesterone increases its activity (Inoue and Creveling, 1991, 1995).
+
+
+ Another enzyme system that affects the body's reactions to stress and modifies processes of inflammation and
+ growth, the monoamino-oxidases, is affected oppositely by estrogen and progesterone. Estrogen's effects are
+ partly mediated by increased formation of serotonin, progesterone's, by decreasing it. Histamine is another
+ promoter of inflammation that is increased by estrogen, decreased by progesterone.
+
+
+ Estrogen's effects in the nervous system go beyond the production of cocaine-like hypomania, or chorea, or
+ epilepsy, and include the activation of the basic stress hormones, increasing the formation in the
+ hypothalamus of pro-opiomelanocortin (POMC), which is a precursor of ACTH to activate the adrenals, and
+ endorphins ("endogenous opiates"), which stimulate growth processes. Both endorphins and ACTH can be found
+ in tumors such as breast cancer. The ACTH stimulates the production of cortisol, that protects against some
+ of the immediate causes of inflammation and growth, but that contributes to the loss of resistance, and
+ increases estrogen synthesis.
+
+
+
+ A protein called the sigma receptor, known for its role in cocaine's action, binds progesterone, and can
+ inhibit the growth of cancer. Some anesthetics have similar effects on tumors, acting through this protein.
+ The sigma receptor, in association with progesterone or pregnenolone, is protective against the excitatory
+ amino acids.
+
+
+ The extracellular medium changes during the development of a tumor. Irritated hypoxic cells, and
+ estrogen-stimulated cells, increase their production of collagen, and the increase of collagen interferes
+ with normal cell functions. Progesterone reduces the formation of collagen, and probably contributes to its
+ removal.
+
+
+ Naloxone or naltrexone, which blocks the actions of the endorphins and morphine, is being used to inhibit
+ the growth of various kinds of cancer, including breast cancer and prostate cancer. Leptin (which is
+ promoted by estrogen) is a hormone produced by fat cells, and it, like estrogen, activates the POMC-related
+ endorphin stress system. The endorphins activate histamine, another promoter of inflammation and cell
+ division.
+
+
+ Progesterone opposes those various biochemical effects of estrogen in multiple ways, for example by
+ inhibiting the ACTH stress response, by restraining cortisol's harmful actions, and by inhibiting leptin.
+
+
+ Mediators of the radiation bystander effect include NO, TNF, COX, and prostaglandins. These are produced by
+ other things that cause inflammation and injury, including estrogen.
+
+
+
+ Cell division, when it is part of the body's continuous renewal and adaptation, isn't a source of mutations
+ or degeneration, but when it is induced by the mediators of inflammation produced in response to injury, it
+ leads to inherited changes, loss of differentiated function, and eventually to genetic instability.
+
+
+ When cell division is so disturbed that the number of chromosomes becomes abnormal, the instability of these
+ cells decreases their ability to survive, but when the causes of the inflammation persist, they will
+ continue to be replaced by other abnormal cells. The toxic products of dying cells can reach a point at
+ which the debris can't be removed, adding to the injury and inflammation. The damaged bystander cells spread
+ their influence through a cancer field, injuring more cells.
+
+
+ One of the "field" effects of cancer is the stimulation of new blood vessel development, angiogenesis.
+ Lactic acid stimulates the formation of new blood vessels, the secretion of collagen, and tumor growth. Low
+ oxygen, nitric oxide, carbon monoxide, prostaglandins and other products of tissue stress can stimulate the
+ growth of new blood vessels, at the same time that they stimulate tumor growth and impair oxidative
+ metabolism. Several of these agents promote each other's activity.
+
+
+ Therapeutic thinking has been influenced by the doctrine of the mutant cell as the initiator of cancer,
+ leading to the idea that only things which kill the cancer cells can cure cancer. But when the body stops
+ activating the processes of inflammation and growth, normal processes of tissue repair have an opportunity
+ to eliminate the tumor. Even the fibroblasts which normally secrete collagen can participate in its removal
+ (Simoes, et al., 1984). Something as simple as eliminating lactate can change their functions.
+
+
+
+ Although the angiogenic action of lactate has been known for several decades, some researchers believed that
+ a specific anti-angiogenic peptide could be found which would stop the growth of cancer cells. The interest
+ in angiogenesis tacitly acknowledges that there is a cancer field, but the faith that cancer could be cured
+ only by killing the mutant cells seems to have guided the search for a single antiangiogenic substance. Such
+ a substance would be toxic to normal tissues, since blood vessels are constantly being renewed.
+
+
+ The more advanced a tumor is, the more numerous the growth-promoting factors are likely to be, and the
+ weaker the body's ability becomes to control them.
+
+
+ The search for toxic factors to kill the cancer cells is unlikely to lead to a generally effective
+ treatment. Even immunological approaches that think in terms of destroying a tumor might be misconceiving
+ the nature of the problem. For example, the protein called "tumor necrosis factor" (TNF) or cachectin was
+ discovered as a result of Lawrence Burton's work in the 1960s. He extracted proteins from the blood that
+ could shrink some tumors in mice with amazing speed. In the right setting, TNF is involved in the
+ destruction of tumors, but when other factors are missing, it can make them worse. Burton was focussing on
+ factors in the immune system that could destroy cancer, but he ignored the basic problem of tissue
+ degeneration that produces tumors which are complex and changing.
+
+
+ If the cancer-productive field is taken into account, all of the factors that promote and sustain that field
+ should be considered during therapy.
+
+
+
+ Two ubiquitous carcinogenic factors that can be manipulated without toxins are the polyunsaturated fatty
+ acids (PUFA) and estrogen. These closely interact with each other, and there are many ways in which they can
+ be modulated.
+
+
+ For example, keeping cells in a well oxygenated state with thyroid hormone and carbon dioxide will shift the
+ balance from estradiol toward the weaker estrone. The thyroid stimulation will cause the liver to excrete
+ estrogen more quickly, and will help to prevent the formation of aromatase in the tissues. Low temperature
+ is one of the factors that increases the formation of estrogen. Lactic acid, serotonin, nitric oxide,
+ prostaglandins, and the endorphins will be decreased by the shift toward efficient oxidative metabolism.
+
+
+ Progesterone synthesis will be increased by the higher metabolic rate, and will tend to keep the temperature
+ higher.
+
+
+ Thyroid hormone, by causing a shift away from estrogen and serotonin, lowers prolactin, which is involved in
+ the promotion of several kinds of cancer.
+
+
+ Vitamin D and vitamin K have some antiestrogenic effects. Vitamin D and calcium lower the
+ inflammation-promoting parathyroid hormone (PTH).
+
+
+ Eliminating polyunsaturated fats from the diet is essential if the bystander effect is eventually to be
+ restrained. Aspirin and salicylic acid can block many of the carcinogenic effects of the PUFA. Saturated
+ fats have a variety of antiinflammatory and anticancer actions. Some of those effects are direct, others are
+ the result of blocking the toxic effects of the PUFA. Keeping the stored unsaturated fats from circulating
+ in the blood is helpful, since it takes years to eliminate them from the tissues after the diet has changed.
+ Niacinamide inhibits lipolysis. Avoiding over-production of lipolytic adrenaline requires adequate thyroid
+ hormone, and the adjustment of the diet to minimize fluctuations of blood sugar.
+
+
+
+ The endorphins are antagonistic to progesterone, and when they are minimized, progesterone tends to
+ increase, and to be more effective. The drugs naloxone and naltrexone, which block the effects of the
+ endorphins, have several remarkable effects that resemble progesterone's. Naltrexone has been successfully
+ used to treat prostate and breast cancer.
+
+
+ Opiates are still commonly used for pain relief in cancer patients, despite the evidence that has
+ accumulated for several decades indicating that they promote inflammation and cancer growth, while
+ suppressing immunity and causing tissue catabolism, exacerbating the wasting that commonly occurs with
+ cancer. Their use, rather than alternatives such as procaine, aspirin, and progesterone, is nothing but a
+ medical fetish.
+
+
+ Stress and estrogen tend to produce alkalosis, while thyroid, carbon dioxide, and adequate protein in the
+ diet help to prevent alkalosis.
+
+
+ Antihistamines and some of the antiserotonin drugs (including "dopaminergic" lisuride and bromocriptine) are
+ sometimes useful in cancer treatment, but the safe way to lower serotonin is to reduce the consumption of
+ tryptophan, and to avoid excessive cortisol production (which mobilizes tryptophan from the muscles).
+ Pregnenolone and sucrose tend to prevent over-production of cortisol.
+
+
+ In the breast, COX-2 converts arachidonic acid into prostaglandins, which activate the enzyme aromatase,
+ that forms estrogen from androgens. Until the tissues are free of PUFA, aspirin and salicylic acid can be
+ used to stop prostaglandin synthesis.
+
+
+
+ Thyroid is needed to keep the cell in an oxidative, rather than reductive state, and progesterone (which is
+ produced elsewhere only when cells are in a rapidly oxidizing state) activates the processes that remove
+ estrogen from the cell, and inactivates the processes that would form new estrogen in the cell.
+
+
+ Thyroid, and the carbon dioxide it produces, prevent the formation of the toxic lactic acid. When there is
+ enough carbon dioxide in the tissues, the cell is kept in an oxidative state, and the formation of toxic
+ free radicals is suppressed. Carbon dioxide therapy is extremely safe.
+
+
+ In the 1930s, primates as well as rodents had been used in experiments to show the carcinogenic effects of
+ estrogen, and the protective effects of progesterone.
+
+
+ By 1950, the results of animal studies of progesterone's anticancer effects were so clear that the National
+ Cancer Institute got involved. But the estrogen industry had already been conducting its campaign against
+ progesterone, and had convinced most doctors that it was inactive when taken orally, and so was inferior to
+ their proprietary drugs that they called "progestins." The result was that it was usually given by
+ injection, dissolved in vegetable oil or synthetic solvents such as benzyl benzoate or benzyl alcohol, which
+ are very toxic and inflammation-producing.
+
+
+ The NCI researchers (Hertz, et al., 1951) treated 17 women with visible cancers of the uterine cervix that
+ had been confirmed by biopsies. They were given daily intramuscular injections of 250 mg of progesterone in
+ vegetable oil. Although they described the treatment as "massive dosage with progesterone," it didn't
+ prevent menstruation in any of the women who had been menstruating before the treatment began. During a
+ healthy pregnancy, a woman produces more progesterone than that.
+
+
+
+ Their article includes some photographs of cervical tumors before treatment, and after 31 days, 50 days, and
+ 65 days of progesterone treatment. The improvement is clear. The examining physicians described softening of
+ the tumor, and stopping of bleeding and pain.
+
+
+ "In eleven of the 17 treated patients visible and palpable evidence of regressive alteration of the tumor
+ mass could be demonstrated. This consisted of (a) distinct reduction in size of the visible portion of the
+ cancer as well as reduction of the palpable extent of the mass, (b) reduction in vascularity and friability
+ of the visible lesion with a clearly demonstrable epithelization of previously raw surfaces and (c) markedly
+ increased pliability of the previously rigid and infiltrated parametria."
+
+
+ "In 10 cases there was associated with this type of gross change a reduction in, or complete cessation of
+ vaginal bleeding and discharge."
+
+
+ "Only one of the 17 patients showed active progression of the carcinomatous process while under the
+ progesterone administration. The six patients whose lesions failed to show clearly demonstrable regressive
+ changes showed minor alterations in size and vascularity of insufficient degree to be convincing to all
+ clinical observers concerned. Nevertheless, none of the lesions under study appeared to be accelerated by
+ progesterone."
+
+
+ Observing very similar patients under similar conditions while they were waiting for surgery, but were not
+ receiving progesterone, they saw no such regressions of tumors.
+
+
+ The photographs and descriptions of the changes in the tumors were remarkable for any cancer study, but to
+ have been produced by a treatment that didn't even alter the patients' menstrual cycle, the reader might
+ expect the authors to discuss their plans for further studies of such a successful method.
+
+
+
+ But instead, they concluded "We do not consider the regressive changes observed to be sufficient to indicate
+ the use of progesterone as a therapeutic agent in carcinoma of the cervix."
+
+
+ (Their research was supported by a grant from the American Cancer Society.)
+
+
+ If the researchers had bothered to test progesterone on themselves or on animals, they would have discovered
+ that it is fully active when taken orally, dissolved in oil, and that nontoxic saturated fats could have
+ been used. Progesterone anesthesia was very well known at that time, so it would have been reasonable to use
+ doses that were at least equivalent to the concentrations present during pregnancy, even if they didn't want
+ to use doses that would approach the anesthetic level. The total daily doses could have been about ten times
+ higher, if they had been given orally as divided doses.
+
+
+ The solvent issue continues to impede research in the use of progesterone for treating cancer, but the main
+ problem is the continuing belief that "the cancer cell" is the problem, rather than the cancer field.
+ Substances are tested for their ability to kill cancer cells in vitro, because of the basic belief
+ that mutated genes are the cause of the disease. When progesterone is tested on cancer cells in
+ vitro,
+
+ the experimenter often sees nothing but the effects of the solvent, and doesn't realize that nearly all of
+ the progesterone has precipitated in the medium, before reaching the cancer cells.
+
+
+ The cancer industry began a few years ago to combine chemicals for chemotherapy, for example adding caffeine
+ to paclitaxel or platinum (cisplatin), or histamine to doxorubicin, but they do it simply to increase the
+ toxicity of the chemical to the tumor, or to decrease its toxicity to the patient. Doctors sometimes refer
+ to combined chemotherapy as a "shotgun approach," meaning that it lacks the acumen of their ideal silver
+ bullet approach. If cancers were werewolves, the cancer industry's search for more refined killing
+ technologies might be going in the right direction. But the genetic doctrine of cancer's origin is just as
+ mythical as werewolves and vampires.
+
+
+ A safe physiological approach to cancer, based on the opposition of progesterone to estrogen, would be
+ applicable to every type of cancer promoted by estrogen, or by factors which produce the same effects as
+ estrogen, and that would include all of the known types of cancer. Estrogen acts even on cells that have no
+ "estrogen receptors," but estrogen receptors can be found in every organ.
+
+
+
+ As estrogen's non-feminizing actions are increasingly being recognized to include contributions to other
+ kinds of disease, including Alzheimer's disease, heart disease, and rheumatoid arthritis, the idea of the
+ bystander effect, and the field of cellular degeneration, will eventually clear the way for a rational use
+ of the therapeutic tools that already exist.
+
+
+ There are several types of drug---carbonic anhydrase inhibitors, to increase carbon dioxide in the tissues,
+ lysergic acid derivatives, to block serotonin and suppress prolactin, anti-opiates, antiexcitotoxic and
+ GABAergic agents, anesthetics, antihistamines, anticholinergics, salicylic acid derivatives---that could
+ probably be useful in a comprehensive therapy for cancer, but their combinations won't be explored as long
+ as treatments are designed only to kill.
+
+
+ Preventing or correcting disturbances in the morphogenetic field should be the focus of attention.
+
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+
+
+ Transdermal progesterone was also shown to reduce estradiol-induced proliferation.
+
+
+ Br J Cancer. 1997;75(2):251-7. Type I insulin-like growth factor receptor gene expression in normal
+ human breast tissue treated with oestrogen and progesterone. Clarke RB, Howell A, Anderson E.
+ "The epithelial proliferation of normal human breast tissue xenografts implanted into athymic nude mice is
+ significantly increased from basal levels by oestradiol (E2), but not progesterone (Pg) treatment at serum
+ concentrations similar to those observed in the luteal phase of the human menstrual cycle." "The data
+ indicate that the IGFR-I mRNA is up-regulated by two to threefold compared with untreated levels by 7 and 14
+ days E2 treatment.
+ In contrast, 7 or 14 days Pg treatment down-regulates the receptor mRNA to approximately half that of
+ untreated levels, whereas combination E2 and Pg treatment produced a twofold increase in IGFR-I
+ mRNA levels compared with untreated tissue."
+
+
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+
+
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+ [progesterone deficiency] group had 5.4 times the risk of premenopausal breast cancer as compared to women
+ in the NH group." "Women in the PD group also experienced a 10-fold increase in deaths from all malignant
+ neoplasm compared to the NH group."
+
+
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+ inhibits growth."
+
+
+
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+
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+
+
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+ cytotoxicity of stearic, oleic and sterculic acids in vitro. Fermor BF, Masters JR, Wood CB,
+ Miller J, Apostolov K, Habib NA.
+
+
+
+ Fertil Steril. 1998 May;69(5):963-9. Estradiol and progesterone regulate the proliferation of human
+ breast epithelial cells. Foidart JM, Colin C, Denoo X, Desreux J, Beliard A, Fournier S, de
+ Lignieres B. "Exposure to progesterone for 14 days reduced the estradiol-induced proliferation of normal
+ breast epithelial cells in vivo." Randomized Controlled Trial
+
+
+ Mol Cell Biochem 1999 Dec;202(1-2):53-61. Bcl-2, survivin and variant CD44 v7-v10 are downregulated
+ and p53 is upregulated in breast cancer cells by progesterone: inhibition of cell growth and induction
+ of apoptosis.
+
+ Formby B, Wiley TS."This study sought to elucidate the mechanism by which progesterone inhibits the
+ proliferation of breast cancer cells."
+
+ "The results demonstrated that progesterone does produce a strong antiproliferative effect on breast cancer
+ cell lines containing progesterone receptors, and induced apoptosis. The relatively high levels of
+ progesterone utilized were similar to those seen during the third trimester of human pregnancy."
+
+
+ Ann Clin Lab Sci 1998 Nov-Dec;28(6):360-9. Progesterone inhibits growth and induces apoptosis in
+ breast cancer cells: inverse effects on Bcl-2 and p53. Formby B, Wiley TS.
+
+
+ Cancer Lett 1999 Jul 1;141(1-2):63-71.
+ Progestins suppress estrogen-induced expression of vascular endothelial growth factor (VEGF) subtypes in
+ uterine endometrial cancer cells. Fujimoto J, Sakaguchi H, Hirose R, Ichigo S, Tamaya T.
+
+
+ Mol Cell Biol. 2006 Oct;26(20):7632-44. TReP-132 Is a Novel Progesterone Receptor Coactivator
+ Required for the Inhibition of Breast Cancer Cell Growth and Enhancement of Differentiation by
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+
+
+ Gizard F, Robillard R, Gross B, Barbier O, Revillion F, Peyrat JP, Torpier G, Hum DW, Staels B.
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+
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+
+ Gyulai L, Dora E, Kovach AG.
+
+
+ Drug Metab Dispos. 1995 Mar;23(3):430-2. Induction of catechol-O-methyltransferase in the luminal
+ epithelium of rat uterus by progesterone: inhibition by RU-486. Inoue K, Creveling CR.
+
+
+ Hertz R, Cromer J.K., Young J.P. and Westfall B.B., pages 366-374, in
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+
+
+ Cancer Res. 2005 Jul 15;65(14):6450-8. Progesterone receptor in non-small cell lung cancer--a potent
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+ Ishibashi H, Suzuki T, Suzuki S, Niikawa H, Lu L, Miki Y, Moriya T, Hayashi S, Handa M, Kondo T,
+ Sasano H. "Cell proliferation was inhibited by progesterone in these progesterone receptor-positive NSCLC
+ cells in a dose-dependent manner, which was inhibited by progesterone receptor blocker. Proliferation of
+ these tumor cells injected into nude mice was also dose-dependently inhibited by progesterone, with a
+ concomitant increase of p21 and p27 and a decrease of cyclin A, cyclin E, and Ki67. Results of our present
+ study suggested that progesterone receptor was a potent prognostic factor in NSCLCs and progesterone
+ inhibited growth of progesterone receptor-positive NSCLC cells. Therefore, progesterone therapy may be
+ clinically effective in suppressing development of progesterone receptor-positive NSCLC patients."
+
+
+ Naunyn Schmiedebergs Arch Pharmacol. 1986 Aug;333(4):368-76. Effect of progesterone on the
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+
+
+ Agressologie 1971;12(2):105-112. [The inhibiting effect of atmospheres oxygenated without CO2 on the
+ respiration of rat tissue slices (brain, liver). Physiopathological implications]. Laborit H,
+ Lamothe C, Thuret F
+
+
+
+ Am J Respir Crit Care Med. 2004 Jan 1;169(1):46-56. Hypercapnic acidosis attenuates
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+ McLoughlin P.
+
+
+ *Endocrinology. 1996 Apr;137(4):1505-6.
+
+
+
+ [Comment on: Laidlaw, et al., Endocrinology. 1995 Jan;136(1):164-71.]
+
+ Experiments on proliferation of normal human breast tissue in nude mice do not show that
+ progesterone does not stimulate breast cells.
+
+ Pike MC, Ursin G, Spicer DV. Letter
+
+
+ *Endocrinology. 1995 Jan;136(1):164-71. The proliferation of normal human breast tissue implanted
+ into athymic nude mice is stimulated by estrogen but not progesterone. Laidlaw IJ, Clarke RB,
+ Howell A, Owen AW, Potten CS, Anderson E. "We conclude that E2 is sufficient to stimulate human breast
+ epithelial cell proliferation at physiologically relevant concentrations and that P does not affect
+ proliferation either alone or after E2 priming."
+
+
+
+ Agressologie 1971;12(2):105-112. [The inhibiting effect of atmospheres oxygenated without CO2 on the
+ respiration of rat tissue slices (brain, liver). Physiopathological implications]. Laborit H,
+ Lamothe C, Thuret F
+
+
+ Endocrinology. 1995 Jan;136(1):164-71. The proliferation of normal human breast tissue implanted
+ into athymic nude mice is stimulated by estrogen but not progesterone. Laidlaw IJ, Clarke RB,
+ Howell A, Owen AW, Potten CS, Anderson E.
+
+
+ Int J Cancer. 2005 Nov 20;117(4):561-8. Gene regulation profile reveals consistent anticancer
+ properties of progesterone in hormone-independent breast cancer cells transfected with progesterone
+ receptor. Leo JC, Wang SM, Guo CH, Aw SE, Zhao Y, Li JM, Hui KM, Lin VC."Progesterone
+ consistently suppressed the expression of genes required for cell proliferation and metastasis and
+ increased the expression of many tumor-suppressor genes."
+
+
+
+ Fertil Steril. 2003 Jan;79(1):221-2. Topical progesterone cream has an antiproliferative effect on
+ estrogen-stimulated endometrium. Leonetti HB, Wilson KJ, Anasti JN. Randomized Controlled Trial
+
+
+ Prostate. 1995 Apr;26(4):194-204. Growth inhibition of androgen-insensitive human prostate carcinoma
+ cells by a 19-norsteroid derivative agent, mifepristone. Lin MF, Kawachi MH, Stallcup MR,
+ Grunberg SM, Lin FF. "Mifepristone, also known as RU 486, is a 19-norsteroid derivative. Currently,
+ mifepristone is being tested in clinical trials on meningioma and breast cancer.""The results
+ demonstrated that while both DHT and Dex alone had essentially no effect on cell growth, progesterone
+ alone resulted in a 20% growth inhibition, while mifepristone had more than 60% inhibition with a 16-day
+ exposure. At an equal concentration, the degree of growth inhibition of PC-3 cells by mifepristone or
+ progesterone was partially diminished by simultaneous exposure to Dex."
+
+
+ Am J Pathol. 2003 Jun;162(6):1781-7. Progesterone induces cellular differentiation in MDA-MB-231
+ breast cancer cells transfected with progesterone receptor complementary DNA.
+ Lin VC, Jin R, Tan PH, Aw SE, Woon CT, Bay BH.
+
+
+
+ Endocrinology. 2003 Dec;144(12):5650-7. Distinct molecular pathways mediate progesterone-induced
+ growth inhibition and focal adhesion. Lin VC, Woon CT, Aw SE, Guo C.
+
+
+ Int J Cancer. 2005 Nov 20;117(4):561-8.
+ Gene regulation profile reveals consistent anticancer properties of progesterone in hormone-independent
+ breast cancer cells transfected with progesterone receptor. Leo JC, Wang SM, Guo CH, Aw SE,
+ Zhao Y, Li JM, Hui KM, Lin VC.
+
+
+ Int J Biometeorol. 1987 Sep;31(3):201-10. Effects of chronic normobaric hypoxic and hypercapnic
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+ B, Bonkovsky HL, Ou LC.
+
+
+
+ J Steroid Biochem Mol Biol. 2000 Jun;73(3-4):171-81. Progesterone effect on cell growth,
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+ culture. Malet C, Spritzer P, Guillaumin D, Kuttenn F. "On a culture system of normal human
+ breast epithelial (HBE) cells, we observed an inhibitory effect on cell growth of a long-term P treatment (7
+ days) in the presence or absence of E2, using two methods...." "Cells exhibited a proliferative appearance
+ after E2 treatment, and returned to a quiescent appearance when P was added to E2." "Moreover, the
+ immunocytochemical study of E2 receptors indicated that E2 increases its own receptor level whereas
+ P and R5020 have the opposite effect, thus limiting the stimulatory effect of E2 on cell growth. In the HBE cell culture system and in long-term treatment, P and R5020 appear predominantly to inhibit
+ cell growth, both in the presence and absence of E2."
+
+
+ Horm Res. 1987;28(2-4):212-8.
+ Antiestrogen action of progesterone in breast tissue. Mauvais-Jarvis P, Kuttenn F, Gompel A.
+ "Most data indicate that progesterone and progestins have a strong antiestrogen effect on breast cell
+ appreciated by the decrease of estradiol receptor content, the decrease of cell multiplication and the
+ stimulation of 17 beta-hydroxysteroid activity which may be considered as a marker of breast cell
+ differentiation dependent of progesterone receptor."
+
+
+
+ Biochem Biophys Res Commun 1982 Jan 29;104(2):570-6. Progesterone-induced inactivation of nuclear
+ estrogen receptor in the hamster uterus is mediated by acid phosphatase.
+ MacDonald RG, Okulicz WC, Leavitt WW.
+
+
+ Cancer Lett. 2005 Apr 18;221(1):49-53. Effects of progesterone on ovarian tumorigenesis in
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+
+ McDonnel AC, Van Kirk EA, Isaak DD, Murdoch WJ.
+
+
+ Int J Cancer. 2004 Nov 1;112(2):312-8. Endogenous sex hormones and subsequent breast cancer in
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+ Pala V, Berrino F.
+
+
+
+ J Clin Endocrinol Metab 2000 Sep;85(9):3442-52. Progesterone withdrawal up-regulates vascular
+ endothelial growth factor receptor type 2 in the superficial zone stroma of the human and macaque
+ endometrium: potential relevance to menstruation. Nayak NR, Critchley HO, Slayden OD, Menrad A,
+ Chwalisz K, Baird DT, Brenner RM.
+
+
+ Endocrinology 1981 Dec;109(6):2273-5.
+ Progesterone-induced estrogen receptor-regulatory factor in hamster uterine nuclei: preliminary
+ characterization in a cell-free system.
+ Okulicz WC, MacDonald RG, Leavitt WW
+ In vitro studies have demonstrated a progesterone-induced activity associated with the uterine nuclear
+ fraction which resulted in the loss of nuclear estrogen receptor.
+
+
+ Mol Endocrinol. 1991 May;5(5):709-17. Progestins induce down-regulation of insulin-like growth
+ factor-I (IGF-I) receptors in human breast cancer cells: potential autocrine role of IGF-II.
+
+
+ Papa V, Hartmann KK, Rosenthal SM, Maddux BA, Siiteri PK, Goldfine ID.
+
+
+ Gynecol Endocrinol. 1999 Jun;13 Suppl 4:11-9. Biological effects of progestins in breast cancer.
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+
+
+ Gynecol Endocrinol. 2001 Dec;15 Suppl 6:44-52. Biological effects of progestins in breast
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+
+
+ J Steroid Biochem Mol Biol. 2005 Feb;93(2-5):221-36. Recent insight on the control of enzymes
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+
+
+
+ Cancer Epidemiol Biomarkers Prev. 2002 Apr;11(4):361-8. Steroid hormone levels during pregnancy and
+ incidence of maternal breast cancer.
+ Peck JD, Hulka BS, Poole C, Savitz DA, Baird D, Richardson BE. "When estrogen-to-progesterone ratios
+ were evaluated, there was an indication of a modest increased incidence of breast cancer for those with
+ high total estrogens and high estrone levels relative to progesterone."
+
+
+ Br J Urol. 1990 Mar;65(3):268-70. Erythrocyte stearic to oleic acid ratio in prostatic
+ carcinoma. Persad RA, Gillatt DA, Heinemann D, Habib NA, Smith PJ.
+
+
+ Int J Cancer. 2006 Nov 9; Inflammation and IGF-I activate the Akt pathway in breast cancer.
+ Prueitt RL, Boersma BJ, Howe TM, Goodman JE, Thomas DD, Ying L, Pfiester CM, Yfantis HG, Cottrell JR, Lee
+ DH, Remaley AT, Hofseth LJ, Wink DA, Ambs S.
+
+
+
+ Biology of reproduction 15, 153-157, 1976, Sex steroids in reproductive tract tissues: Regulation of
+ estradiol concentrations by progesterone. Resko JA, Boling JL, Brenner RM and Blandau RJ.
+
+
+ Carla Rothenberg, History of hormone therapy, http:leda.law.harvard.edu/leda/data/711/Rothenberg05. pdf. 2005.
+
+
+ J Clin Endocrinol Metab 1996 Apr;81(4):1495-501. Characterization of reproductive hormonal dynamics
+ in the perimenopause.
+
+ altered ovarian function in the perimenopause can be observed as early as age 43 yr and include
+ hyperestrogenism, hypergonadotropism, and decreased luteal phase progesterone excretion. These
+ hormonal alterations may well be responsible for the increased gynecological morbidity that characterizes
+ this period of life."
+
+
+
+ Cancer Res. 1984 Feb;44(2):841-4. High testosterone and low progesterone circulating levels in
+ premenopausal patients with hyperplasia and cancer of the breast. Secreto G, Recchione C,
+ Fariselli G, Di Pietro S.
+
+
+ Gen Comp Endocrinol. 1988 Dec;72(3):443-52. Progesterone down-regulation of nuclear estrogen
+ receptor: a fundamental mechanism in birds and mammals.
+ Selcer KW, Leavitt WW.
+
+
+ Clin Exp Obstet Gynecol 2000;27(1):54-6.
+ Hormonal reproductive status of women at menopausal transition compared to that observed in a group of
+ midreproductive-aged women. Sengos C, Iatrakis G, Andreakos C, Xygakis A, Papapetrou P.
+ "CONCLUSION: The reproductive hormonal patterns in
+ perimenopausal women favor a relatively hypergonadotropic hyper-estrogenic milieu."
+
+
+
+ J Natl Cancer Inst Monogr. 1994;(16):85-90. Menstrual timing of treatment for breast cancer.
+
+ Senie RT, Kinne DW.
+
+
+ J Neurosci. 2001 Aug 1;21(15):5723-9. Progesterone blockade of estrogen activation of mu-opioid
+ receptors regulates reproductive behavior.
+ Sinchak K, Micevych PE.
+
+
+ J Clin Pathol. 2005 Oct;58(10):1033-8. Proliferating fibroblasts at the invading tumour edge of
+ colorectal adenocarcinomas are associated with endogenous markers of hypoxia, acidity, and oxidative
+ stress.
+ Sivridis E, Giatromanolaki A, Koukourakis MI.
+
+
+
+ Neuroscience. 1991;42(2):309-20. Progesterone administration attenuates excitatory amino acid
+ responses of cerebellar Purkinje cells. Smith SS.
+
+
+ Cancer Causes Control. 2004 Feb;15(1):45-53. Serum levels of sex hormones and breast cancer risk in
+ premenopausal women: a case-control study (USA). Sturgeon SR, Potischman N, Malone KE, Dorgan
+ JF, Daling J, Schairer C, Brinton LA. "For luteal progesterone, the RR for the highest versus lowest
+ tertile was 0.55 (0.2-1.4)."
+
+
+ Biomed Pharmacother 1984;38(8):371-9. Breast cancer and oral contraceptives: critique of the
+ proposition that high potency progestogen products confer excess risk.
+ Sturtevant FM A recent report by Pike et al. from the U. S. A. concluded on the basis of
+ epidemiologic evidence that an increased risk of breast cancer was manifested by young women who had used
+ combination oral contraceptives (OC) with a high "potency" of progestogen over a prolonged period. This
+ conclusion is criticized in the present article, centering on three cardinal defects in the Pike study: (1)
+ The assigned potencies of OC's are fiction and were derived from out-dated delay-of-menses data; (2)
+ Well-known risk factors for breast cancer were ignored; (3) The method assumed no error of recall of OC
+ brand, dose and duration of use occurring many years before telephone interviews. Noting that others have
+ not been able to confirm these findings, it is concluded that there is no scientific basis for accepting the
+ suggestion of Pike et al.
+
+
+
+ Cancer Res. 2004 Nov 1;64(21):7886-92. Reduction of human metastatic breast cancer cell
+ aggressiveness on introduction of either form a or B of the progesterone receptor and then treatment
+ with progestins. Sumida T, Itahana Y, Hamakawa H, Desprez PY.
+
+
+ Endocr Relat Cancer 1999 Jun;6(2):307-14.
+ Aromatase overexpression and breast hyperplasia, an in vivo model--continued overexpression of aromatase
+ is sufficient to maintain hyperplasia without circulating estrogens, and aromatase inhibitors abrogate
+ these preneoplastic changes in mammary glands. Tekmal RR, Kirma N, Gill K, Fowler K "To test
+ directly the role of breast-tissue estrogen in initiation of breast cancer, we have developed the
+ aromatase-transgenic mouse model and demonstrated for the first time that increased mammary estrogens
+ resulting from the overexpression of aromatase in mammary glands lead to the induction of various
+ preneoplastic and neoplastic changes that are similar to early breast cancer." "Our current studies show
+ aromatase overexpression is sufficient to induce and maintain early preneoplastic and neoplastic changes in
+ female mice without circulating ovarian estrogen. Preneoplastic and neoplastic changes induced in mammary
+ glands as a result of aromatase overexpression can be completely abrogated with the administration of the
+ aromatase inhibitor, letrozole. Consistent with complete reduction in hyperplasia,
+ we have also seen downregulation of estrogen receptor and a decrease in cell proliferation
+ markers, suggesting aromatase-induced hyperplasia can be treated with aromatase inhibitors. Our studies
+ demonstrate that aromatase overexpression alone, without circulating estrogen, is responsible for
+ the induction of breast hyperplasia and these changes can be abrogated using aromatase
+ inhibitors."
+
+
+
+ Ann N Y Acad Sci 1986;464:106-16.
+ Uptake and concentration of steroid hormones in mammary tissues.
+ Thijssen JH, van Landeghem AA, Poortman J "For estradiol the highest tissue levels were found in the
+ malignant samples. No differences were seen in these levels between pre- and postmenopausal women
+ despite the largely different peripheral blood levels." "Striking differences were seen between
+ the breast and uterine tissues for the total tissue concentration of estradiol, the ratio between estradiol
+ and estrone, and the subcellular distribution of both estrogens.
+ At similar receptor concentrations in the tissues these differences cannot easily be explained." "Lower concentrations of DHEAS and DHEA were observed in the malignant tissues compared with the
+ normal ones and the benign lesions."
+
+
+ Cancer. 1983 Jun 1;51(11):2100-4. Elevated serum acute phase protein levels as predictors of
+ disseminated breast cancer. Thompson DK, Haddow JE, Smith DE, Ritchie RF.
+
+
+
+ Crit Care Med. 2003 Nov;31(11):2705-7. Carbon dioxide: a "waste product" with potential therapeutic
+ utilities in critical care.
+ Torbati D.
+
+
+ J Steroid Biochem Mol Biol 2000 Jun;73(3-4):141-5. Elevated steroid sulfatase expression in breast
+ cancers. Utsumi T, Yoshimura N, Takeuchi S, Maruta M, Maeda K, Harada N. In situ estrogen
+ synthesis makes an important contribution to the high estrogen concentration found in breast cancer tissues.
+ Steroid sulfatase which hydrolyzes several sulfated steroids such as estrone sulfate, dehydroepiandrosterone
+ sulfate, and cholesterol sulfate may be involved. In the present study, we therefore, assessed steroid
+ sulfatase mRNA levels in breast malignancies and background tissues from 38 patients by reverse
+ transcription and polymerase chain reaction. The levels in breast cancer tissues were significantly
+ increased at 1458.4+/-2119.7 attomoles/mg RNA (mean +/- SD) as compared with 535.6+/-663.4 attomoles/mg RNA
+ for non-malignant tissues (P<0.001). Thus, increased steroid sulfatase expression may be partly
+ responsible for local overproduction of estrogen and provide a growth advantage for tumor cells.
+
+
+ Fed Proc. 1980 Jun;39(8):2533-8. Influence of endogenous opiates on anterior pituitary
+ function. Van Vugt DA, Meites J.
+
+
+
+ Clin Endocrinol (Oxf) 1978 Jul;9(1):59-66. Sex hormone concentrations in post-menopausal
+ women.
+ Vermeulen A, Verdonck L. "Plasma sex hormone concentrations (testosterone, (T), androstenedione (A),
+ oestrone (E1) and oestradiol (E2) were measured in forty post-menopausal women more than 4 years post-normal
+ menopause." "Sex hormone concentrations in this group of postmenopausal women (greater than 4YPM)
+ did not show any variation as a function of age, with the possible exception of E2 which showed
+ a tendency to decrease in the late post-menopause."
+
+
+ J Steroid Biochem 1984 Nov;21(5):607-12.
+ The endogenous concentration of estradiol and estrone in normal human postmenopausal
+ endometrium. Vermeulen-Meiners C, Jaszmann LJ, Haspels AA, Poortman J, Thijssen JH The
+ endogenous estrone (E1) and estradiol (E2) levels (pg/g tissue) were measured in 54 postmenopausal, atrophic
+ endometria and compared with the E1 and E2 levels in plasma (pg/ml). The results from the tissue levels of
+ both steroids
+ showed large variations and there was no significant correlation with their plasma levels. The mean E2
+ concentration in tissue was 420 pg/g, 50 times higher than in plasma and the E1 concentration of 270
+ pg/g was 9 times higher.
+
+
+ The E2/E1 ratio in tissue of 1.6, was higher than the corresponding E2/E1 ratio in plasma, being 0.3.
+ We conclude that normal postmenopausal atrophic endometria contain relatively high concentrations of
+ estradiol and somewhat lower estrone levels. These tissue levels do not lead to histological
+ effects.
+
+
+ J Natl Cancer Inst Monogr. 2000;(27):67-73. Endogenous estrogens as carcinogens through metabolic
+ activation. Yager JD.
+
+
+ Regul Pept. 2003 Jul 15;114(2-3):101-7. Inhibition of cytosolic phospholipase A2 mRNA expression: a
+ novel mechanism for acetylsalicylic acid-mediated growth inhibition and apoptosis in colon cancer
+ cells. Yu HG, Huang JA, Yang YN, Luo HS, Yu JP, Meier JJ, Schrader H, Bastian A, Schmidt WE,
+ Schmitz.
+
+
+
+ Brain Res. 1999 Aug 28;839(2):313-22. Opioid growth factor and organ development in rat and human
+ embryos. Zagon IS, Wu Y, McLaughlin PJ.
+
+
+ J Biol Chem. 2005 Apr 29;280(17):17480-7. Epub 2005 Feb 22. A novel antiestrogenic mechanism in
+ progesterone receptor-transfected breast cancer cells.
+ Zheng ZY, Bay BH, Aw SE, Lin VC.
+
+
+ © Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Food-junk and some mystery ailments: Fatigue, Alzheimer's, Colitis, Immunodeficiency.
+
+
+ Food-junk and some mystery ailments: Fatigue, Alzheimer's, Colitis, Immunodeficiency.
+
+
+
+ Years ago, I noticed that Oregon was one of the few states that still had real whipping cream and cottage
+ cheese without additives, so I have been trustingly using cream in my coffee every day. Last week, I noticed
+ that my cream listed carrageenan in its ingredients. Over the years, I have avoided carrageenan-containing
+ foods such as apple cider, hot dogs, most ice creams and prepared sauces and jellies, because they caused me
+ to have serious allergic symptoms. Carrageenan has been found to cause colitis and anaphylaxis in humans,
+ but it is often present in baby “formulas” and a wide range of milk products, with the result that many
+ people have come to believe that it was the milk-product that was responsible for their allergic symptoms.
+ Because the regulators claim that it is a safe natural substance, it is very likely that it sometimes
+ appears in foods that don’t list it on the label, for example when it is part of another ingredient.
+ In the 1940s, carrageenan, a polysaccharide made from a type of seaweed, was recognized as a dangerous
+ allergen. Since then it has become a standard laboratory material to use to produce in-flammatory tumors
+ (granulomas), immunodeficiency, arthritis, and other in-flammations. It has also become an increasingly
+ common material in the food industry. Articles are often written to praise its usefulness and to claim
+ that it doesn't produce cancer in healthy animals. Its presence in food, like that of the polyester
+ imitation fat, microcrystalline cellulose, and many other polymers used to stabilize emulsions or to
+ increase smoothness, is often justified by the doctrine that these molecules are too large to be
+ absorbed. There are two points that are deliberately ignored by the food-safety regulators, 1) these
+ materials can interact dangerously with intestinal bacteria, and 2) they can be absorbed, in the process
+ called "persorption."
+
+
+ The sulfites (sodium bisulfite, potassium metabisulfite, etc.) have been used as preservatives in foods
+ and drugs for a long time, even though they were known to cause intense allergic reactions in some
+ people. Fresh vegetables and fish, dried fruits, ham and other preserved meats, hominy, pickles, canned
+ vegetables and juices, and wines were commonly treated with large amounts of the sulfites to prevent
+ darkening and the development of unpleasant odors. People with asthma were known to be more sensitive
+ than other people, but the sulfites could cause a fatal asthma-like attack even in someone who had never
+ had asthma. Even when this was known, drugs used to treat asthma were preserved with sulfites. Was the
+ information just slow to reach the people who made the products? No, the manufacturers knew about the
+ deadly nature of their products, but they kept on selling them. The FDA didn't answer letters on the
+ subject, and medical magazines such as J.A.M.A. declined to publish even brief letters seriously
+ discussing the issue. Obviously, since many people died from what the drug companies called "paradoxical
+ bronchoconstriction" when they used the products, the drug companies had to be protected from lawsuits,
+ and the medical magazines and the government regulators did that through the control of information.
+
+
+ I think a similar situation exists now in relation to the effects of carrageenan.
+
+
+ Stress and anxiety sharply reduce the circulation of blood to the intestine and liver. Prolonged stress
+ damages the ability of the in-testinal cells to exclude large molecules. Local irritation and
+ inflammation of the intestine also increase its permeability and decrease its ability to exclude harmful
+ materials. But even the normal intestine is able to permit the passage of large molecules and particles,
+ in many cases particles larger than the cells that line the intestine; this persorption of particles has
+ been demonstrated using particles of plastic, starch grains which are sometimes several times larger
+ than blood cells, and many other materials, including carrageenan. One of the reasons it has been easy
+ to convince the public that persorption doesn't happen is that there is a powerful myth in our culture
+ about the existence of a "semipermeable" "plasma membrane" on cells through which only certain specific
+ substances may pass.
+
+
+ About 30 years ago some biologists made a movie of living cells under the microscope, showing an ameboid
+ cell entering another cell, swimming around, and leaving, without encountering any perceptible
+ resistance; persorption of food particles, moving in one side of a cell and out the other, wouldn't seem
+ so mysterious if more people had seen films of that sort.
+
+
+ Also in the 1960s, Gerhard Volkheimer rediscovered the phenomenon of persorption, which had been
+ demonstrated a century earlier. Starch grains, or other hard particles, can be found in the blood,
+ urine, and other fluids after they have been ingested. The iodine stain for starch, and the
+ characteristic shape of the granules, makes their observation very easy. The absorption of
+ immunologically intact proteins and other particles has been demonstrated many times, but myth is more
+ important than fact; all of my biol-ogy professors, for example, denied that proteins could be absorbed
+ by any part of the digestive system.
+
+
+ The accepted description of the absorption of chylomicrons, tiny particles of fat, helps to understand
+ the way medical professors think about the intestine. These particles, they say, are disassembled by the
+ intestine cells on one side, their molecular parts are taken up by the cells, and similar particles are
+ excreted out the other side of the cells, into the lymphatic vessels. As they visualize one of these
+ cells, it consists of at least four barriers, with each theoretical cell surface membrane consisting of
+ an outer water-compatible phase, in intramembranal lipid region, and an inner water-compatible phase
+ where the membrane rests on the “cell contents.” Endocytosis, for example the ingestion of a bacterial
+ particle by a phagocyte, is described in a similar way, to avoid any breach in the “lipid bilayer
+ membrane.”
+
+
+ This mental armature has made it essentially impossible for the biomedical culture to assimilate the
+ facts of persorption, which would have led 150 years ago to the scientific study of allergy and
+ immunology in relation to the digestive system.
+
+
+ Volkheimer found that mice fed raw starch aged at an abnormally fast rate, and when he dissected the
+ starch-fed mice, he found a multitude of starch-grain-blocked arterioles in every organ, each of which
+ caused the death of the cells that depended on the blood supplied by that arteriole. It isn’t hard to
+ see how this would affect the functions of organs such as the brain and heart, even without considering
+ the immunological and other implications of the presence of foreign particles randomly distributed
+ through the tissue.
+
+
+ In 1979 some of my students in Mexico wanted a project to do in the lab. Since several traditional foods
+ are made with corn that has been boiled in alkali, I thought it would be valuable to see whether this
+ treatment reduced the ability of the starch grains to be persorbed. For breakfast one day, they ate only
+ atole, tamales, and tortillas, all made from the alkali treated corn. None of the students could find
+ any starch grains after centrifuging their blood and urine. That led me to substitute those foods
+ whenever possible for other starches.
+
+
+
+ I have written previously about some of the environmental factors, including radiation, estrogens, and
+ unsaturated fats, that are known to damage the immune system and the brain, and that we have been
+ increasingly exposed to since 1940.
+
+
+ To better understand the nature of the diseases that are now becoming so common, we can look at them in
+ a series, from the bowel, to the liver, to the immune system, and to the brain and hormones.
+
+
+ The incidence of several inflammatory diseases, for example Crohn's disease, a chronic inflammation of
+ the intestine, has been increasing during the last 50 years in the industrialized countries, and at the
+ same time, the incidence of several liver diseases has also been increasing.
+
+
+ The entry of bacteria into the blood stream, which can lead to septicemia, is ordinarily considered to
+ be of importance only in extreme immunodeficiency states, such as old age or in premature infants, but
+ the death rate of young adults from septicemia has been increasing rapidly since the 1940s.
+
+
+ The permeability of the intestine that allows bacteria to enter the blood stream is very serious if the
+ phagocytic cells are weakened. Carrageenan poisoning is one known cause of the disappearance of
+ macrophages. Its powerful immunosuppression would tend to be superimposed onto the immunological damage
+ that has been produced by radiation, unsaturated fats, and estrogens.
+
+
+ The liver tumor that is characteristic of young women using the oral contraceptive pill is a
+ hepatocellular adenoma, which is considered to be a premalignant tumor. In Japan, Mexico, and several
+ European countries, the incidence of hepatocellular tu-mors has increased steadily and tremendously in
+ recent decades, and it has increased in men as well as in women. This is the sort of tumor that very
+ likely represents an increased burden of toxins absorbed from the bowel. Carrageenan contributes to the
+ disappearance of the liver enzymes (the cytochrome P-450 system) that detoxify drugs, hormones, and a
+ variety of other chemicals.
+
+
+ Carrageenan enters even the intact, uninflamed gut, and damages both chemical defenses and immunological
+ defenses. When it has produced inflammatory bowel damage, the amount absorbed will be greater, as will
+ the absorption of bacterial endotoxin. Carra-geenan and endotoxin synergize in many ways, including
+ their effects on nitric oxide, prostaglandins, toxic free radicals, and the defensive enzyme systems.
+
+
+ The continuing efficient production of energy is a basic aspect of metabolic defense, and this is
+ interrupted by carrageenan and endotoxin. The energy failure becomes part of a vicious circle, in which
+ permeability of the intestine is increased by the very factors that it should exclude.
+
+
+ Once the protective barrier-functions of the intestine and liver have been damaged, allergens and many
+ materials with specific biological effects can enter the tissues. The polysaccharide components of
+ connective tissue constitute a major part of our regulatory system for maintaining differentiated cell
+ functioning, and absorbed starches act as “false signals,” with a great capacity for deranging cellular
+ functioning. Several types of research indicate that carrageenan changes cellular function in complex
+ ways, imitating changes seen in cancer, for example.
+
+
+ R.J.V. Pulvertaft found "a close similarity between Burkitt cells and human lymphocytes stimulated by
+ bean extract." He concluded that "…the possibility of a relation between Burkitt's lymphoma and a diet
+ of beans should not be neglected," though he emphasized that other factors must be considered, since
+ most people who eat beans don't develop the disease. The intestinal parasites which are common in
+ tropical Africa can cause inflammation of the bowel, leading to the absorption of large amounts of
+ antigens.
+
+
+ Since the bowel becomes inflamed in influenze, it is reasonable to think that some of the symptoms of
+ "the flu" are produced by absorbed bowel toxins.
+
+
+ The variations in the post-influenza syndromes are very likely influenced by the nature of the bacteria
+ or foods which are present, chronically or at the time of an uncompensated stress or inflammatory
+ disease. K.M. Stevens has argued that while rheumatic fever and glomerulonephritis are caused by the
+ antigens of streptococci, systemic lupus erythematosis (SLE) is probably caused by the antigens of
+ gram-positive lactobacilli found in the normal flora.
+
+
+ Migraine, SLE, chronic fatigue syndrome, thyroid problems, and some kinds of porphyria seem to be more
+ common in women of re-productive age, and are often exacerbated by premenstrual hormone changes.
+ According to Stevens, "SLE is almost entirely a disease of women of child-bearing age. One possibility
+ for this selection could be that women during this period harbour a peculiar flora. This is indeed the
+ case; large numbers of gram-positive lactobacilli are present in the vagina only during the thirty-odd
+ years when regular menstrual activity is present."
+
+
+ In 1974, I noticed that I consistently got a migraine headache after drinking a lactobacillus milk
+ product, and stopped using (and recommending) yogurt and other lactobacillus foods, though I suspected
+ it was the lactic acid which caused the immediate symptoms. Lactic acid is a metabolic burden,
+ especially when combined with an estrogen excess, but Stevens' main point, about the significance of our
+ immunological response to systemic bacterial antigens, deserves more attention.
+
+
+ On a typical diet, tissues progressively accumulate linoleic acid, and this alters the structure of
+ mitochondrial cardiolipin, which governs the response of the mitochondrial enzymes to the thyroid
+ hormone. This process is especially evident in the female liver. In the “autoimmune” diseases, such as
+ lupus, there are typically antibodies to cardiolipin, as if the body were trying to reject its own
+ tissues, which have been altered by the storage of linoleic acid. The altered mitochondrial function,
+ which is involved in so many symptoms, can become part of a vicious circle, with endotoxin and estrogen
+ having central roles, once the stage has been set by the combination of diet, stress, and toxins.
+
+
+ A few months ago I had a questionnaire circulated in a “fibromyositis” discussion group on the internet,
+ and the consistency of responses was interesting.
+
+
+ The questions were: 1) Have you noticed that any of your symptoms are worse premenstrually?
+
+
+ 2) Have you noticed that any symptom is less severe premenstrually?
+
+
+ 3) Do any symptoms seem to be worse periodically, but without being associated with the premenstrual
+ time?
+
+
+ 4) Did your symptoms appear after use of oral contraceptives or IUD?
+
+
+ Except for one woman who was taking oral contraceptives at the time she became sick, and kept taking
+ them, and who didn’t notice any cycle, all of the answers to the first three questions (15 of the 16 who
+ responded) were identical: 1) yes, 2) no, 3) no.
+
+
+ The premenstrual estrogen-dominance usually leads progressively to higher prolactin and lower thyroid
+ function. Estrogen is closely associated with endotoxinemia, and with histamine and nitric oxide
+ formation, and with the whole range of inflammatory and “autoimmune” diseases. Anything that irritates
+ the bowel, leading to increased endotoxin absorption, contributes to the same cluster of metabolic
+ consequences.
+
+
+ I have previously discussed the use of antibiotics (and/or carrot fiber and/or charcoal) to relieve the
+ premenstrual syndrome, and have mentioned the study in which the lifespan was extended by occasionally
+ adding charcoal to the diet. A few years ago, I heard about a Mexican farmer who collected his
+ neighbors' runt pigs, and got them to grow normally by adding charcoal to their diet. This probably
+ achieves the same thing as adding antibiotics to their food, which is practiced by pig farmers in the US
+ to promote growth and efficient use of food. Charcoal, besides binding and removing toxins, is also a
+ powerful catalyst for the oxidative destruction of many toxic chemicals. In a sense, it anticipates the
+ action of the protective enzymes of the intestinal wall and the liver.
+
+
+ Some women with premenstrual fatigue have found that the “premenstrual” phase tends to get longer and
+ longer, until they have chronic fatigue. I found that to be one of the easiest "PMS" problems to
+ correct. When people are older, and have been sick longer, the fatigue problem is likely to involve more
+ systems of the body. The larger the quantity of "toxic fat" stored in the body, the more careful the
+ person must be about increasing metabolic and physical activity. Using more vitamin E, short-chain
+ saturated fats, and other anti-lipid-peroxidation agents is important.
+
+
+ The inflammatory diseases that develop after prolonged stress are sometimes hard to correct. But
+ avoiding exposure to the major toxic allergens--such as carrageenan--is an essential consideration, just
+ as important as correcting the thyroid function and avoiding the antithyroid substances.
+
+
+ Low cholesterol is very commonly involved in the diseases of stress, and--like inadequate dietary
+ protein--will make the system less responsive to supplementary thryoid hormone.
+
+
+ The proliferative aspects of the inflammatory diseases represent, I think, a primitive form of
+ regeneration. Arthritis, atherosclerosis, various granulomatous processes, breast diseases, liver
+ adenomas, etc., provide an opportunity for investigating the various systems and substances that guide
+ cell proliferation toward reconstruction, rather than obstructive and deformative, degenerative,
+ processes. Degenerative diseases probably all contain clues for understanding regeneration, as I have
+ suggested in relation to Alzheimer’s disease and inflammation. I will be talking about these in other
+ newsletters, but the first step will always be to minimize exposure to the disruptive substances.
+
+
+
+ REFERENCES
+
+ Pathol Biol (Paris) 1979 Dec;27(10):615-626 [Biological and pharmacological effects of
+ carrageenan].[Article in French] Roch-Arveiller M, Giroud JP “Carrageenan is sulfated polysaccharide
+ which has been extensively used as emulsifier and thickening agent in the food industry, for its ability
+ to induce acute inflammation in pharmacology and for its selectively toxic effect for macrophages in
+ immunology. Carrageenan is a complex substance which displays various biological properties. The authors
+ have shown the extent of these actions and reviewed the latest investigations on this subject.”
+
+
+ Kirchheiner B J Allergy Clin Immunol 1995 May;95(5 Pt 1):933-936 Anaphylaxis to carrageenan: a
+ pseudo-latex allergy. Tarlo SM, Dolovich J, Listgarten C “Anaphylactic reactions during a barium enema
+ have been attributed to allergy to latex on the barium enema device. The observation of anaphylaxis
+ during barium enema without latex exposure or latex allergy led to the performance of an allergy skin
+ test to the barium enema solution.” “Individual components of the barium enema solution were obtained
+ for double-blind skin testing. A RAST to identify specific IgE antibodies to the skin test active agent
+ was established.” “Carrageenan, a component of the barium enema solution, produced positive reactions to
+ allergy skin test and RAST. Gastrointestinal symptoms for which the patient was being investigated by
+ the barium enema subsequently disappeared with a diet free of carrageenan. CONCLUSIONS: Carrageenan is a
+ previously unreported cause of anaphylaxis during barium enema. It is an allergen widely distributed in
+ common foods and potentially could account for some symptoms related to milk products or baby formula.”
+
+
+ Cancer Detect Prev 1981;4(1-4):129-134 Harmful effects of carrageenan fed to animals. Watt J, Marcus R
+ “An increased number of reports have appeared in the literature describing the harmful effects of
+ degraded and undegraded carrageenan supplied to several animal species in their diet or drinking fluid.
+ The harmful effects include foetal toxicity, teratogenicity, birth defects, pulmonary lesions,
+ hepatomegaly, prolonged storage in Kupffer cells, ulcerative disease of the large bowel with
+ hyperplastic, metaplastic, and polypoidal mucosal changes, enhancement of neoplasia by carcinogens, and,
+ more ominously, colorectal carcinoma. Degraded carrageenan as a drug or food additive has been
+ restricted in the United States by the FDA, but undegraded carrageenan is still widely used throughout
+ the world as a food additive. Its harmful effects in animals are almost certainly associated with its
+ degradation during passage through the gastrointestinal tract. There is a need for extreme caution in
+ the use of carrageenan or carrageenan-like products as food additives in our diet, and particularly in
+ slimming recipes.”
+
+
+ Acta Pathol Microbiol Scand [A] 1980 May;88(3):135-141 Stereomicroscopic and histologic changes in the
+ colon of guinea pigs fed degraded carrageenan. Olsen PS, Poulsen SS “A colitis-like state induced in
+ Guinea Pigs fed degraded carrageenan orally. By means of a combined semimacroscopic and histologic
+ technique the course of the disease was followed during 28 days. The changes were primarily seen and
+ became most prominent in the caecum. The first lesions were observed following 24 hours of treatment as
+ small rounded foci initially with degenerative changes and inflammation in the surface epithelium, later
+ forming superficial focal ulcerations. Ulcerative changes gradually progressed during the experiment,
+ forming linear and later large, geographical ulcerations. Topographically the ulcerative process was
+ strongly related to the larger submucosal vessels. Nonulcerated parts of the mucosa were not changed
+ until following 7-14 days of treatment. The mucosa became bulging, granulated and finally villus-like.
+ Accumulation of macrophages was found under the surface epithelium after 7-17 days. Possible
+ pathogenetic mechanisms are discussed, especially the development of the early lesions and the
+ significance of the macrophages.
+
+
+ Cancer Res 1997 Jul 15;57(14):2823-2826 Filament disassembly and loss of mammary myoepithelial cells
+ after exposure to lambda-carrageenan. Tobacman JK “Carrageenans are naturally occurring sulfated
+ polysaccharides, widely used in commercial food preparation to improve the texture of processed foods.
+ Because of their ubiquity in the diet and their observed preneoplastic effects in intestinal cells,
+ their impact on human mammary myoepithelial cells in tissue culture was studied. At concentrations as
+ low as 0.00014%, lambda-carrageenan was associated with disassembly of filaments with reduced
+ immunostaining for vimentin, alpha-smooth muscle-specific actin, and gelsolin; increased staining for
+ cytokeratin 14; and cell death. The absence of mammary myoepithelial cells is associated with invasive
+ mammary malignancy; hence, the destruction of these cells in tissue culture by a low concentration of a
+ widely used food additive suggests a dietary mechanism for mammary carcinogenesis not considered
+ previously.”
+
+
+ Agents Actions 1981 May;11(3):265-273 Carrageenan: a review of its effects on the immune system. Thomson
+ AW, Fowler EF “Carrageenans (kappa, lambda and iota) are sulphated polysaccharides isolated from marine
+ algae that can markedly suppress immune responses both in vivo and in vitro. Impairment of complement
+ activity and humoral responses to T-dependent antigens, depression of cell-mediated immunity,
+ prolongation of graft survival and potentiation of tumour growth by carrageenans have been reported. The
+ mechanism responsible for carrageenan-induced immune suppression is believed to be its selective
+ cytopathic effect on macrophages. This property of carrageenan has led to its adoption as a tool for
+ analysing the role of these cells in the induction and expression of immune reactivity. Systemic
+ administration of carrageenan may, however, induce disseminated intravascular coagulation and inflict
+ damage on both the liver and kidney. This is an important consideration in the interpretation of the
+ effects of carrageenan in vivo and precludes its use as a clinical immune suppressant.”
+
+
+ Biomedicine 1978 May;28(3):148-152 Carrageenan and the immune response. Thomson AW “Since the biological
+ effects of carrageenan were reviewed in 1972 by Di Rosa it has become clear from a large number of
+ reports that this algal polysaccharide markedly influences immune responses. Profound suppression of
+ immunity evidenced by impaired antibody production, graft rejection, delayed hypersensitivity and
+ anti-tumour immunity, has been observed in carrageenan-treated animals and the immunodepressive ability
+ of carrageenan confirmed by in vitro studies. Efforts at analysis of carrageenan-induced immune
+ suppression have focussed on the selective cy-totoxic effect of this agent onmononuclear phagocytes.
+ Faith in the ability of carrageenan to eliminate those cells has led to its use in examination of the
+ role played by mononuclear phagocytes in various aspects of immune reactivity. This review documents and
+ discusses the effects of carrageenan on immune responses and assesses the value of carrageenan as a
+ useful tool in both current and future work aimed at broadening our knowledge of mechanisms underlying
+ immune reactions.”
+
+
+ Teratology 1981 Apr;23(2):273-278 Teratogenic effect of lambda-carrageenan on the chick embryo. Monis B,
+ Rovasio RA “Carrageenans are widely used as food additives. Thus, it seemed of interest to test their
+ possible teratogenic action. For this purpose, 530 chick eggs were injected in the yolk sac with 0.1 ml
+ of a solution of 0.1% lambda-carrageenan in 0.9% sodium chloride. As controls, 286 eggs were injected
+ with 0.1 ml of 9.0% sodium chloride. In addition, 284 eggs received no treatment. After incubation for
+ 48--50 hours at 39 degrees C, embryos were fixed, cleared, and observed with a stereoscopic microscope.
+ The frequency of abnormal embryos in the group receiving lambda-carrageenan was higher than in the
+ controls (p less than 0.04). Partial duplication of the body, abnormal flexures of the trunk,
+ anencephaly, a severely malformed brain, thickening of the neural tube wall, an irregular neural tube
+ lumen with segmentary occlusion and a reduction in crown-rump length and number of somites were
+ distinctly seen in thelambda-carrageenan-injected group. Moreover, the average number of anomalies per
+ embryo in the lambda-carrageenan-injected group was nearly twice that in the controls. Present data
+ indicate that lambda-carrageenan has teratogenic effects on early stages of the development of the chick
+ embryo.”
+
+
+ Food Addit Contam 1989 Oct;6(4):425-436 Intestinal uptake and immunological effects of
+ carrageenan--current concepts. Nicklin S, Miller K “Carrageenans are a group of high molecular weight
+ sulphated polygalactans which find extensive use inthe food industry as thickening, gelling and
+ protein-suspending agents. Although there is no evidence to suggest that the persorption of small
+ amounts of carrageenans across the intestinal barrier poses an acute toxic hazard, they are known to be
+ biologically active in a number of physiological systems and extended oral administration in laboratory
+ animals has been shown to modify both in vivo and in vitro immune competence. Whereas this effect could
+ be attributed to carrageenan having a selective toxic effect on antigen-processing macrophages,
+ additional studies suggest that macrophages can also influence immune responses by the timed release of
+ immunoregulatory mediators. Evidence in support of this comes from in vitro studies which demonstrate
+ that carrageenan-treated macrophages can, depending on conditions and time of administration, release
+ either stimulatory or inhibitory factors. The former is known to be the immunostimulatory agent
+ interleukin 1 (IL-1). The inhibitory factor, which is produced at an early stage following exposure to
+ non-toxic doses of carrageenans, has yet to be formally identified but it is believed to be a
+ prostaglandin because of its specific mode of action and short biological half-life. At present it is
+ impossible to relate these studies to the human situation. Although it is established that carrageenans
+ can cross the intestinal barrier of experimental animals, there is no evidence to suggest that the
+ limited uptake that may occur in man in any way interferes with normal immune competence. Nevertheless,
+ increased exposure may occur in the neonate during weaning, and adults and children following allergic
+ reactions and episodes of gastrointestinal disease. Further studies under such conditions now seem
+ warranted in order to elucidate the possible immunological consequences which may be associated with
+ enhanced uptake of carrageenans in vulnerable groups.”
+
+
+ Health Rep 1990;2(4):343-359 “Crohn's disease and ulcerative colitis: morbidity and mortality,” Rod
+ Riley. “This study analyzes hospital discharges and deaths from 1971 to 1986 for patients with
+ inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis. The data are
+ based on hospital morbidity and mortality statistics provided to Statistics Canada by the provinces. For
+ Crohn's disease, age-standardized rates per 100,000 population for hospital discharges increased by 148%
+ for males and by 192% for females over the study period. In 1986, the rate for females was 48% higher
+ than the rate for males. For both males and females, age-specific discharge rates were highest in the
+ 20-24 age group. For ulcerative colitis, male age-standardized discharge rates decreased by 17% from
+ 1971 to 1977, and then increased by 41% from 1977 to 1986. For females, the rates decreased by 18% from
+ 1971 to 1976, then remained fairly stable from 1976 to 1986. Male and female discharge rates were
+ similar over the study period. For females, rates were highest in the 20-34 age groups; for males, they
+ were highest in the 65 and older age groups. In 1971, rates for both types of IBD were almost the same,
+ but by the end of the study period the rate per 100,000 population for Crohn's disease was 34 for
+ females and 23 for males, while for ulcerative colitis the rates were 13 for females and 14 for males.
+ During the 16-year study period, cause of death data showed 556 deaths directly attributed to Crohn's
+ disease and 761 deaths at-tributed to ulcerative colitis. The under 45 age group accounted for 25% of
+ deaths due to Crohn's disease and for 17% of deaths due to ulcerative colitis. The time trends for IBD
+ hospital discharge rates in Canada closely parallel the findings of hospital discharge rates in the
+ United States and England-Wales. A comparison with epidemiological population surveys strongly suggests
+ that increased discharge rates are due mostly to increases in incidence and prevalence of IBD in the
+ general population.”
+
+
+
+
+ Gut 1988 Mar;29(3):346-351, Cardiff Crohn's disease jubilee: the incidence over 50 years. Rose JD,
+ Roberts GM, Williams G, Mayberry JF, Rhodes J “The incidence of Crohn's disease in Cardiff between 1931
+ and 1985 has been examined using hospital diagnostic indices supplemented in recent years by records
+ from clinicians, and the departments of pathology and radiology. Four hundred and seven new patients
+ were confirmed after all notes had been reviewed. There has been a large increase from 0.18 cases/10(5)
+ of the population per year in the 1930s to current values of 8.3/10(5)/year. The incidence continues to
+ rise and shows an increasing proportion of patients with colorectal disease. Peak age specific
+ incidences occur in the third and eighth decades of life.”
+
+
+ Am J Hematol 1992 Mar;39(3):176-182 Polysaccharide encapsulated bacterial infection in sickle cell
+ anemia: a thirty year epidemiologic experience. Wong WY, Powars DR, Chan L, Hiti A, Johnson C, Overturf
+ G “Annual age-specific incidence rates of Streptococcus pneumoniae or Haemophilus influenzae bacterial
+ septicemia in sickle cell anemia (SS) were determined for the years of 1957 through 1989. Forty-nine
+ patients had 64 episodes of septicemia among a population of 786 SS patients observed for 8,138
+ person-years. Peak frequency of infection occurred between 1968-1971 and 1975-1981 with a conspicuous
+ absence of episodes in 1972, 1973, 1982-1984, and 1986-1987, thus demonstrating cycles of high and low
+ attack rates. The annual age-specific incidence rate of septicemia varied from 64.5 (1965) to 421.1
+ (1980) per 1,000 person-years for those under 2 years of age and never exceeded 10.2 per 1,000 in those
+ over 4 years of age. Following the introduction of pneumococcal polyvalent vaccine in 1978, incidence of
+ infection decreased in SS children greater than 2 years of age. No modification of the risk of infection
+ was observed in immunized children less than 2 years of age. During these three decades, there has been
+ a ten-fold increase in the number of SS adults over 20 years of age. The relative risk of chronic sickle
+ complications comparing the survivors of septicemia to the non-infected patients was: subsequent death
+ 1.76, retinopathy 4.06, avascular necrosis 1.95, symptomatic cholelithiasis 1.33, stroke 1.30, and
+ priapism 1.26. These data suggest that prognosis for lifetime severe SS is initially manifested as an
+ increased risk of septicemia during childhood.”
+
+
+ Gastroenterol Clin Biol 1986 Jun;10(6-7):468-474 [Trends of mortality from cirrhosis in France between
+ 1925 and 1982 Coppere H, Audigier JC “In 1982, 13,866 deaths secondary to cirrhosis were reported.
+ Between 1925 and 1982, the number of deaths increased by 163 p. 100. This overall change was observed
+ gradually: profound drop in the cirrhosis mortality rate during the Second World War, increase between
+ 1945 and 1967, stabilization between 1967 and 1975 and more pronounced decline from then on. Cirrhosis
+ mortality rate per 100,000 increased from 9.17 to 28.21 (+208 p. 100) in males and from 3.63 to 10.38
+ (+186 p. 100) in females from 1945 to 1982. The increase was approximately the same whatever the age. A
+ cohort effect was observed in both sexes. There were two successive waves of increased mortality
+ separated by an interval of non augmentation for the cohorts born between 1906 and 1915 and between 1931
+ and 1940. Since 1967, mortality due to cirrhosis has stopped increasing in both sexes. These changes may
+ be related to decreasing alcohol consumption in France, certainly one of the major objectives in present
+ day health programs. Abrupt reduction of alcohol consumption should be followed by a dramatic fall in
+ the number of deaths from cirrhosis. Progressive decline of consumption is possibly associated with a
+ decrease in the incidence of the disease. In 2,000, the rate for cirrhosis mortality is expected to be
+ the same as that observed in the middle of the 20th century.”
+
+
+ Cancer Res 1987 Sep 15;47(18):4967-4972 Changing incidence of hepatocellular carcinoma in Japan. Okuda
+ K, Fujimoto I, Hanai A, Urano Y “A trend in the incidence of hepatocellular carcinoma (HCC) in Japan was
+ studied from the data of the Osaka Cancer Registry (population, 8,512,351 in 1981) for the period of
+ 1963-1983, the Vital Statistics of Japan, Ministry of Health and Welfare, and the Japan Autopsy Registry
+ which contained 594,132 individually filed cases in the 26-year period from 1958 to 1983. Both cancer
+ registry data and autopsy records showed a more than 2-fold increase in HCC incidence, particularly in
+ the last 10 years or so, among males and a less pronounced increase in females. The same trend was borne
+ out by the cancer registries of Nagasaki City and Miyagi Prefecture and the Vital Statistics. When
+ studied with the autopsy data, it was found that the numbers of autopsies for cirrhosis without HCC and
+ autopsies for HCC (with and without cirrhosis) were about the same in 1958-1961 and that currently
+ (1980-1983) the latter is about 2 times the former. As one of the possible causes of increase in HCC
+ incidence other than prolonged survival of patients with cirrhosis, chronic non-A, non-B hepatitis is
+ discussed. “
+
+
+ Hepatogastroenterology 1997 Sep;44(17):1401-1403 Hepatocellular carcinoma and hepatic cirrhosis in
+ Mexico: a 25 year necroscopy review. Cortes-Espinosa T, Mondragon-Sanchez R, Hurtado-Andrade H,
+ Sanchez-Cisneros R “BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a common form of cancer which is
+ found throughout the world. In recent years, the rates of HCC seem to have increased in European and
+ North American countries.” “RESULTS: Of 12556 autopsies studied, 73 cases of histologically proven HCC
+ were reported, representing a total necropsy carcinoma incidence of 0.59%. Fifty-five cases were
+ associated with cirrhosis (0.43%), and 18 were not (0.14%). HCC was two times more common in males (67%)
+ than in females (33%), with a ratio of 2:1. During this period, the necropsy incidence of HCC rose
+ steadily to twice its original level (1965-69 incidence 0.35%; 1985-89 incidence 0.69%). The necropsy
+ incidence of cirrhosis was 4% (329 males, 185 females). The overall TC/T index was 75% (87% for males
+ and 50% for females). The overall TC/C index was 10.7% (13% for males and 6.4% for females).
+ CONCLUSIONS: There was a two-fold increase in the incidence of HCC in the Mexican population studied
+ over a 25-year period. HCC was associated with cirrhosis in the majority of cases. HCC was two times
+ more common in males than in females in patients with cirrhosis; in patients without cirrhosis, the
+ ratio was 1:1. The incidence of cirrhosis was 4%, which remained unchanged with the passage of time.”
+
+
+ Hepatogastroenterology 1984 Oct;31(5):215-217 Hepatocellular carcinoma and cirrhosis: a review of their
+ relative incidence in a 25-year period in the Florence area. Bartoloni St Omer F, Giannini A, Napoli P
+ “An eight-fold increase in the incidence of hepatocellular carcinoma in the Florence area was detected
+ in a 25-year retrospective review of adult autopsy records in the Institute of Pathology of the
+ University of Florence. During the same period, the incidence of cirrhosis did not show a parallel
+ increase. The relationship between hepatocellular carcinoma, cirrhosis and HB virus is briefly discussed
+ in the light of these findings.”
+
+
+ J Clin Pathol 1978 Feb;31(2):108-110 Hepatocellular carcinoma and hepatic cirrhosis in the west of
+ Scotland: a 25-year necropsy review. Burnett RA, Patrick RS, Spilg WG, Buchanan WM, Macsween RN “A
+ two-fold increase in the incidence of hepatocellular carcinoma in the west of Scotland is reported on
+ the basis of a 25-year retrospective necropsy review (313 cases). This increase is not accompanied by a
+ corresponding increase in the incidence of hepatic cirrhosis. The relationship between hepatocellular
+ carcinoma and hepatic cirrhosis is discussed in the light of these findings.”
+
+
+ J Hyg Epidemiol Microbiol Immunol 1990;34(4):343-348 “Increasing trend of hyperbilirubinemia incidence
+ in the blood donors population,” Pintera J.
+
+
+ Hepatogastroenterology 1984 Oct;31(5):211-214 Primary hepatic cancer and liver cirrhosis. Autopsy study
+ covering fifty years. Bethke BA, Schubert GE “Autopsy reports from 1931 to 1980 were used to study the
+ incidence of liver cirrhosis (LC) and the association between LC and hepatocellular carcinoma (HCC) in
+ our area (Wuppertal, Germany). An increase in LC and in LC with HCC has occurred since World War II,
+ with HCC being most frequently associated with postnecrotic cirrhosis. The prevalence of HCC in men with
+ LC was highest (13.5%) in 1966-1970, whereas the prevalence of HCC with LC in women rose abruptly to a
+ peak (11.8%) during the last 5 years of the study. Possible etiological factors for the association
+ between LC and HCC are discussed.”
+
+
+ Riv Eur Sci Med Farmacol 1990 Jun;12(3):165-168 [Oral contraceptive and hepatic effects].[Article in
+ Italian] Tarantino G, Morelli L, Califano C “The general use of synthetic estrogens like DC pointed out
+ that near many skilled collateral effects, some others that are showing with a decrease of bile
+ excretion (cholestasis), reversible with their administration interruption; with hepatic cells adenoma
+ that are potentially premalignant and can transform into hepatocellular carcinoma; with vascular
+ complications such as (most frequently in carcinomatousis) "hepatic peliosis" and "thrombosis" of
+ suprahepatic veins (Budd-Chiari's syndrome). There is no overall increase in the incidence of
+ gallbladder disease (cholelithiasis and cholecystitis).”
+
+
+ Hepatology 1990 Nov;12(5):1106-1110 Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy
+ study with analysis of risk factors. Wanless IR, Lentz JS “Steatohepatitis (fatty liver hepatitis),
+ histologically identical to alcoholic disease, occurs in some obese patients after jejunoileal bypass. A
+ similar lesion occurs rarely in obese patients without bypass surgery, but the risk factors are poorly
+ understood. Hepatic steatosis, steatohepatitis and fibrosis were sought in 351 apparently nonalcoholic
+ patients at autopsy and various risk factors were evaluated.” “Thus this study supports the hypothesis
+ that fatty acids have a role in the hepatocellular necrosis found in some obese individuals.”
+
+
+ Prostaglandins 1977 Aug;14(2):295-307 Reduced exudation and increased tissue proliferation during
+ chronic inflammation in rats deprived of endogenous prostaglandin precursors. Bonta IL, Parnham MJ,
+ Adolfs MJ “Two models of chronic inflammation were studied in rats deprived of endogenous precursors of
+ prostaglandins by feeding the animals on essential fatty acid deficient (EFAD) food. During
+ kaolin-induced pouch-granuloma, exudate production was markedly reduced in EFAD rats, when compared with
+ normal animals. The exudates from normal rats contained large amounts of PGE, but in the exudates from
+ EFAD rats the amount of PGE was very markedly reduced. Similarly, with carrageenan-impregnated polyether
+ sponges, the exudative component of inflammation was reduced in EFAD rats. However, the proliferative
+ component was significantly increased, particularly in relation to the stunted growth of EFAD rats.
+ Sponge exudates from EFAD rats contained fewer leucocytes than those from normal animals but the fall in
+ leucocyte count was much smaller than the very marked reduction in PGE activity. EFAD rats also
+ exhibited a significant increase in adrenal weights. The results are discussed in the light of the
+ ambivalent (pro- or anti-inflammatory) role of endogenous PGS. It appears that, in the proliferative
+ phase of inflammation, the anti-inflammatory role of PGs is more dominant.”
+
+
+ J Hepatol 1997 Sep;27(3):578-582 Subfulminant hepatic failure in autoimmune hepatitis type 1: an unusual
+ form of presentation. Herzog D, Rasquin-Weber AM, Debray D, Alvarez F “Autoimmune hepatitis type 1 is
+ known to progress insidiously and in many cases cirrhosis is already established at the first
+ presentation of symptoms. It affects mostly females, with peaks of incidence around 10 and 50 years of
+ age. Subfulminant hepatic failure is an unusual initial form of presentation of AIH type 1 and it was
+ observed in three post-pubertal female patients. Rapid disease evolution or no response to
+ immunosuppressive therapy led to liver transplantation in all patients. Two did not have cirrhosis, and
+ the third had focal cirrhosis. The occurrence of the unusual subfulminant form of autoimmune hepatitis
+ in three latepubertal girls (Tanner V) suggests that estrogen may play a role in the severity of the
+ disease.”
+
+
+ Acta Hepatogastroenterol (Stuttg) 1977 Apr;24(2):97-101 Plasma prolactin and prolactin release in liver
+ cirrhosis. Wernze H, Schmitz E “A significant increase of basal plasma prolactin levels
+ (radioimmunoassayed) in 75 patients with liver cirrhosis was found in comparison to 50 male controls
+ (8.5+/-4.5 (SD) vs. 5.5+/-1.7 ng/ml p less than 0.001). The extent and incidence of hyperprolactinaemia
+ in 48 patients with alcoholic cirrhosis was more pronounced than in 27 cases of cirrhosis of
+ non-alcoholic aetiologies (mean 9.7+/-4.8 vs. 5.7+/-2.1 ng/ml). No relation to ascites formation as well
+ as to the development of gynaecomastia was apparent. Prolactin release following thyrotropin-releasing
+ hormone was markedly enhanced in alcoholic as compared to non-alcoholic cirrhosis. Possibly
+ hyperprolactinaemia and increased pituitary hormone reserve reflects hyperoestrogenism but changes of
+ the hypothalamic regulation cannot be excluded as yet.”
+
+
+ Jpn J Pharmacol 1991 Apr;55(4):551-554 Endotoxin- and inflammation-induced depression of the hepatic
+ drug metabolism in rats. Ishikawa M, Sasaki K, Nishimura K, Takayanagi Y, Sasaki K “Carrageenan-induced
+ inflammation and exposure to endotoxin considerably decreased the content of cytochrome P-450 and
+ activities of ethylmorphine N-demethylase and meperidine N-demethylase, but did not decrease the
+ activities of aniline hydroxylase or NADPH-cytochrome c reductase, compared with the respective
+ activities in rats treated with carrageenan alone. These results suggest that under these experimental
+ conditions, the two host-related environmental factors interact and enhance a decrease in rat hepatic
+ microsomal drug metabolizing enzymes depending on the substrate used.”
+
+
+ Infect Immun 1991 Feb;59(2):679-683 Enhancement of lipopolysaccharide-induced tumor necrosis factor
+ production in mice by carrageenan pretreatment. Ogata M, Yoshida S, Kamochi M, Shigematsu A, Mizuguchi Y
+ “Tumor necrosis factor (TNF) is a cytokine which mediates endotoxin shock and causes multiple organ
+ damage. It is thought that macrophage (MP) activation is necessary to increase lipopolysaccharide
+ (LPS)-induced TNF production and lethality. Carrageenan (CAR) is sulfated polygalactose which destroys
+ MP; it is used as a MP blocker. We found that CAR pretreatment can increase both endotoxin-induced TNF
+ production and the mortality rate in mice. The ddY mice (7 to 8 weeks old) were injected
+ intraperitoneally with CAR (5-mg dose) and challenged intravenously with LPS 24 h later. Without CAR
+ pretreatment, LPS doses of less than 10 micrograms did not induce TNF in sera. After pretreatment,
+ however, about 3 x 10(3) to 4 x 10(4) U of TNF per ml was produced after LPS injection at doses of 0.1
+ to 10 micrograms, respectively. TNF production was significantly increased by CAR pretreatment at LPS
+ doses of more than 10 micrograms. CAR pretreatment rendered the mice more sensitive to the lethal effect
+ of LPS; 50% lethal doses of LPS in CAR-pretreated mice and nonpretreated mice were 26.9 and 227
+ micrograms, respectively. The mortality of the two groups was significantly different at doses of 50,
+ 100, and 200 mi-crograms of LPS. CAR increased LPS-induced TNF production and mortality within 2 h, much
+ earlier than MP activators, which needed at least 4 days. Our results made clear that TNF production is
+ enhanced not only by a MP activator but also by a MP blocker.”
+
+
+ Prog Clin Biol Res 1989;286:237-242 Effect of macrophage inhibition in carrageenan- and
+ D-galactosamine-induced sensitivity to low-dose endotoxin. Kujawa KI, Berning A, Odeyale C, Yaffe LJ.
+
+
+ J Surg Res 1984 Jul;37(1):63-68 Evidence for aerobic glycolysis in lambda-carrageenan-wounded skeletal
+ muscle. Caldwell MD, Shearer J, Morris A, Mastrofrancesco B, Henry W, Albina JE “Classically, increased
+ lactate production in wounded tissue is ascribed to anaerobic glycolysis although its oxygen consumption
+ has been found to be similar to normal tissue. This apparent inconsistency was studied in a standardized
+ isolated perfused wound model. Male Sprague-Dawley rats were wounded (group W) with intramuscular
+ injections of lambda-carrageenan and fed ad lib.; not wounded and pair fed to the decreased food intake
+ of the wounded animals (group PFC); or not wounded and fed ad lib. (group ALC). After 5 days, the
+ hindlimbs of animals from each group were either perfused using a standard perfusate with added
+ [U-14C]glucose or [1-14C]pyruvate or assayed for the tissue content of lactate and pyruvate. In
+ addition, the effect of a 30% hemorrhage on the tissue lactate and pyruvate concentration was examined.
+ Wounding increased glucose uptake and lactate production by 100 and 96%, respectively, above that seen
+ in ALC animals. Oxygen consumption was unchanged by wounding (5.74, 5.14, and 5.83 mumole/min/100 g in
+ W, PFC, and ALC, respectively). Glucose and pyruvate oxidation were also unaltered among the groups.
+ Hemorrhage resulted in a comparable increase in lactate and pyruvate in tissue from wounded and pair-fed
+ control animals (above those concentrations found in tissue harvested without preexisting hemorrhage).
+ As a consequence, the same relationship in L/P ratio was maintained after hemorrhage. Taken together,
+ these results confirm the presence of aerobic glycolysis in wounded tissue (unchanged oxygen
+ consumption, glucose, and pyruvate oxidation). In addition, pyruvate dehydrogenase activity in the wound
+ was apparently the same as that found in muscle from pair-fed control animals.”
+
+
+ Food Chem Toxicol 1984 Aug;22(8):615-621 Effect of orally administered food-grade carrageenans on
+ antibody-mediated and cell-mediated immunity in the inbred rat. Nicklin S, Miller K “Experiments were
+ performed to investigate the immunological consequences associated with the persorption of poorly
+ degradable carregeenans from the diet. Using an inbred strain of rat it was demonstrated
+ histochemically, by the carrageenan-specific Alcian blue staining technique, that small quantities of
+ food-grade carrageenans given at 0.5% in drinking-water for 90 days could penetrate the intestinal
+ barrier of adult animals. This apparently occurred via an intact mucosa in the absence of inflammatory
+ or pathological lesions. The carrageenan was demonstrated in macrophage-like cells present within the
+ villi and lamina propria of the small intestine. The oral administration of kappa, lambda or iota
+ food-grade carrageenans did not affect local (biliary) or systemic antibody responses to gut commensal
+ microorganisms, or to orally-administered sheep erythrocytes. However, when sheep red blood cells were
+ administered parenterally the ensuing anti-sheep red blood cell haemagglutinating antibody response was
+ temporarily suppressed in carrageenan-fed rats. lambda-Carrageenan and iota-carrageenan both
+ significantly (P less than or equal to 0.01 and P less than or equal to 0.05, respectively) reduced the
+ mid-phase (14-28 days) haemagglutinin response; kappa-carrageenan (L100) was less effective but caused
+ significant depression at day 21 (P less than or equal to 0.01). Individual responses were, however,
+ within the control range 35 days after sheep erythrocyte administration, thus indicating the temporary
+ nature of this effect. Although carrageenan administration depressed the anti-sheep erythrocyte antibody
+ response, it did not affect T-cell immune competence as measured by the popliteal lymph node assay for
+ graft-versus-host reactivity.”
+
+
+ J Nutr 1986 Feb;116(2):223-232 Effects of certain dietary fibers on apparent permeability of the rat
+ intestine. Shiau SY, Chang GW “Apparent intestinal permeability was determined indirectly by orally
+ administering a poorly absorbed dye, phenol red, to rats and measuring its recovery in feces and in
+ urine. Increased apparent permeability was recognized by increased dye recovery in urine and by an
+ increased ratio of urinary to fecal dye recovery. Guar gum, pectin, carrageenan type I (80% kappa, 20%
+ lambda), carra-geenan type II (iota) and cellulose were each fed at levels of 5 and 15% (wt/wt) of the
+ diet for 31 d to male Fischer 344 rats. The average initial weight of rats was 230 g. Rats fed 15% guar
+ gum gained significantly less weight than most of the other rats (P less than 0.05). Phenol red recovery
+ was measured at 2 and 4 wk after the beginning of the experiment. At 2 wk urinary recoveries of phenol
+ red were high in rats fed fiber-free and carrageenan type II diets, indicating increased apparent
+ permeability. By 4 wk, adaptation had apparently taken place.” “These data are consistent with the
+ hypothesis that intestinal permeability to foreign substances may be altered considerably by diet.”
+
+
+ Pathologe 1993 Sep;14(5):247-252 [Persorption of microparticles].[Article in German] Volkheimer G
+ “Solid, hard microparticles, such as starch granules, pollen, cellulose particles, fibres and crystals,
+ whose diameters are well into the micrometre range, are incorporated regularly and in considerable
+ numbers from the digestive tract. Motor factors play an important part in the paracellular penetration
+ of the epithelial cell layer. From the subepithelial region the microparticles are transported away via
+ lymph and blood vessels. They can be detected in body fluids using simple methods: only a few minutes
+ after oral administration they can be found in the peripheral blood-stream. We observed their passage
+ into urine, bile, cerebrospinal fluid, the alveolar lumen, the peritoneal cavity, breast milk, and
+ transplacentally into the fetal blood-stream. Since persorbed microparticles can embolise small vessels,
+ this touches on microangiological problems, especially in the region of the CNS. The long-term deposit
+ of embolising microparticles which consist of potential allergens or contaminants, or which are carriers
+ of contaminants, is of immunological and environmental-technical importance. Numerous ready-made
+ foodstuffs contain large quantities of microparticles capable of persorption.”
+
+
+ Eur J Pediatr 1993 Jul;152(7):592-594 Oral cornstarch therapy: is persorption harmless? Gitzelmann R,
+ Spycher MA ”Sediments prepared from freshly voided urine of four patients with glycogenosis Ia, or
+ leucine-sensitive hypoglycaemia, on oral cornstarch therapy contained starch granules, evidence for
+ persorption i.e. the incorporation of undissolved starch particles. In these patients, amyluria was more
+ marked than in untreated controls. While cornstarch therapy is successful and causes few side-effects,
+ the possibility of late adverse reactions to persorbed starch should not be disregarded.”
+
+
+ Med Hypotheses 1991 Jun;35(2):85-87 “Persorption of raw starch: a cause of senile dementia? Freedman BJ
+ “Intact starch granules in food can pass through the intestinal wall and enter the circulation. They
+ remain intact if they have not been cooked for long enough in the presence of water. Some of these
+ granules embolise arterioles and capillaries. In most organs the collateral circulation suffices for
+ continued function.In the brain, however, neurones may be lost. Over many decades the neuronal loss
+ could be of clinical importance. To test this hypothesis, there is a need to examine brains for the
+ presence of embolised starch granules. Examining tissues polariscopically clearly distinguishes starch
+ granules from other objects of similar appearance.”
+
+
+ Kitasato Arch Exp Med 1990 Apr;63(1):1-6 [The Herbst-Volkheimer effect]” [Article in German], Prokop, O.
+ “More than 150 years ago the foundations were laid for the so-called HERBST effect which was
+ subsequently forgotten. In the sixties the phenomenon was rediscovered by VOLKHEIMER at the Charite
+ Hospital in Berlin and then reviewed through many experiments and publications. What is meant by the
+ HERBST effect? If an experimental animal or even human being is given a larger amount of maize starch or
+ also biscuits or some other products containing starch, starch bodies can be detected rapidly in venous
+ blood already after minutes or half an hour later and in the urine after one hour and later. The term
+ "persorption" has been coined for this interesting phenomenon. It is indeed surprising that it has met
+ with so little attention. As a matter of fact, it constitutes the basis for our understanding of peroral
+ immunization and of allergies. In the same way, feeding of carbon particles results in their appearance
+ and detection in blood, kidney and urine. The same result is obtained by the intake of diatoms and what
+ is even more important with meat fibres. I hope you are aware of the implications. When Professor NAGAI
+ stayed in Berlin, we tried to receive the phenomenon. Since only a few cell nuclei are necessary for
+ "genetic fingerprinting" we thought that after intake of 200 or 400 g of raw meat the type of food eaten
+ could be determined from the urinary sediment by means of the fingerprint method which would be of
+ forensic significance. Therefore, we eat meat and raw liver and examined the urinary sediment.”
+
+
+ Z Arztl Fortbild (Jena) 1993 Mar 12;87(3):217-221 [The phenomenon of persorption--history and
+ facts].[Article in German] Volkheimer G.
+
+
+ J Pediatr 1994 Sep;125(3):392-399 Clinical and molecular epidemiology of enterococcal bacteremia in a
+ pediatric teaching hospital. Christie C, Hammond J, Reising S, Evans-Patterson J “An apparent increase
+ in the in-cidence of enterococcal bacteremias from 7 to 48/1000 bacteremias during 1986 to 1991 (p <
+ 0.01) prompted this descriptive clinical and molecular epidemiologic study of 83 episodes occurring in
+ 80 children between 1986 and 1992.” “The increase in enterococcal bacteremias was not due to a clonal
+ strain dissemination but to an increase in cases of heterogeneous enterococcal strains. We conclude that
+ enterococcal septicemia is now an important cause of serious morbidity and death in critically ill
+ children.”
+
+ R.F.V. Pulvertaft, PHA in relation to Burkitt's tumour, Lancet sept 12, pp 552-554, 1964.
+ K.M. Stevens, The aetiology of SLE, Lancet, Sept. 5, 506-508, 1964.
+
+
+ Ray Peat's Newsletter
+
+ Not for republication without written permission PO Box 5764, Eugene, OR 97405 Raymond PeatJuly, 1995
+
+
+ Persorption refers to a process in which relatively large particles pass through the intact wall of the
+ intestine and enter the blood or lymphatic vessels. It can be demonstrated easily, but food regulators
+ prefer to act as though it didn't exist. The doctrine that polymers--gums, starches, peptides, polyester
+ fat substitutes--and other particulate substances can be safely added to food because they are "too
+ large to be absorbed" is very important to the food in-dustry and its shills.
+
+
+ When the bowel is inflamed, toxins are absorbed. The natural bacterial endotoxin produces many of the
+ same inflammatory effects as the food additive, carrageenan. Like inflammatory bowel disease, the
+ incidence of liver tumors and cirrhosis has increased rapidly. Liver damage leads to hormonal imbalance.
+ Carrageenan produces inflammation and immunodeficiency, synergizing with estrogen, endotoxin and
+ unsaturated fatty acids.
+
+
+ “Volkheimer found that mice fed raw starch aged at an abnormally fast rate, and when he dissected the
+ starch-fed mice, he found a multitude of blocked arterioles in every organ, each of which caused the
+ death of the cells that depended on the blood supplied by that arteriole. It isn’t hard to see how this
+ would affect the functions of organs such as the brain and heart, even without considering the
+ immunological and other implications....”
+
+
+
+
+
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+
+ Cascara, energy, cancer and the FDA's laxative abuse
+
The medical culture and the general culture share some attitudes about the nature of the most common
+ ailments--colds, cancer, arthritis, constipation, heart problems, etc., and they often agree about which things
+ can be treated at home, and which require special medical care. These background ideas are important because
+ they influence the actions of insurance companies, legislators, and regulatory agencies. They also influence the
+ judgments people make about their own health, and, too often, the way physicians treat their patients.The
+ prevalence of chronic constipation in North America has been estimated to be 27%, and in a ten year study, the
+ occurrence of new cases was about 16%.--the prevalence increases with aging. In some studies, women are 3 times
+ as likely as men to suffer from constipation. A recent Canadian article commented that "While chronic
+ constipation (CC) has a high prevalence in primary care, there are no existing treatment recommendations to
+ guide health care professionals." Almost everyone in the US is familiar with the idea of "laxative abuse," of
+ using laxatives when they aren"t absolutely necessary, and with the idea that chronic laxative use will create a
+ dependency, the way an addictive drug does. Contemporary doctors are likely to prescribe stool softeners for
+ constipated old people, rather than "stimulant laxatives," probably because "softener" doesn"t have the
+ pejorative connotation that "stimulant drug" has--not because there is a scientific basis for the choice.Many
+ doctors advise constipated patients to drink more water and exercise. While there is some physiological basis
+ for recommending exercise, the advice to drink more water is simply unphysiological. A study in Latin America
+ found no evidence of benefit from either of those recommendations, and recommended the use of fiber in the diet.
+ The right kind of fiber can benefit a variety of bowel problems. However, some types of fiber can exacerbate the
+ problem, and some types (such as oat bran) have been found to increase bowel cancer in animal studies.Despite
+ the greater prevalence of constipation in women and older people, even specialists in gastroenterology are very
+ unlikely to consider the role of hypothyroidism or other endocrine problems in chronic constipation.Because of
+ the cultural clich"s about constipation--that it"s caused by not eating enough fiber or drinking enough water,
+ for example--and the belief that it"s not very important, there is seldom an effort made to understand the
+ actual condition of the intestine, and the causes of the problem. Aging and stress increase some of the
+ inflammatory mediators, tending to reduce the barrier function of the bowel, letting larger amounts of bacterial
+ toxins enter the bloodstream, interfering with energy metabolism, creating inflammatory vicious circles of
+ increasing leakiness and inflammation. Often people visualize something like a sausage casing when they think of
+ the intestine, but when the intestine is becoming inflamed its wall may swell to become an inch thick. As it
+ thickens, the channel narrows to a few millimeters in diameter, and may even close in some regions. In the
+ swollen, edematous, inflamed condition the contractile mechanism of the smooth muscle is impaired. The failure
+ of contraction is caused by the same structural changes that increase permeability. (Garcia, et al., 1996;
+ Skarsgard, et al., 2000; Plaku and von der Weid, 2006; Uray, et al., 2006; Miller and Sims, 1986; Schouten, et
+ al., 2008; Gosling, et al., 2000.)Obviously, in the very swollen, structurally deformed intestine, with almost
+ no lumen, neither a stimulant nor a simple fibrous bulk could restore functioning, because even with stimulation
+ the smooth muscle is unable to contract, and the closed channel won"t admit bulk. Even gas is sometimes unable
+ to pass through the inflamed intestine. Mechanical thinking about the intestine fails when inflammation is
+ involved; now that inflammation is known to play an important role in Alzheimer"s disease and heart disease, it
+ will be more acceptable to consider its role in constipation.The contractile ability of smooth muscle, that"s
+ impaired by swelling and inflammation, can be restored by antiinflammatory agents, for example aspirin (or other
+ inhibitor of prostaglandin synthesis) or antihistamines. This applies to the muscles of lymphatic vessels (Wu,
+ et al., 2005, 2006; Gosling, 2000), that must function to reduce edema, as well as to the bowel muscles that
+ cause peristalsis. If someone thinks of constipation as the result of a lack of neuromuscular stimulation, then
+ it might seem reasonable to design a drug that intensifies the contractions produced by one of the natural
+ transmitter substances, such as serotonin, histamine, or acetylcholine. That"s apparently what Novartis did,
+ with tegaserod, a drug that increases the bowel"s sensitivity to serotonin. That drug, called Zelnorm, was
+ approved by the FDA in 2002, after a couple of years of publications praising it. At the time of its approval,
+ there was already evidence that people using it were more likely to have abdominal surgery, especially for
+ gallbladder disease, and there was doubt about its effectiveness.Strangely, the drug was approved to be used for
+ only 4 to 6 weeks, taking two tablets daily without interruption. When patients benefitted from the first
+ treatment, they might be eligible for an additional 4 to 6 weeks, but then it would be necessary for them to
+ find another way to deal with their constipation.Zelnorm side effects: abdominal pain, chest pain, flushing,
+ facial edema, hypertension, hypotension, angina pectoris, syncope, arrythmia, anxiety, vertigo, ovarian cyst,
+ miscarriage, menorrhagia, cholecystitis, appendicitis, bilirubinemia, gastroenteritis, increased creatine
+ phosphokinase. back pain, cramps, breast cancer, attempted suicide, impaired concentration,
+ increased appetite, sleep disorder, depression, anxiety, asthma, increased sweating, renal pain, polyuria.
+ (Later, it was found to cause heart attacks and intestinal ischemia/necrosis.) Why would the FDA approve a drug,
+ without evidence that it was more effective than harmless things that were already widely available?Zelnorm
+ Prices ~ In the US, Novartis estimates that Zelnorm tablets will sell for somewhere in the range of $3 to $4
+ each. The drug is expected to generate $1 billion in annual sales for Novartis.During the years just before the
+ new drug was approved, there were several publications reporting that emodin, the main active factor in cascara,
+ a traditional laxative, had some remarkable antiviral and anticancer activities. Other studies were reporting
+ that it protected against some known mutagens and carcinogens. Less than 3 months before approving Zelnorm, the
+ FDA announced its Final rule [Federal Register: May 9, 2002 (Volume 67, Number 90)] "Certain Additional
+ Over-the-Counter Drug Category II and III Active Ingredients." "the stimulant laxative ingredients aloe
+ (including aloe extract and aloe flower extract) and cascara sagrada (including casanthranol, cascara
+ fluidextract aromatic, cascara sagrada bark, cascara sagrada extract, and cascara sagrada fluidextract),"
+ determining that they "are not generally recognized as safe and effective or are misbranded. This final rule is
+ part of FDA's ongoing OTC drug product review. This rule is effective November 5, 2002."Historically, the FDA
+ has ruled against traditional generic drug products when the drug industry is ready to market a synthetic
+ substitute product.In 2007, the FDA withdrew its approval for Zelnorm, but allowed it to be licensed as an
+ "Investigational New Drug." "On April 2, 2008, after more than eight months of availability, the company has
+ re-assessed the program and has made a decision to close it. Novartis is in the process of communicating
+ this decision to physicians participating in the program. Patients who had access to Zelnorm via this
+ program are instructed to discuss alternative treatment options with their physicians."Cascara and aloe
+ are not among the treatment options approved by the FDA, so cascara isn"t widely available (though anyone can
+ grow aloe plants easily). However, there is considerable interest in the drug industry in the possibility of
+ developing products based on emodin, or aloe-emodin, as anticancer or antiviral drugs. Even if it were proved to
+ be safe and effective for use as a laxative, its potential use as an alternative to extremely profitable cancer
+ and virus treatments would make it a serious threat to the drug industry.Although the standard medical journals
+ have only recently begun writing about it as a cancer treatment, emodin and related chemicals have been of
+ interest as a non-toxic way to treat cancer, allergies, and viral and bacterial diseases for a long time. In
+ 1900, Moses Gomberg demonstrated the synthesis of a stable free radical (triphenylmethyl), but for years many
+ chemists believed free radicals couldn"t exist. A student of Gomberg"s, William F. Koch, came to believe that
+ cellular respiration involved free radicals, and experimented with the metabolic effects of many organic
+ molecules, quinones of several kinds, that can form free radicals, looking for the most useful ones. For more
+ than 50 years the U.S. Government and the main medical instititutions actively fought the idea that a free
+ radical or quinone could serve as a biological catalyst to correct a wide variety of health problems. A free
+ radical has an unpaired electron. In 1944 Yevgeniy Zavoisky devised a way to measure the behavior of unpaired
+ electrons in crystals, but it was many years before it was recognized that they are essential to cellular
+ respiration. Alex Comfort demonstrated them in living tissue in 1959. By the time coenzyme Q10,
+ ubiquinone, was officially discovered, Koch had moved to Brazil to continue his work with the biological effects
+ of the quinones, including the anthraquinone compound of brazilwood, which is used as a dye. He also used a
+ naphthoquine, lapachon Although vitamin K was identified as a quinone (naphthoquinone) not long after coQ10 was found to be a ubiquitous component of the mitochondrial respiratory system, it wasn"t immediately
+ recognized as another participant in that system, interacting with coQ10.Although Koch was unable to
+ publish in any English language medical journal after 1914, his work was widely known. In the 1930s, Albert
+ Szent-Gyorgyi, following Koch"s ideas about electrons in cells, interacting with free radicals, began working on
+ the links between electronic energy and cellular movement. Since free (or relatively free) electrons absorb
+ light, Szent-Gyorgyi worked with many colorful substances. When he came to the US in 1947, and wanted to expand
+ his research, a team of professors from Harvard investigated, and told the government funding agency that his
+ work didn"t deserve support. For the rest of his life, he worked on related ideas, expanding ideas that Koch had
+ first developed.Emodin and the anthraquinones (and naphthoquinones, such as lapachone) weren"t the reagents that
+ Koch considered the most powerful, but emodin can produce to some degree all of the effects that he believed
+ could be achieved by correcting the cellular respiratory apparatus: Antiinflammatory,
+ antifibrotic (Wang, et al., 2007) antiviral, antidepressant, heart protective, antioxidant, memory enhancing,
+ anticancer, anxiolytic and possibly antipsychotic.Working backward from these effects, we get a better
+ perspective on the "laxative" function of emodin and cascara. Koch and Szent-Gyorgyi believed that cellular
+ movement and secretion were electronically regulated. In one of his demonstrations, Szent-Gyorgyi showed that
+ muscles could be caused to contract when they were exposed to two substances which, when combined, partially
+ exchange an electron, causing an intense color reaction, but without causing an ordinary chemical
+ (oxidation-reduction) reaction. This kind of reaction is called a Donor-Acceptor reaction, and it is closely
+ related to the phenomenon of semiconduction. The reacting molecules have to be exactly "tuned" to each other,
+ allowing an electron to resonate between the molecules.In a muscle, any D-A matched pair of molecules would
+ cause a contraction, but the same molecules, combined in pairs that weren"t exactly tuned to each other, failed
+ to cause contraction. Szent-Gyorgyi believed that biological signal substances operated in a similar way, by
+ adjusting the electronic balance of cellular proteins. An effective laxative (besides preventing inflammation)
+ causes not only coordinated contraction of the smooth muscles of the intestine, but also adjusts secretions and
+ absorption, so that an appropriate amount of fluid stays in the intestine, and the cells of the intestine don"t
+ become water-logged.In the presence of bacterial endotoxin, respiratory energy production fails in the cells
+ lining the intestine. Nitric oxide is probably the main mediator of this effect.The shift from respiration to
+ glycolysis, from producing carbon dioxide to producing lactic acid, involves a global change in cell functions,
+ away from specialized differentiated functioning, toward defensive and inflammatory processes.This global change
+ involves a change in the physical properties of the cytoplasm, causing a tendency to swell, and to admit
+ dissolved substances that normally wouldn"t enter the cells.The interface between the cells lining the intestine
+ and the bacteria-rich environment involves processes similar to those in cells at other interfacial situations
+ throughout the body--kidney, bladder, secretory membranes of glands, capillary cells, etc. The failure of the
+ intestinal barrier is especially dangerous, because of the generalized toxic consequences, but the principles of
+ maintaining and restoring it are general, and they have to do with the nature of life. Some leakage from the
+ lumen of the intestine or the lumen of a blood vessel can occur between cells, but it is often claimed that the
+ "paracellular" route accounts for all leakage. (Anthraquinones may inhibit paracellular leakage [Karbach &
+ Wanitschke, 1984].) When a cell is inflamed or overstimulated or fatigued, its cytoplasmic contents leak out. In
+ that state, its barrier function is weakened, and external material can leak in. This was demonstrated long ago
+ by Nasonov, but the "membrane" doctrine is incompatible with the facts, so the paracellular route is claimed to
+ explain leakage. Since the cells that form the barrier begin to form regulatory substances such as nitric oxide
+ when they are exposed to endotoxin, it is clear that major metabolic and energetic changes coincide in the cell
+ with the observed leakiness. Permeability varies with the nature of the substance, its oil and water solubility,
+ and the direction of its movement, arguing clearly that it isn"t a matter of mere holes between cells.Besides
+ endotoxin, estrogen, vibrational injury, radiation, aging, cold, and hypoosmolarity, increase NO synthesis and
+ release, and increase cellular permeabilities throughout the body. Estrogen excess (relative to progesterone and
+ androgens), as in pregnancy, stress, and aging, reduces intestinal motility, probably by increasing nitric oxide
+ production. The anthraquinones inhibit the formation of nitric oxide, which is constantly being promoted by
+ endotoxin.Cells regulate their water content holistically, and, to a great extent, autonomously, by adjusting
+ their structural proteins and their metabolism, but in the process they communicate with surrounding cells and
+ with the organism as a whole, and consequently they will receive various materials needed to improve their
+ stability, by adjusting their energy production, sensitivity, and structural composition.When these intrinsic
+ corrective processes are inadequate, as in hypothyroidism, with increased estrogen and serotonin, extrinsic
+ factors, including special foods and drugs, can reinforce the adaptive mechanisms. These "adaptogens" can
+ sometimes restore the system to perfect functioning, other times they can merely prevent further injury.
+ Sometimes the adaptogens are exactly like those the body normally has, but that are needed in larger amounts
+ during stress. Coenzyme Q10, vitamin K, short-chain fatty acids, ketoacids, niacinamide, and glycine
+ are examples of this sort--they are always present, but increased amounts can improve resistance to stress.
+ Another kind of adaptogen resembles the body"s intrinsic defensive substances, but isn"t produced in significant
+ quantities in our bodies. This type includes caffeine and the anthraquinones (such as emodin) and aspirin and
+ other protective substances from plants. These overlap in functions with some of our intrinsic regulatory
+ substances, and can also complement each other"s effects.Emodin inhibits the formation of nitric oxide,
+ increases mitochondrial respiration, inhibits angiogenesis and invasiveness, inhibits fatty acid synthase
+ (Zhang, et al., 2002), inhibits HER-2 neu and tyrosine phosphorylases (Zhang, et al., 1995, 1999), and promotes
+ cellular differentiation in cancer cells (Zhang, et al., 1995). The anthraquinones, like other antiinflammatory
+ substances, reduce leakage from blood vessels, but they also reduce the absorption of water from the intestine.
+ Reduced water absorption can be seen in a slight shrinkage of cells in certain circumsstances, and is probably
+ related to their promotion of cellular differentiation. All of these are basic antistress mechanisms, suggesting
+ that emodin and the antiinflammatory anthraquinones are providing something central to the life process
+ itself.Zelnorm was said to "act like serotonin." Serotonin slows metabolism, reduces oxygen consumption, and
+ increases free radicals such as superoxide and nitric oxide; the production of reactive oxygen
+ species is probably an essential part of its normal function. Emodin has an opposing effect, increasing the
+ metabolic rate. It increases mitochondrial oxygen consumption and ATP synthesis, while decreasing oxidative
+ damage (Du and Ko, 2005, 2006; Huang, et al., 1995).The Zelnorm episode was just an isolated case of a drug
+ company"s exploiting cultural beliefs, with the FDA providing a defensive framework, but the contrast between
+ tegaserod and emodin hints at a deeper and more deadly problem. W.F. Koch"s approach to immunity emphasized the
+ role of energy in maintaining the coherence of the organism, in which toxins were oxidized and made nontoxic.
+ There was no emphasis on destruction either of bacteria or of cancer cells, but only of the toxic factors that
+ interfered with respiration. He demonstrated that the udders of healthy cows could contain more bacteria than
+ those with mastitis, but the bacterial toxins were absent after the cows were treated with his catalyst. He
+ identified the "activated carbonyl group" as the essential feature of antibiotics, the same group that makes
+ coenzyme Q10 function in the respiratory system. Koch"s understanding of the oxidative apparatus of
+ life, as a matter of electron balances, involved the idea that molecules with a low ionization potential, making
+ them good electron donors, amines specifically, interfered with respiration, while quinones, with a high
+ affinity for electrons, making them electron acceptors, activated respiration. The toxic effects of tryptophan
+ derivatives, indoles, and other amines related to the behavior of their electrons. (Serotonin wasn"t known at
+ the time Koch was doing his basic research.) Koch believed that similar electronic functions were responsible
+ for the effects of viruses.Both chemical and physical interactions of substances cause electrons to shift in
+ each substance, according to its composition. The shift of electrons accounts for the ability of adsorbed
+ molecules or ions to form multiple layers on a surface, and changes in the electrons of a complex biological
+ molecule affect the shape and function not only of that molecule, but of the molecules associated with it.
+ Interactions of the large molecules of cells, and their adsorbed substances, tend toward stable arrangements, or
+ phases. The type of energy production, and the nature of the regulatory molecules that are present, influence
+ the stability of the various states of an organism"s cells. (For more information on cooperative adsorption, see
+ www.gilbertling.org.)Koch and Szent-Gyorgyi were
+ applying to biology and medicine concepts that were simultaneously being developed in metallurgy,
+ electrochemistry, colloid and surface science, and electronics. They were in the scientific mainstream, and it
+ was the medical-pharmaceutical industry that moved away from this kind of exploration of the interactions of
+ substances, electrons, and organisms.For Koch, antibiotics and anticancer agents weren"t necessarily distinct
+ from each other, and would be expected to have other beneficial effects as well.But an entirely different view
+ of the immune system was taking over the medical culture just as Koch began his research. Mechnikov"s
+ morphogenic view, in which the essential function of "the immune system" was to maintain the integrity of the
+ organism, was submerged by Ehrlich"s approach, which emphasized killing pathogens, and at the same time, the
+ genetic theory of cancer was replacing the developmental-environmental theory. Following the early work on the
+ carcinogenicity of estrogens, and the estrogenicity of carcinogens such as polycyclic aromatic hydrocarbons from
+ soot, a few German and French chemists (e.g., Schmidt and the Pullmans) began calculating the high electron
+ densities of highly reactive regions of the anthracene molecule, showing formally why certain molecules are
+ carcinogenic. At that time, their work was compatible with a developmental view of cancer. But the fact that the
+ polycyclic molecules could interact with the new model of the DNA gene caused the Pullmans" work to be reduced
+ to nothing but a minor theory of mutagenesis.Anthraquinones, because of the presence of several oxygen
+ molecules, had low electron densities and were stable. The tetracyclines, with related structure, have some
+ similar properties, and are antiinflammatory, as well as antibiotic. When a polycyclic bacterial antibiotic,
+ adriamycyn (later called doxorubicin), was found to be too toxic to use as an antibiotic, the fact that it was
+ toxic to cancer cells caused it to be developed as a cancer drug. It continued to be widely used even after it
+ was found to cause heart failure in many of the "cured" patients, because of its "success" in killing cancer
+ cells.The fact that many kinds of cancer cells can be killed by emodin makes it slightly interesting as a cancer
+ drug, but its simple generic nature has caused the drug industry to look for a more Ehrlichian magic bullet; for
+ example, they are still looking for ways to keep doxorubicin from destroying the heart. Emodin isn"t a magic
+ bullet (in fact it isn"t a bullet/toxin of any sort), but when combined with all the other adaptogens, it does
+ have a place in cancer therapy, as well as in treating many other ailments. None of the basic metaphors of
+ mainstream medicine--receptors, lock-and-key, membrane pores and pumps--can account for the laxative,
+ anticancer, cell-protective effects of emodin. The new interest in it provides an opportunity to continue to
+ investigate the effects of adjusting the electrical state of the cell substance, building on the foundations
+ created by William F. Koch, Albert Szent-Gyorgyi, and Gilbert Ling.
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+ pathway. Huang Q, Shen HM, Ong CN.Med Res Rev. 2007 Sep;27(5):609-30.
+ Anti-cancer properties of anthraquinones from rhubarb.
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+ Effect of anthraquinone derivatives on lipid peroxidation in rat heart mitochondria: structure-activity
+ relationship. Huang SS, Yeh SF, Hong CY.J Nat Prod. 1995 Sep;58(9):1365-71. Effect of
+ anthraquinone derivatives on lipid peroxidation in rat heart mitochondria: structure-activity
+ relationship. Huang SS, Yeh SF, Hong CY.J Nat Prod. 1995 Sep;58(9):1365-71. Effect of
+ anthraquinone derivatives on lipid peroxidation in rat heart
+ mitochondria: structure-activity relationship. Huang SS, Yeh SF, Hong CY.Eur J Pharmacol. 2006
+ Dec 28;553(1-3):46-53. Epub 2006 Sep 23. Anthraquinone derivative emodin inhibits tumor-associated
+ angiogenesis through inhibition of extracellular signal-regulated kinase 1/2 phosphorylation.
+ Kaneshiro T, Morioka T, Inamine M, Kinjo T, Arakaki J, Chiba I, Sunagawa N, Suzui M, Yoshimi N.Naunyn
+ Schmiedebergs Arch Pharmacol. 1984 Oct;327(4):336-41. Influence of serosal hydrostatic pressure on net
+ water and electrolyte transport across the isolated rat colonic mucosa exposed to different
+ secretagogues. Karbach U, Wanitschke R.Int J Oncol. 2005 Sep;27(3):839-46. Emodin
+ suppresses hyaluronic acid-induced MMP-9 secretion and invasion of glioma cells. Kim MS, Park MJ,
+ Kim SJ, Lee CH, Yoo H, Shin SH, Song ES, Lee SH.Food Chem Toxicol. 1991 Nov;29(11):765-70. Effect of
+ emodin on cooked-food mutagen activation. Lee H, Tsai SJ.Int J Mol Med. 2005 Jul;16(1):41-7.
+ Regulatory effects of emodin on NF-kappaB activation and inflammatory cytokine expression in RAW 264.7
+ macrophages.
+ Li HL, Chen HL, Li H, Zhang KL, Chen XY, Wang XW, Kong QY, Liu J.J Ocul Pharmacol Ther. 2007
+ Apr;23(2):152-71. Aloe-emodin metabolites protected N-methyl-d-aspartate-treated retinal ganglion cells
+ by Cu-Zn superoxide dismutase. Lin HJ, Lai CC, Lee Chao PD, Fan SS, Tsai Y, Huang SY, Wan L, Tsai
+ FJ.www.gilbertling.org
+ J Ethnopharmacol. 2007 Jul 25;112(3):552-6. Epub 2007 May 6. Ameliorating effect of emodin, a
+ constitute of Polygonatum multiflorum, on cycloheximide-induced impairment of memory consolidation in rats.
+ Lu MC, Hsieh MT, Wu CR, Cheng HY, Hsieh CC, Lin YT, Peng WH.Indian J Biochem Biophys. 2009
+ Feb;46(1):130-2. Alterations in plasma nitric oxide during aging in humans. Maurya PK, Rizvi
+ SI. Nitric oxide (NO) is relatively harmless, but along with superoxide radical becomes precursor of many toxic
+ species, such as peroxy and hydroxyl radicals, hydrogen peroxide, and peroxynitrite. In the present study, we
+ determined plasma NO as a function of human age and correlated NO levels with total antioxidant capacity of the
+ plasma. Results showed significant increase in NO level as a function of human age and plasma NO level
+ positively correlated with total antioxidant potential. Increased NO may contribute to the development of
+ oxidative stress during aging.World J Gastroenterol. 2005 May 21;11(19):2941-4.
+ Effects of emodin and double blood supplies on liver regeneration of reduced size graft liver in rat
+ model. Meng KW, Lv Y, Yu L, Wu SL, Pan CE.Fed Proc. 1986 Feb;45(2):84-8.
+ Contractile elements in the regulation of macromolecular permeability.
+ Miller FN, Sims DE.Microcirculation. 2006 Apr-May;13(3): 219-27. Mast cell degranulation alters
+ lymphatic contractile activity through action of histamine. Plaku KJ, von der Weid PY.Int Arch
+ Allergy Immunol. 2008;147(2):125-34. Acute allergic skin reactions and intestinal contractility changes
+ in mice orally sensitized against casein or whey. Schouten B, van Esch BC, Hofman GA, van den Elsen
+ LW, Willemsen LE, Garssen J.Circulation. 2000 Mar 21;101(11):1303-10. Profound inhibition of myogenic
+ tone in rat cardiac allografts is due to eNOS- and iNOS-based nitric oxide and an intrinsic defect in
+ vascular smooth muscle contraction. Skarsgard PL, Wang X, McDonald P, Lui AH, Lam EK, McManus BM,
+ van Breemen C, Laher I.Med Res Rev. 2007 Sep;27(5):591-608. Molecular mechanism of emodin action:
+ transition from laxative ingredient to an antitumor agent.
+ Srinivas G, Babykutty S, Sathiadevan PP, Srinivas P.Mutat Res. 1995 Jul;329(2):205-12. Emodin
+ inhibits the mutagenicity and DNA adducts induced by 1-nitropyrene. Su HY, Cherng SH, Chen CC, Lee
+ H.Talanta. 2006 Jan 15;68(3):883-7. Epub 2005 Aug 9.
+ The enhanced electrochemiluminescence of lucigenin by some hydroxyanthraquinones.
+ Su Y, Wang J, Chen G.Eur J Med Chem. 2005 Apr;40(4):321-8. Molecular basis of the low activity
+ of antitumor anthracenediones, mitoxantrone and ametantrone, in oxygen radical generation catalyzed by NADH
+ dehydrogenase.
+ Enzymatic and molecular modelling studies. Tarasiuk J, Mazerski J, Tkaczyk-Gobis K, Borowski E.
+ "It was shown that the distribution of the molecular electrostatic potential (MEP), around the quinone
+ system was crucial for this ability.
+ We have found for non-stimulating anthracenediones that the clouds of positive MEP cover the quinone
+ carbon atoms while for agents effective in stimulating reactive oxygen species formation the clouds
+ of negative MEP cover continuously the aromatic core together with the quinone system."Br J Nutr. 2008
+ Jul;100(1):130-7. Epub 2008 Feb 18. The effect of ageing with and without non-steroidal
+ anti-inflammatory drugs on gastrointestinal microbiology and immunology.Tiihonen K, Tynkkynen S,
+ Ouwehand A, Ahlroos T, Rautonen N.Crit Care Med. 2006 Oct;34(10):2630-7. Intestinal edema decreases
+ intestinal contractile activity via decreased myosin light chain phosphorylation. Uray KS, Laine
+ GA, Xue H, Allen SJ, Cox CS Jr.Planta Med. 2002 Oct;68(10):869-74. Inducible nitric oxide synthase
+ inhibitors of Chinese herbs III. Rheum palmatum. Wang CC, Huang YJ, Chen LG, Lee LT, Yang LL.World
+ J Gastroenterol. 2007 Jan 21;13(3):378-82. Effect of emodin on pancreatic fibrosis in rats.
+ Wang CH, Gao ZQ, Ye B, Cai JT, Xie CG, Qian KD, Du Q.Eur J Pharmacol. 1995 Jan 5;272(1):87-95. Inhibition of hind-paw edema and cutaneous vascular plasma extravasation in mice by acetylshikonin.
+ Wang JP, Raung SL, Chang LC, Kuo SC.Yao Xue Xue Bao. 2004 Apr;39(4):254-8. Inhibitory effects
+ of emodin on angiogenesis.
+ Wang XH, Wu SY, Zhen YS.Pharmacology. 1988;36 Suppl 1:98-103. Influence of rhein on rat colonic
+ Na+,K+-ATPase and permeability in vitro. Wanitschke R, Karbach U.Am J Physiol Gastrointest Liver
+ Physiol. 2006 Oct;291(4):G566-74. Contractile activity of lymphatic vessels is altered in the TNBS model
+ of guinea pig ileitis. Wu TF, Carati CJ, Macnaughton WK, von der Weid PY.Mem Inst Oswaldo Cruz.
+ 2005 Mar;100 Suppl 1:107-10. Lymphatic vessel contractile activity and intestinal inflammation.
+ Wu TF, MacNaughton WK, von der Weid PY.Life Sci. 2007 Oct 13;81(17-18):1332-8. Emodin-mediated
+ protection from acute myocardial infarction via inhibition of inflammation and apoptosis in local ischemic
+ myocardium.
+ Wu Y, Tu X, Lin G, Xia H, Huang H, Wan J, Cheng Z, Liu M, Chen G, Zhang H, Fu J, Liu Q, Liu DX.Zhonghua
+ Gan Zang Bing Za Zhi. 2001 Aug;9(4):235-6. [Effects of emodin on hepatic fibrosis in rats]
+ [Article in Chinese] Zhan Y, Wei H, Wang Z, Huang X, Xu Q, Li D, Lu H.Chin Med J (Engl). 2002
+ Jul;115(7):1035-8. Effect of emodin on proliferation and differentiation of 3T3-L1 preadipocyte and FAS
+ activity. Zhang C, Teng L, Shi Y, Jin J, Xue Y, Shang K, Gu J.Cancer Res. 1995 Sep 1;55(17):3890-6.
+ Suppressed transformation and induced differentiation of HER-2/neu-overexpressing breast cancer cells by
+ emodin.
+ Zhang L, Chang CJ, Bacus SS, Hung MC.Oncogene. 1996 Feb 1;12(3):571-6. Sensitization of
+ HER-2/neu-overexpressing non-small cell lung cancer cells to chemotherapeutic drugs by tyrosine kinase
+ inhibitor emodin.Zhang L, Hung MC.Clin Cancer Res. 1999 Feb;5(2):343-53. Tyrosine kinase
+ inhibitor emodin suppresses growth of HER-2/neu-overexpressing breast cancer cells in athymic mice and
+ sensitizes these cells to the inhibitory effect of paclitaxel. Zhang L, Lau YK, Xia W, Hortobagyi
+ GN, Hung MC.J Surg Res. 2006 Mar;131(1):80-5. Epub 2005 Nov 3.
+ Effects of emodin on Ca2+ signal transduction of smooth muscle cells in multiple organ dysfunction
+ syndrome. Zheyu C, Qinghui QI, Lixin L, Tao MA, Xu J, Zhang L, Lunan Y.Tohoku J Exp Med. 2008
+ May;215(1):61-9. Emodin promotes atherosclerotic plaque stability in fat-fed apolipoprotein E-deficient
+ mice. Zhou M, Xu H, Pan L, Wen J, Guo Y, Chen K.
+
+ © Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com
+
+
+
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+ Cataracts: water, energy, light, and aging Because of the baby boom
+ population bulge, the market for cataract surgery and the little plastic intraocular lenses is growing
+ wonderfully. According to the World Health Organization, there were about 20 million cataract surgeries
+ performed in 2010, with 32 million expected in 2020. In the US, about 3 million cataract surgeries are
+ performed annually. Revenue from sale of the intraocular lenses in the US alone was $775,000,000 in 2010,
+ and is expected to reach $965,000,000 by 2017. In 2010, the Alcon company earned $1,200,000,000 from one
+ type of intraocular lens. (Market Research.com) To promote the sale of the "premium'" lenses, which cost
+ thousands of dollars, patients are told that the more expensive lenses will save them money in the long run,
+ by making ordinary glasses unnecessary (sometimes).
+
+
+ The lens replacement surgery is now sometimes recommended when a cataract has caused only a slight
+ decrease in visual acuity, or even a suspected decrease in acuity. I haven't known anyone who had the
+ surgery who had been informed of the incidence of complications of the surgery, which result in
+ permanent blindness for thousands of the patients every year.
+ Some of the causes of cataracts have been known for many years, but the knowledge is usually ignored
+ by the medical profession. Medical myths about the causes of disease support present practices. Myths
+ about the causes of cancer, heart failure, hypertension, menopause, osteoporosis, sarcopenia,
+ depression, dementia, and cataracts are designed to reinforce each other, forming an interlocking
+ system, an ideology of the organism.
+ The conventional ideology identifies pathological cells and defective proteins and bad genes as the
+ causes of organ failure and disease, and "aging" is seen as a dimension in which entropy tends to
+ increase those defects.
+ This ideology discourages thoughts of "field" effects in which the function of a molecule, a cell, or
+ an organ affects, and is affected by, things that aren't in direct contact with it. This is why the
+ removal of a lens is treated so casually. There is some knowledge about the effects of systemic disease
+ on the eye, but very little about the effects of particular parts of the eye on systemic physiology, and
+ relatively few physicians are aware of the effects of one part of the eye on the other parts of the eye.
+ A few of these physiological interactions within the eye are very interesting. For example, injury to
+ the lens powerfully stimulates regeneration of nerves in the retina (Fischer, et al., 2000). Things
+ which injure the lens enough to cause cataracts to develop might also be injuring the retina, but the
+ emission of stimulating substances from the lens must be a compensating influence.
+ Every normal tissue of the eye is emitting substances that affect other parts of the eye, and probably
+ other parts of the body. Until the 1970s, the literature was dominated by the view that the lens was a
+ lifeless material, like hair and toenails, and even in 2013 there is great reluctance of researchers to
+ recognize its vital cellular activity.
+ After an artificial lens has been implanted, there are great changes in the vitreous humor (which
+ fills the space between the retina and the lens), with a reversal of the gradient of viscosity, and with
+ changes in many proteins, including transthyretin, alpha antitrypsin, retinoic acid binding protein,
+ antioxidant proteins, and the enzymes carbonic anhydrase and triosephosphate isomererase (Neal, et al.,
+ 2005).
+ I haven't seen any recent studies of the effects of lens removal on the nervous system, but a 1953
+ study of 21 patients reported a high percentage of behavioral disturbances following the surgery:
+ "Following the operation 20 patients showed some alteration in behavior including changes in mood,
+ psychomotor disturbances, paranoid and somatic delusions, hallucinations, disorientation and
+ confabulations. In 3 cases the disturbance was characterized as severe." "It is concluded that disturbed
+ behavior is an integral part of the reaction of almost all cataract patients because of a complex
+ interaction of a number of factors" (Linn, et al., 1953).
+ In animal studies, when the lens capsule is closed after removal of the lens, within a few weeks a
+ well formed lens has regenerated (Gwon, et al., 1993); cell division is stimulated in the cells
+ remaining attached to the capsule, similar to the regeneration of the adrenal cortex after its
+ removal.
+ Artificial replacement lenses are designed (with an ultrasharp edge) to block the regenerative
+ migration of cells within the capsule, because the cells can quickly form a new cataract behind the
+ plastic lens; those cataracts commonly form in reaction to the lens. The use of arsenic to kill these
+ cells has been proposed, and probably used (Zhang, et al., 2010).
+ The easy money in lens surgery has obviously discouraged professional interest in preventing
+ cataracts, or curing them, or stimulating the regeneration of new lenses. Research in the prevention of
+ cataracts has encountered serious barriers to performing the clinical trials that would be necessary for
+ approval. "… Clinicians have even developed the opinion that lens and cataract research is
+ no longer necessary to overcome cataract blindness." (Sasaki, et al., 2000.) However, it isn't
+ inconceivable that someone could find a way to make prevention, cure, or regeneration significantly
+ remunerative.
+ Although the lens has no blood supply, fluid carrying nutrients and oxygen is constantly flowing
+ through it, providing the cells with glucose, amino acids, and ATP, that it uses for maintaining its
+ structure. Its proteins are being renewed continually, broken down and synthesized (Ozaki, et al.,
+ 1985). There is clear evidence that some of the core cells retain a nucleus, and that large molecules
+ can move between cells (Lieska, et al., 1992; Shestopalov and Bassnett, 2000; Stewart, 2008; Mathias and
+ Rae, 2004). Despite this evidence, prominent researchers are still promoting the paradigm of inertness,
+ the lens as analogous to a toenail. As in other cells, ATP maintains the proper water content in the
+ cells. Besides providing energy and amino acids, the circulating fluid carries minerals and many
+ hormones and regulatory substances.
+ The absence of a blood supply to the lens has kept people from thinking of its pathology in terms of
+ the inflammatory processes that are now recognized in other conditions, for example in dementia, heart
+ disease, and cancer, but the same basic processes can be seen in the development of cataracts. Improved
+ knowledge of lens physiology is very likely to lead to major improvements in therapies for the other
+ conditions. In the lens, the state of water changes before there is any other evidence that a cataract
+ is developing (Mori, 1993); detecting similar water changes in other tissues might improve diagnosis and
+ treatment of other problems. Things that acutely lower the ATP content of cells increase their water
+ content, and in the process, the water functions differently, becoming more randomly
+ arranged.
+ The idea that the properties of water change as cell functions change contradicts the common
+ reductionist assumption that water is just the medium in which molecular interactions occur. Since
+ Kelvin's 1858 demonstration that the heat capacity of water changes with its shape, and Drost-Hansen's
+ demonstrations that its density decreases near surfaces, attention to the physical properties of water
+ has made it possible to understand many biological mysteries, such as the decrease of volume (Abbott and
+ Baskin, 1962) when a nerve or muscle cell is excited. Although the invention of the MRI grew directly
+ from Damadian's understanding of water's centrality to biology's most important issues, the technology's
+ most important contributions, related to changes in water structure, haven't been recognized,
+ understood, or assimilated by medicine.
+ The electrical properties of the protein framework of a cell interact with the state of the water in
+ the cell, and with the things dissolved in the water, including phosphate, calcium, sodium, and
+ potassium. Actin, one of the major muscle proteins, forms a meshwork in the cytoplasm of lens fiber
+ cells, and myosin, the other major muscle protein, has been found in association with the actin
+ (Al-Ghoul, et al., 2010). ATP (alternating with ADP+inorganic phosphate) is involved in muscle
+ contraction and relaxation, and it is involved in the conversion of actin from a filament into a
+ globular form. Changes in the amount of ATP and ADP are important for influencing the interactions of
+ water and proteins.
+ The actin skeleton is involved in the fiber cell's elongation as it develops from a roundish
+ epithelial cell, and it's probably responsible for the ability of lens cells to contract when stimulated
+ (Oppitz, et al., 2003; Andjelica, et al., 2011). These muscle-like effects of actin are believed to be
+ responsible for the movement of organelles and other cell motion, such as cytoplasmic streaming. But, as
+ a major part of the cell's structure, it could also be expected to act as the framework for
+ electroosmotic flow of water, accounting for the circulation that maintains the cell's energy. The
+ observed static electrical properties of lens cell fragments could account for a complete daily renewal
+ of the fluid (Pasquale, et al., 1990), but the metabolic gradients in whole cells would probably cause
+ faster flow.
+ With oxidative energy production occurring in the surface cells, an electrical gradient will be
+ created, causing water to flow away from the site of respiration. (Electroosmosis probably also accounts
+ for the somewhat mysterious exit of water from the eyeball and brain, in perivascular flow.) The flow of
+ water through these cells is very fast, but Ichiji Tasaki has demonstrated similarly fast movement of
+ water in nerves and artificial polymers in association with electrical activity (2002; Tasaki and Iwasa,
+ 1981, 1982; Iwasa, et al., 1980).
+ At least since Gullstrand's unfounded assertions in his 1911 Nobel lecture, it has been assumed that
+ the lens, like a water-filled balloon, keeps the same volume when it flattens, for distant focus.
+ Zamudio, et al. (2008), have shown that "…the lens volume decreases as the lens flattens during
+ unaccommodation." "The lens volume always decreases as the lens flattens." They determined that "…the
+ changes in lens volume, as reflected by the speed of the equatorial diameter recovery in
+ in vitro
+ cow and rabbit lenses during simulated accommodation, occurred within a physiologically relevant time
+ frame (200 ms), implying a rapid movement of fluid to and from the lens during accommodation." This is
+ the duration of the action potential of healthy heart muscle, though it's probably not as fast as the
+ very superficial changes that Tasaki saw in nerves. It's the sort of change rate that could be expected
+ in an organ whose change of shape is the result of stimulation. Accommodation, with this immediate
+ hydration, is produced by cholinergic stimulation, and in the healthy lens this hydration is rapidly
+ reversible, as the stimulating acetylcholine disappears and the lens flattens.
+ The failing heart muscle, unable to relax fully, becomes harder as its water content increases, and
+ cancer cells, locked into a contracted excited state, become stiffer as their water content increases.
+ Similarly, cataracts have been described as more rigid than normal lens tissue (Heys and Truscott, 2008;
+ Hu, et al., 2000), yet their water content is higher (Racz, et al., 2000). Along with the increased
+ water, the stressed cells take up very large amounts of calcium, and sodium increases while potassium
+ decreases. Inorganic phosphate increases in the stressed cells, some of it entering with the circulating
+ fluid, but some of it produced from the ATP which is decreasing. Serotonin, iron, lipid peroxidation
+ products, nitric oxide, and prostaglandin are also increased. The increased calcium activates
+ proteolytic enzymes that break down protein.
+ In the failing heart and growing tumors, there is an increase in the quantity and the cross-linking of
+ collagen in the extracellular matrix, contributing to the overall hardness, besides the contracted state
+ of the cells themselves. In the cataract, cross-linking of various proteins, including collagen, also
+ seems to be involved in the problem, along with the altered state of the water (Mishra, et al., 1997;
+ Eldred, et al., 2011). The cross-linking enzyme transglutaminase is induced by stressors such as
+ ultraviolet light which produce cataracts.
+ When the available energy doesn't meet the cell's energy requirements, if the cell isn't quickly
+ killed by the stress it will use some adaptive mechanisms, stopping some repair processes to reduce
+ energy expenditure, possibly stopping specialized functions to reduce energy needs. Fibrotic changes
+ occur as a result of defensive reactions in stressed cells, usually following long periods of fatigue
+ and inflammation. Cortisol generally protects cells by blocking over-stimulation and providing increased
+ material for energy and repair, but it can kill cells (nerve cells and thymus cells) that depend on
+ glucose oxidation, leading to immunodeficiency and excitotoxic brain damage. The glucose-dependent lens
+ fiber cells express the same glucose transporters, GLUT1 and GLUT3, as the brain, and the "nerve
+ specific" GLUT3 is concentrated in the dense nucleus of the lens (Donaldson, et al., 2003). Exposure to
+ excessive cortisol or hypoglycemia is able to quickly produce cataracts, showing the basic importance of
+ glucose metabolism for lens health.
+ Oxidative metabolism in the surface cells is probably largely responsible for the streaming of fluid
+ through the fiber cells, providing some ATP and the nutrients that allow the fiber cells to maintain and
+ repair their structure, but I suspect that local metabolism of glucose by the fiber cells provides most
+ of the energy for keeping the protein-water system in its orderly relaxed state.
+ The aging lens, like all normal tissues, is drier, has a lower water content, than younger tissues,
+ but when a cataract begins to develop, there is a sharp increase in the water content in that area,
+ something that happens in any excited or fatigued tissue. (In a stimulated nerve or muscle, for example,
+ although in a closed system there would be a slight decrease in volume as its water becomes relatively
+ randomized, there is normally a sudden absorption of water from the extracellular space, where the water
+ has the same random organization.) With the decreasing energy charge of the cell, represented by
+ decreasing ATP and increasing ADP and inorganic phosphate, the long range order of the water decreases,
+ changing the activity of enzymes in a variety of ways, for example by the exchange of a high magnesium
+ content for a high calcium content. While the renewal of proteins decreases because of an energy
+ deficit, the activation of proteolytic enzymes by calcium degrades the cell architecture and the
+ crystallin that makes up about 90% of the cell's protein, and these damaged proteins become
+ progressively cross-linked, in a process analogous to the cross-linking of collagen in sun-damaged skin,
+ or in cancer or a fibrotic failing heart.
+ The diffusion of water in these congested cataract areas becomes random, more like ordinary bulk
+ water, and it's likely that this randomization of the water, along with the architectural
+ disorganization of proteins and changing electrical fields, impedes the longitudinal flow of nourishing
+ fluid through the lens. MRI studies show relatively free diffusion of water longitudinally in the lens
+ fiber cells from front to back, but not transversely (Moffat and Pope, 2002). Water that's highly
+ ordered by nearby surfaces can still be very mobile parallel to the surface.
+ The parasympathetic nerve transmitter acetylcholine is formed in the lens, as well as its receptor and
+ the enzyme which destroys it, cholinesterase. Chemicals that inhibit cholinesterase, and drugs that
+ mimic the action of acetylcholine on the receptor, cause cataracts. These drugs (Michon and Kinoshita,
+ 1968; Harkonen and Tarkkanen, 1976) cause the lens to take up water, sodium, and calcium, and to lose
+ potassium, and by increasing the cells' energy expenditure, they accelerate the consumption of glucose
+ while blocking other metabolism. Since these are known effects of stimulation by acetylcholine, it's
+ reasonable to assume that acetylcholine is involved in the natural formation of cataracts.
+ Besides the direct excitatory effects of acetylcholine, the increase of intracellular calcium and
+ decrease of magnesium (Agarwal, et al., 2012) caused by it promote the synthesis of nitric oxide (which,
+ for example, blocks the function of cytochrome oxidase, reducing the production of ATP), and the
+ interference with glucose metabolism in itself is cataractogenic (Greiner, et al., 1981).
+ Ultraviolet light powerfully stimulates the formation of nitric oxide (Chaudhry, et al., 1993), and is
+ one of the known causes of cataracts. Since the cornea is more directly exposed than the lens to the
+ ultraviolet rays of sunlight, the effects of injury can be seen more quickly. Exposure of the cornea to
+ ultraviolet light causes swelling, reduced transparency, and the formation of nitric oxide, which enters
+ the aqueous humor (Cejka, et al., 2012; Cejkova, et al., 2005). Swelling in itself, regardless of the
+ cause, decreases the transparency of the cornea (Stevenson, et al., 1983); anything interfering with its
+ energy metabolism causes swelling.
+ The blue color of ordinary water is caused by its absorption of red light, possibly by its hydrogen
+ bonds (Braun and Smirnov, 1993), but there haven't been many studies of the physical effects of red
+ light on water itself. Since water absorbs much more strongly in the infrared wavelengths, there is a
+ tendency to explain the benefits of sunlight by its infrared rays. Red and orange wavelengths penetrate
+ tissue very effectively, because of their weaker absorption by water, allowing them to react with
+ pigments in the cell, such as cytochrome oxidase, which is activated (or re-activated) by red light,
+ increasing the production of ATP. This effect counteracts the toxic effects of ultraviolet light, but
+ there are probably other mechanisms involved in the many beneficial effects of red light.
+ Recent work by a group at the University of Ulm in Germany (Andrei Sommer, et al., 2011) has revealed
+ an effect of red light (670 nm) on water that I think helps to explain some of its protective and
+ restorative actions. Shining laser light onto layers of water adsorbed on a solid surface, they were
+ able to show "a breathing-like volume expansion of the topmost sheets of water molecules." They explain
+ this as the result of a stabilization of a more ordered state of the hydrogen bonds of the water. They
+ are applying this to chemotherapy, since the expansion of water in the cell where much of the water is
+ in adsorbed layers similar to their experimental set-up, alternating with its volume contraction as the
+ light is pulsed, causes water to move in and out of the cell quickly, taking some of the drug with it.
+ They have also proposed that degenerative changes in the connective tissues involve a loss of ordered
+ water, and have experimented with light treatments to restore elasticity and flexibility.
+ Since the water in cataracts is in a less ordered state than in the transparent lens, the re-ordering
+ effect of red light could be valuable, and if the effects are the same as in their experiments with
+ cancer cells, the increased volume of the re-ordered water would cause a movement of water out of the
+ cataract, as it does in cancer cells in their experiment. And the known restorative effect of red light
+ on oxidative production of ATP would almost certainly be helpful.
+ Among the popular medical treatments that are likely to contribute to the development of cataract are
+ glucocorticoids, and drugs that increase serotonin (Dietze and Tilgner, 1973; Korsakova and Sergeeva,
+ 2010), and drugs that increase nitric oxide. Free fatty acids are toxic to the lens, which contains the
+ enzymes for synthesizing prostaglandins and related promoters of inflammation; the products of lipid
+ peroxidation are increased in people with cataracts. Endotoxin from the intestine increases the
+ formation of nitric oxide, so it's essential to minimize intestinal inflammation.
+ High altitude very strongly protects against cataracts (Brilliant, et al., 1983). Low oxygen tension
+ itself protects the lens's clarity (Akoyev, et al., 2009), possibly by the protective effect of
+ increased carbon dioxide against glycation of protein amino groups. Aspirin's known anticataract effect
+ apparently involves a similar protection of crystallin against glycation, but aspirin has several other
+ protective effects, including prevention of protein cross-linking, and the inhibition of the synthesis
+ of nitric oxide and prostaglandins and other disruptive materials (Crabbe, 1998; Beachy, et al., 1987;
+ Lonchampt, et al., 1983). Progesterone's inhibition of nitric oxide production is probably protective
+ for the lens, paralleling its effects in other organs. Inhibitors of nitric oxide, such as
+ aminoguanidine, are protective. Anticholinergics, including atropine, inhibit over-hydration of the lens
+ and prevent cataracts caused by excessive cholinergic stimulation (e.g., Kaufman, et al., 1977).
+ Caffeine, in animal experiments, prevents cataracts. Uric acid, which inhibits nitric oxide formation,
+ is reduced in people with cataracts. The factors that prevent or promote other degenerative diseases are
+ similarly protective or harmful for the lens.
+ REFERENCES
+ J Physiology 1962; 161, 379-391. Volume changes in frog muscle during contraction. Abbott C &
+ Baskin RJ.
+ Exp Eye Res. 2012 Aug;101:82-9. Magnesium deficiency: does it have a role to play in cataractogenesis?
+ Agarwal R, Iezhitsa I, Agarwal P, Spasov A.
+ Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1271-82. Hypoxia-regulated activity of PKCepsilon in the
+ lens. Akoyev V, Das S, Jena S, Grauer L, Takemoto DJ.
+ Anat Rec (Hoboken). 2010 Nov;293(11):1805-15. A novel terminal web-like structure in cortical lens
+ fibers: architecture and functional assessment. Al-Ghoul KJ, Lindquist TP, Kirk SS, Donohue ST.
+ Acta Ophthalmol. 2011 Dec;89(8):e645-53. Human anterior lens capsule epithelial cells ontraction.
+ Andjelic S, Zupancic G, Perovšek D, Hawlina M.
+ Prostaglandins Leukot Med. 1983 Apr;10(4):381-7. Evidence of leukotriene B4 biosynthesis in epithelial
+ lens cells. Lonchampt MO, Bonne C, Regnault F, Massé JP, Coquelet C, Sincholle D.
+ Photochem Photobiol. 1987 May;45(5):677-8. Photoperoxidation of lens lipids: inhibition by aspirin.
+ Beachy NA, Morris SM, Richards RD, Varma SD.
+ J. Chem. Edu., 1993, 70(8), 612, Why is water blue? Braun CL and Smirnov SN.
+ Ophthalmic Physiol Opt. 1983;3(1):33-9. Corneal transparency changes resulting from osmotic stress.
+ Stevenson R, Vaja N, Jackson J.
+ Am J Epidemiol. 1983 Aug;118(2):250-64. Associations among cataract prevalence, sunlight hours, and
+ altitude in the Himalayas. Brilliant LB, Grasset NC, Pokhrel RP, Kolstad A, Lepkowski JM, Brilliant GE,
+ Hawks WN, Pararajasegaram R.
+ Cell Mol Biol (Noisy-le-grand). 1998 Nov;44(7):1047-50. Cataract as a conformational disease--the
+ Maillard reaction, alpha-crystallin and chemotherapy. Crabbe MJ.
+ Clin Exp Pharmacol Physiol. 2004 Dec;31(12):890-5. Functional imaging: new views on lens structure and
+ function. Donaldson PJ, Grey AC, Merriman-Smith BR, Sisley AM, Soeller C, Cannell MB, Jacobs MD.
+ Physiol Res. 2012 Jul 20;61(3):299-306. Central corneal thickness considered an index of corneal
+ hydration of the UVB irradiated rabbit cornea as influenced by UVB absorber. Cejka C, Luyckx J, Cejkova
+ J.
+ Histol Histopathol. 2005 Apr;20(2):467-73. Irradiation of the rabbit cornea with UVB rays stimulates
+ the expression of nitric oxide synthases-generated nitric oxide and the formation of cytotoxic
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+ laser radiation. Chaudhry H, Lynch M, Schomacker K, Birngruber R, Gregory K, Kochevar I.
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+ different types of human age-related cataract].[Article in Russian]Korsakova NV, Sergeeva VE.
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+ Arch Ophthalmol. 1968 Jan;79(1):79-86. Experimental miotic cataract. I. Effects of miotics on lens
+ structure, cation content, and hydration. Michon J Jr, Kinoshita JH.
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+ cataract]. Mori K.
+ Toxicology. 2007 Dec 5;242(1-3):7-15. Adverse effects of excessive nitric oxide on cytochrome c
+ oxidase in lenses of hereditary cataract UPL rats. Nagai N, Ito Y.
+ Invest Ophthalmol Vis Sci. 2003 Nov;44(11):4813-9. Ca2+-mobilization and cell contraction after
+ muscarinic cholinergic stimulation of the chick embryo lens. Oppitz M, Mack A, Drews U.
+ Exp Eye Res. 1992 May;54(5):807-11. A reassessment of protein synthesis by lens nuclear fiber cells.
+ Lieska N, Krotzer K, Yang HY.
+ Exp Eye Res. 2004 Mar;78(3):689-98. The lens: local transport and global transparency. Mathias RT, Rae
+ JL.
+ Exp Eye Res. 2002 Jun;74(6):677-87. Anisotropic water transport in the human eye lens studied by
+ diffusion tensor NMR micro-imaging. Moffat BA, Pope JM.
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+ Ozaki L, Jap P, Bloemendal H.
+ Biophys J. 1990 Oct;58(4):939-45. Electrostatic properties of fiber cell membranes from the frog lens.
+ Pasquale LR, Mathias RT, Austin LR, Brink PR, Ciunga M.
+ Exp Eye Res. 2000 Apr;70(4):529-36. 1H spin-spin relaxation in normal and cataractous human, normal
+ fish and bird eye lenses. Racz P, Hargitai C, Alfoldy B, Banki P, Tompa K.
+ Ophthalmologica. 2000;214(6):390-8. High hurdle of clinical trials to demonstrate efficacy of
+ anticataractogenic drugs. Sasaki K, Hockwin O, Sakamoto Y, Sasaki H, Kojima M.
+ J Cell Sci. 2000 Jun;113 ( Pt 11):1913-21. Expression of autofluorescent proteins reveals a novel
+ protein permeable pathway between cells in the lens core. Shestopalov VI, Bassnett S.
+ J. Phys. Chem. Lett. 2011, 2, 562565, Breathing Volume into Interfacial Water with Laser Light, Sommer
+ AP, Hodeck KF, Zhu D, Kothe A, Lange KM, Fecht H-J, Aziz EF.
+ Mol Vis. 2013;19:463-75. Carbon turnover in the water-soluble protein of the adult human lens.
+ Stewart DN, Lango J, Nambiar KP, Falso MJ, FitzGerald PG, Rocke DM, Hammock BD, Buchholz BA.
+ D.N.Stewart, 2008 dissertation UC Davis, Existence of protein turnover in adult human nuclear fiber
+ cells.
+ J Theor Biol 218(4): 497-505, Oct 2002. Spread of discrete structural changes in synthetic
+ polyanionic gel: a model of propagation of a nerve impulse. Tasaki I.
+ J Physiol (Paris) 77: 1055-1059, 1981. Rapid mechanical changes in crab nerve and squid axon during
+ action potentials. Tasaki I and Iwasa K.
+ Ups J Med Sci. 1980;85(3):211-5. Swelling of nerve fibers during action potentials. Tasaki I, Iwasa
+ K.
+ Science 210: 338-339, 1980. Swelling of nerve fibers associated with action potentials. Iwasa K,
+ Tasaki, I, and Gibbons RC.
+ Am J Physiol Cell Physiol. 2008 Jun;294(6):C1430-5. Surface change of the mammalian lens during
+ accommodation. Zamudio AC, Candia OA, Kong CW, Wu B, Gerometta R.
+ Zhonghua Yan Ke Za Zhi. 2000 Sep;36(5):337-40. [The nuclear hardness and associated factors of
+ age-related cataract]. [Article in Chinese] Hu C, Zhang X, Hui Y.
+
+
+ © Ray Peat Ph.D. 2014. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Coconut Oil
+
+
+ Coconut Oil
+
+
+
+ I have already discussed the many toxic effects of the unsaturated oils, and I have frequently mentioned
+ that coconut oil doesn't have those toxic effects, though it does contain a small amount of the unsaturated
+ oils. Many people have asked me to write something on coconut oil. I thought I might write a small book on
+ it, but I realize that there are no suitable channels for distributing such a book--if the seed-oil industry
+ can eliminate major corporate food products that have used coconut oil for a hundred years, they certainly
+ have the power to prevent dealers from selling a book that would affect their market more seriously. For the
+ present, I will just outline some of the virtues of coconut oil.
+
+
+ The unsaturated oils in some cooked foods become rancid in just a few hours, even at refrigerator
+ temperatures, and are responsible for the stale taste of left-over foods. (Eating slightly stale food isn't
+ particularly harmful, since the same oils, even when eaten absolutely fresh, will oxidize at a much higher
+ rate once they are in the body, where they are heated and thoroughly mixed with an abundance of oxygen.)
+ Coconut oil that has been kept at room temperature for a year has been tested for rancidity, and showed no
+ evidence of it. Since we would expect the small percentage of unsaturated oils naturally contained in
+ coconut oil to become rancid, it seems that the other (saturated) oils have an antioxidative effect: I
+ suspect that the dilution keeps the unstable unsaturated fat molecules spatially separated from each other,
+ so they can't interact in the destructive chain reactions that occur in other oils. To interrupt
+ chain-reactions of oxidation is one of the functions of antioxidants, and it is possible that a sufficient
+ quantity of coconut oil in the body has this function. It is well established that dietary coconut oil
+ reduces our need for vitamin E, but I think its antioxidant role is more general than that, and that it has
+ both direct and indirect antioxidant activities.
+
+
+ Coconut oil is unusually rich in short and medium chain fatty acids. Shorter chain length allows fatty acids
+ to be metabolized without use of the carnitine transport system. Mildronate, which I discussed in an article
+ on adaptogens, protects cells against stress partly by opposing the action of carnitine, and comparative
+ studies showed that added carnitine had the opposite effect, promoting the oxidation of unsaturated fats
+ during stress, and increasing oxidative damage to cells. I suspect that a degree of saturation of the
+ oxidative apparatus by short-chain fatty acids has a similar effect--that is, that these very soluble and
+ mobile short-chain saturated fats have priority for oxidation, because they don't require carnitine
+ transport into the mitochondrion, and that this will tend to inhibit oxidation of the unstable,
+ peroxidizable unsaturated fatty acids.
+
+
+ When Albert Schweitzer operated his clinic in tropical Africa, he said it was many years before he saw any
+ cases of cancer, and he believed that the appearance of cancer was caused by the change to the European type
+ of diet. In the l920s, German researchers showed that mice on a fat-free diet were practically free of
+ cancer. Since then, many studies have demonstrated a very close association between consumption of
+ unsaturated oils and the incidence of cancer.
+
+
+
+ Heart damage is easily produced in animals by feeding them linoleic acid; this "essential" fatty acid turned
+ out to be the heart toxin in rape-seed oil. The addition of saturated fat to the experimental heart-toxic
+ oil-rich diet protects against the damage to heart cells.
+
+
+ Immunosuppression was observed in patients who were being "nourished" by intravenous emulsions of "essential
+ fatty acids," and as a result coconut oil is used as the basis for intravenous fat feeding, except in
+ organ-transplant patients. For those patients, emulsions of unsaturated oils are used specifically for their
+ immunosuppressive effects.
+
+
+ General aging, and especially aging of the brain, is increasingly seen as being closely associated with
+ lipid peroxidation.
+
+
+
+ Several years ago I met an old couple, who were only a few years apart in age, but the wife looked many
+ years younger than her doddering old husband. She was from the Philippines, and she remarked that she always
+ had to cook two meals at the same time, because her husband couldn't adapt to her traditional food. Three
+ times every day, she still prepared her food in coconut oil. Her apparent youth increased my interest in the
+ effects of coconut oil.
+
+
+ In the l960s, Hartroft and Porta gave an elegant argument for decreasing the ratio of unsaturated oil to
+ saturated oil in the diet (and thus in the tissues). They showed that the "age pigment" is produced in
+ proportion to the ratio of oxidants to antioxidants, multiplied by the ratio of unsaturated oils to
+ saturated oils. More recently, a variety of studies have demonstrated that ultraviolet light induces
+ peroxidation in unsaturated fats, but not saturated fats, and that this occurs in the skin as well as in
+ vitro. Rabbit experiments, and studies of humans, showed that the amount of unsaturated oil in the diet
+ strongly affects the rate at which aged, wrinkled skin develops. The unsaturated fat in the skin is a major
+ target for the aging and carcinogenic effects of ultraviolet light, though not necessarily the only one.
+
+
+ In the l940s, farmers attempted to use cheap coconut oil for fattening their animals, but they found that it
+ made them lean, active and hungry. For a few years, an antithyroid drug was found to make the livestock get
+ fat while eating less food, but then it was found to be a strong carcinogen, and it also probably produced
+ hypothyroidism in the people who ate the meat. By the late l940s, it was found that the same antithyroid
+ effect, causing animals to get fat without eating much food, could be achieved by using soy beans and corn
+ as feed.
+
+
+ Later, an animal experiment fed diets that were low or high in total fat, and in different groups the fat
+ was provided by pure coconut oil, or a pure unsaturated oil, or by various mixtures of the two oils. At the
+ end of their lives, the animals' obesity increased directly in proportion to the ratio of unsaturated oil to
+ coconut oil in their diet, and was not related to the total amount of fat they had consumed. That is,
+ animals which ate just a little pure unsaturated oil were fat, and animals which ate a lot of coconut oil
+ were lean.
+
+
+ In the l930s, animals on a diet lacking the unsaturated fatty acids were found to be "hypermetabolic."
+ Eating a "normal" diet, these animals were malnourished, and their skin condition was said to be caused by a
+ "deficiency of essential fatty acids." But other researchers who were studying vitamin B6 recognized the
+ condition as a deficiency of that vitamin. They were able to cause the condition by feeding a fat-free diet,
+ and to cure the condition by feeding a single B vitamin. The hypermetabolic animals simply needed a better
+ diet than the "normal," fat-fed, cancer-prone animals did.
+
+
+ G. W. Crile and his wife found that the metabolic rate of people in Yucatan, where coconut is a staple food,
+ averaged 25% higher than that of people in the United States. In a hot climate, the adaptive tendency is to
+ have a lower metabolic rate, so it is clear that some factor is more than offsetting this expected effect of
+ high environmental temperatures. The people there are lean, and recently it has been observed that the women
+ there have none of the symptoms we commonly associate with the menopause.
+
+
+
+ By l950, then, it was established that unsaturated fats suppress the metabolic rate, apparently creating
+ hypothyroidism. Over the next few decades, the exact mechanisms of that metabolic damage were studied.
+ Unsaturated fats damage the mitochondria, partly by suppressing the repiratory enzyme, and partly by causing
+ generalized oxidative damage. The more unsaturated the oils are, the more specifically they suppress tissue
+ response to thyroid hormone, and transport of the hormone on the thyroid transport protein.
+
+
+ Plants evolved a variety of toxins designed to protect themselves from "predators," such as grazing animals.
+ Seeds contain a variety of toxins, that seem to be specific for mammalian enzymes, and the seed oils
+ themselves function to block proteolytic digestive enzymes in the stomach. The thyroid hormone is formed in
+ the gland by the action of a proteolytic enzyme, and the unsaturated oils also inhibit that enzyme. Similar
+ proteolytic enzymes involved in clot removal and phagocytosis appear to be similarly inhibited by these
+ oils.
+
+
+ Just as metabolism is "activated" by consumption of coconut oil, which prevents the inhibiting effect of
+ unsaturated oils, other inhibited processes, such as clot removal and phagocytosis, will probably tend to be
+ restored by continuing use of coconut oil.
+
+
+
+ Brain tissue is very rich in complex forms of fats. The experiment (around 1978) in which pregnant mice were
+ given diets containing either coconut oil or unsaturated oil showed that brain development was superior in
+ the young mice whose mothers ate coconut oil. Because coconut oil supports thyroid function, and thyroid
+ governs brain development, including myelination, the result might simply reflect the difference between
+ normal and hypothyroid individuals. However, in 1980, experimenters demonstrated that young rats fed milk
+ containing soy oil incorporated the oil directly into their brain cells, and had structurally abnormal brain
+ cells as a result.
+
+
+
+ Lipid peroxidation occurs during seizures, and antioxidants such as vitamin E have some anti-seizure
+ activity. Currently, lipid peroxidation is being found to be involved in the nerve cell degeneration of
+ Alzheimer's disease.
+
+
+ Various fractions of coconut oil are coming into use as "drugs," meaning that they are advertised as
+ treatments for diseases. Butyric acid is used to treat cancer, lauric and myristic acids to treat virus
+ infections, and mixtures of medium-chain fats are sold for weight loss. Purification undoubtedly increases
+ certain effects, and results in profitable products, but in the absence of more precise knowledge, I think
+ the whole natural product, used as a regular food, is the best way to protect health. The shorter-chain
+ fatty acids have strong, unpleasant odors; for a couple of days after I ate a small amount of a medium-chain
+ triglyceride mixture, my skin oil emitted a rank, goaty smell. Some people don't seem to have that reaction,
+ and the benefits might outweigh the stink, but these things just haven't been in use long enough to know
+ whether they are safe.
+
+
+ We have to remember that the arguments made for aspartame, monosodium glutamate, aspartic acid, and
+ tryptophan--that they are like the amino acids that make up natural proteins--are dangerously false. In the
+ case of amino acids, balance is everything. Aspartic and glutamic acids promote seizures and cause brain
+ damage, and are intimately involved in the process of stress-induced brain aging, and tryptophan by itself
+ is carcinogenic. Treating any complex natural product as the drug industry does, as a raw material to be
+ fractionated in the search for "drug" products, is risky, because the relevant knowledge isn't sought in the
+ search for an association between a single chemical and a single disease.
+
+
+ While the toxic unsaturated paint-stock oils, especially safflower, soy, corn and linseed (flaxseed) oils,
+ have been sold to the public precisely for their drug effects, all of their claimed benefits were false.
+ When people become interested in coconut oil as a "health food," the huge seed-oil industry--operating
+ through their shills--are going to attack it as an "unproved drug."
+
+
+ While components of coconut oil have been found to have remarkable physiological effects (as antihistamines,
+ antiinfectives/antiseptics, promoters of immunity, glucocorticoid antagonist, nontoxic anticancer agents,
+ for example), I think it is important to avoid making any such claims for the natural coconut oil, because
+ it very easily could be banned from the import market as a "new drug" which isn't "approved by the FDA." We
+ have already seen how money and propaganda from the soy oil industry eliminated long-established products
+ from the U.S. market. I saw people lose weight stably when they had the habit of eating large amounts of
+ tortilla chips fried in coconut oil, but those chips disappeared when their producers were pressured into
+ switching to other oils, in spite of the short shelf life that resulted in the need to add large amounts of
+ preservatives. Oreo cookies, Ritz crackers, potato chip producers, and movie theater popcorn makers have
+ experienced similar pressures.
+
+
+
+ The cholesterol-lowering fiasco for a long time centered on the ability of unsaturated oils to slightly
+ lower serum cholesterol. For years, the mechanism of that action wasn't known, which should have suggested
+ caution. Now, it seems that the effect is just one more toxic action, in which the liver defensively retains
+ its cholesterol, rather than releasing it into the blood. Large scale human studies have provided
+ overwhelming evidence that whenever drugs, including the unsaturated oils, were used to lower serum
+ cholesterol, mortality increased, from a variety of causes including accidents, but mainly from cancer.
+
+
+ Since the l930s, it has been clearly established that suppression of the thyroid raises serum cholesterol
+ (while increasing mortality from infections, cancer, and heart disease), while restoring the thyroid hormone
+ brings cholesterol down to normal. In this situation, however, thyroid isn't suppressing the synthesis of
+ cholesterol, but rather is promoting its use to form hormones and bile salts. When the thyroid is
+ functioning properly, the amount of cholesterol in the blood entering the ovary governs the amount of
+ progesterone being produced by the ovary, and the same situation exists in all steroid-forming tissues, such
+ as the adrenal glands and the brain. Progesterone and its precursor, pregnenolone, have a generalized
+ protective function: antioxidant, anti-seizure, antitoxin, anti-spasm, anti-clot, anti-cancer, pro-memory,
+ pro-myelination, pro-attention, etc. Any interference with the formation of cholesterol will interfere with
+ all of these exceedingly important protective functions.
+
+
+ As far as the evidence goes, it suggests that coconut oil, added regularly to a balanced diet, lowers
+ cholesterol to normal by promoting its conversion into pregnenolone. (The coconut family contains steroids
+ that resemble pregnenolone, but these are probably mostly removed when the fresh oil is washed with water to
+ remove the enzymes which would digest the oil.) Coconut-eating cultures in the tropics have consistently
+ lower cholesterol than people in the U.S. Everyone that I know who uses coconut oil regularly happens to
+ have cholesterol levels of about 160, while eating mainly cholesterol rich foods (eggs, milk, cheese, meat,
+ shellfish). I encourage people to eat sweet fruits, rather than starches, if they want to increase their
+ production of cholesterol, since fructose has that effect.
+
+
+ Many people see coconut oil in its hard, white state, and--as a result of their training watching television
+ or going to medical school--associate it with the cholesterol-rich plaques in blood vessels. Those lesions
+ in blood vessels are caused mostly by lipid peroxidation of unsaturated fats, and relate to stress, because
+ adrenaline liberates fats from storage, and the lining of blood vessels is exposed to high concentrations of
+ the blood-borne material. In the body, incidentally, the oil can't exist as a solid, since it liquefies at
+ 76 degrees. (Incidentally, the viscosity of complex materials isn't a simple matter of averaging the
+ viscosity of its component materials; cholesterol and saturated fats sometimes lower the viscosity of cell
+ components.)
+
+
+ Most of the images and metaphors relating to coconut oil and cholesterol that circulate in our culture are
+ false and misleading. I offer a counter-image, which is metaphorical, but it is true in that it relates to
+ lipid peroxidation, which is profoundly important in our bodies. After a bottle of safflower oil has been
+ opened a few times, a few drops that get smeared onto the outside of the bottle begin to get very sticky,
+ and hard to wash off. This property is why it is a valued base for paints and varnishes, but this varnish is
+ chemically closely related to the age pigment that forms "liver spots" on the skin, and similar lesions in
+ the brain, heart, blood vessels, lenses of the eyes, etc. The image of "hard, white saturated coconut oil"
+ isn't relevant to the oil's biological action, but the image of "sticky varnish-like easily oxidized
+ unsaturated seed oils" is highly relevant to their toxicity.
+
+
+ The ability of some of the medium chain saturated fatty acids to inhibit the liver's formation of fat very
+ likely synergizes with the pro-thyroid effect, in allowing energy to be used, rather than stored. When fat
+ isn't formed from carbohydrate, the sugar is available for use, or for storage as glycogen. Therefore,
+ shifting from unsaturated fats in foods to coconut oil involves several anti-stress processes, reducing our
+ need for the adrenal hormones. Decreased blood sugar is a basic signal for the release of adrenal hormones.
+ Unsaturated oil tends to lower the blood sugar in at least three basic ways. It damages mitochondria,
+ causing respiration to be uncoupled from energy production, meaning that fuel is burned without useful
+ effect. It suppresses the activity of the respiratory enzyme (directly, and through its anti-thyroid
+ actions), decreasing the respiratory production of energy. And it tends to direct carbohydrate into fat
+ production, making both stress and obesity more probable. For those of us who use coconut oil consistently,
+ one of the most noticeable changes is the ability to go for several hours without eating, and to feel hungry
+ without having symptoms of hypoglycemia.
+
+
+
+ One of the stylish ways to promote the use of unsaturated oils is to refer to their presence in "cell
+ membranes," and to claim that they are essential for maintaining "membrane fluidity." As I have mentioned
+ above, it is the ability of the unsaturated fats, and their breakdown products, to interfere with enzymes
+ and transport proteins, which accounts for many of their toxic effects, so they definitely don't just
+ harmlessly form "membranes." They probably bind to all proteins, and disrupt some of them, but for some
+ reason their affinity for proteolytic and respiration-related enzymes is particularly obvious. (I think the
+ chemistry of this association is going to give us some important insights into the nature of organisms.
+
+
+ Metchnikof's model that I have discussed elsewhere might give us a picture of how those factors relate in
+ growth, physiology, and aging.) Unsaturated fats are slightly more water-soluble than fully saturated fats,
+ and so they do have a greater tendency to concentrate at interfaces between water and fats or proteins, but
+ there are relatively few places where these interfaces can be usefully and harmlessly occupied by
+ unsaturated fats, and at a certain point, an excess becomes harmful. We don't want "membranes" forming where
+ there shouldn't be membranes. The fluidity or viscosity of cell surfaces is an extremely complex subject,
+ and the degree of viscosity has to be appropriate for the function of the cell. Interestingly, in some
+ cells, such as the cells that line the air sacs of the lungs, cholesterol and one of the saturated fatty
+ acids found in coconut oil can increase the fluidity of the cell surface.
+
+
+
+ In many cases, stressful conditions create structural disorder in cells. These influences have been called
+ "chaotropic," or chaos-producing. In red blood cells, which have sometimes been wrongly described as
+ "hemoglobin enclosed in a cell membrane," it has been known for a long time that lipid peroxidation of
+ unsaturated fats weakens the cellular structure, causing the cells to be destroyed prematurely. Lipid
+ peroxidation products are known to be "chaotropic," lowering the rigidity of regions of cells considered to
+ be membranes. But the red blood cell is actually more like a sponge in structure, consisting of a "skeleton"
+ of proteins, which (if not damaged by oxidation) can hold its shape, even when the hemoglobin has been
+ removed. Oxidants damage the protein structure, and it is this structural damage which in turn increases the
+ "fluidity" of the associated fats.
+
+
+
+ So, it is probably true that in many cases the liquid unsaturated oils do increase "membrane fluidity," but
+ it is now clear that in at least some of those cases the "fluidity" corresponds to the chaos of a damaged
+ cell protein structure. (N. V. Gorbunov, "Effect of structural modification of membrane proteins on
+ lipid-protein interactions in the human erythrocyte membrane," Bull. Exp. Biol. & Med. 116(11), 1364-67.
+ 1993.
+
+
+ Although I had stopped using the unsaturated seed oils years ago, and supposed that I wasn't heavily
+ saturated with toxic unsaturated fat, when I first used coconut oil I saw an immediate response, that
+ convinced me my metabolism was chronically inhibited by something that was easily alleviated by "dilution"
+ or molecular competition. I had put a tablespoonful of coconut oil on some rice I had for supper, and half
+ an hour later while I was reading, I noticed I was breathing more deeply than normal. I saw that my skin was
+ pink, and I found that my pulse was faster than normal--about 98, I think. After an hour or two, my pulse
+ and breathing returned to normal. Every day for a couple of weeks I noticed the same response while I was
+ digesting a small amount of coconut oil, but gradually it didn't happen any more, and I increased my daily
+ consumption of the oil to about an ounce. I kept eating the same foods as before (including a quart of ice
+ cream every day), except that I added about 200 or 250 calories per day as coconut oil. Apparently the
+ metabolic surges that happened at first were an indication that my body was compensating for an anti-thyroid
+ substance by producing more thyroid hormone; when the coconut oil relieved the inhibition, I experienced a
+ moment of slight hyperthyroidism, but after a time the inhibitor became less effective, and my body adjusted
+ by producing slightly less thyroid hormone. But over the next few months, I saw that my weight was slowly
+ and consistently decreasing. It had been steady at 185 pounds for 25 years, but over a period of six months
+ it dropped to about 175 pounds. I found that eating more coconut oil lowered my weight another few pounds,
+ and eating less caused it to increase.
+
+
+ The anti-obesity effect of coconut oil is clear in all of the animal studies, and in my friends who eat it
+ regularly. It is now hard to get it in health food stores, since Hain stopped selling it. The Spectrum
+ product looks and feels a little different to me, and I suppose the particular type of tree, region, and
+ method of preparation can account for variations in the consistency and composition of the product. The
+ unmodified natural oil is called "76 degree melt," since that is its natural melting temperature. One bottle
+ from a health food store was labeled "natural coconut oil, 92% unsaturated oil," and it had the greasy
+ consistency of old lard. I suspect that someone had confused palm oil (or something worse) with coconut oil,
+ because it should be about 96% saturated fatty acids.
+
+
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
+
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+
+ Progesterone, not estrogen, is the coronary protection factor of women.
+
+
+ Progesterone, not estrogen, is the coronary protection factor of women.
+
+
+
+
+ In the 1940s, around the time that Hans Selye was reporting that estrogen causes shock, and that
+ progesterone protects against many stress-related problems, the anthropologist Ashley Montague published
+ The Natural Superiority of Women. Later, as I looked at the history of endocrine research, it
+ seemed apparent that progesterone was responsible for many of the biological advantages of females, such
+ as a longer average life-span, while testosterone was responsible for men’s advantage in muscular
+ strength.
+
+
+ Although evidence of estrogen’s toxicity had been accumulating for decades, pharmaceutical promotion was
+ finding hundreds of things to treat with estrogen, which they called “the female hormone.” By the 1940s,
+ it was known to produce excessive blood clotting, miscarriage, cancer, age-like changes in connective
+ tissue, premenstrual syndrome, varicose veins, orthostatic hypotension, etc., but, as Mark Twain said, a
+ lie can run around the world before the truth gets its boots on.
+
+
+ After the DES fiasco, in which “the female hormone” which had been sold to prevent miscarriages was
+ proven to cause them, the estrogen industry decided to offer men the protection against heart attacks
+ that women supposedly got from their estrogen. The men who received estrogen in the study had an
+ increased incidence of heart attacks, so that campaign was postponed for about 30 years.
+
+
+ The Shutes used vitamin E to treat the excessive blood clotting caused by estrogen, and vitamin E was
+ considered to be an estrogen antagonist. Estrogen affected the liver’s production of clot-regulating
+ proteins, and it also relaxed large veins, allowing blood pooling that slowed the blood sufficiently to
+ give it time to form clots before returning to the lungs. Early in the century, unsaturated fats were
+ found to inactivate the proteolytic enzymes that dissolve clots, and vitamin E was known, by the 1940s,
+ to provide protection against the toxicity of the unsaturated fats. The toxic synergy of estrogen and
+ unsaturated fats had already been recognized.
+
+
+ But in the 1950s, the seed oil industry, ignoring the toxic, carcinogenic effects of the unsaturated
+ oils, began intensified promotion of their products as beneficial foods. (Decades earlier, Mark Twain
+ had reported on the plans of the cottonseed industry to make people eat their by-product instead of
+ butter.)
+
+
+ While estrogen was being offered as the hormone that protects against heart attacks, the liquid
+ vegetable oils were being advertised as the food that would prevent heart attacks. Just a few years
+ after the estrogen industry suffered the setbacks of the DES and heart attack publicity, the oil
+ industry cancelled some tests of the “heart protective diet,” because it was causing both more heart
+ attacks and more cancer deaths.
+
+
+ Somehow, these two fetid streams converged: Estrogen, like the unsaturated oils, lowered the
+ amount of cholesterol in the blood, and an excess of blood cholesterol was said to cause
+ heart attacks. (And, more recently, the estrogenic effects of the seed oils are claimed to offer
+ protection against cancer.)
+
+
+ The ability to lower the cholesterol “risk factor” for heart attacks became a cultural icon, so that the
+ contribution of estrogen and unsaturated oils to the pathologies of clotting could be ignored. Likewise,
+ the contribution of unsaturated fats’ lipid peroxidation to the development of atherosclerotic plaques
+ was simply ignored. But one of estrogen’s long established toxic effects, the reduction of tone in
+ veins, was turned into something like a “negative risk factor”: The relaxation of blood
+ vessels would prevent high blood pressure and its consequences, in this new upside down paradigm.
+ This vein-dilating effect of estrogen has been seen to play a role in the development of
+ varicose veins, in orthostatic hypotension, and in the formation of blood clots in the slow-moving
+ blood in the large leg veins.
+
+
+ When it was discovered that the endothelial relaxing factor was nitric oxide, a new drug business came
+ into being. Nitroglycerine had been in use for decades to open blood vessels, and, ignoring the role of
+ nitrite vasodilators in the acquired immunodeficiency syndrome, new drugs were developed to increase the
+ production of nitric oxide. The estrogen industry began directing research toward the idea that estrogen
+ works through nitric oxide to “improve” the function of blood vessels and the heart.
+
+
+ (Besides the argument based on “risk factors,” many people cite the published observations that “women
+ who take estrogen are healthier” than women who don’t use it. But studies show that their “control
+ groups” consisted of women who weren’t as healthy to begin with.)
+
+
+ In the 1970s, after reading Szent-Gyorgyi’s description of the antagonistic effect of progesterone and
+ estrogen on the heart, I reviewed the studies that showed that progesterone protects against estrogen’s
+ clotting effect. I experimented with progesterone, showing that it increases the muscle tone in the
+ walls of veins, which is very closely related to the effects Szent-Gyorgyi described in the heart. And
+ progesterone opposes estrogen’s ability to increase the amount of free fatty acids circulating in the
+ blood.
+
+
+ More recently, it has been discovered that progesterone inhibits the expression of the enzyme nitric
+ oxide synthase, while estrogen stimulates its expression. At the time of ovulation, when estrogen is
+ high, a woman breathes out 50% more nitric oxide (“NO”) than men do, but at
+ other times, under the influence of increased progesterone and thyroid, and reduced estrogen, women
+ exhale much less NO than men do. (Nitric oxide is a free radical, and it decomposes into other toxic
+ compounds, including the free radical peroxynitrile, which damages cells, including the blood vessels.
+ brain, and heart. Carbon dioxide tends to inhibit the production of peroxynitrile.)
+
+
+ If nitric oxide produced under the influence of estrogen were important in preventing cardiovascular
+ disease, then men’s larger production of nitric oxide would give them greater protection than women
+ have.
+
+
+ From more realistic perspectives, nitric oxide is being considered as a cause of aging, especially brain
+ aging. Nitric oxide interacts with unsaturated fats to reduce oxygen use, damage mitochondria,
+ and cause edema.
+
+
+
+
+ I think we can begin to see that the various “heart protective” ideas that have been promoted to the
+ public for fifty years are coming to a dead end, and that a new look at the fundamental problems
+ involved in heart disease would be appropriate. Basic principles that make heart disease more
+ understandable will also be useful for understanding shock, edema, panic attacks, high altitude
+ sickness, high blood pressure, kidney disease, some lung diseases, MS, multiple organ failure, and
+ excitotoxicity or “programmed” cell death of the sort that causes degenerative nerve diseases and
+ deterioration of other tissues.
+
+
+ The research supporting this view is remarkably clear, but it isn’t generally known because of the
+ powerful propaganda coming from the drug and oil industries and their public servants.
+
+
+ Broda Barnes was right when he said that the “riddle of heart attacks” was solved when he demonstrated
+ that hypothyroidism caused heart attacks, and that they were prevented by correcting hypothyroidism. He
+ also observed that correcting hypothyroidism prevented the degenerative conditions (including heart
+ disease) that so often occur in diabetics. Since hypothyroidism and diabetes are far more frequent in
+ women, who have fewer heart attacks than men, it is appropriate to wonder why women tolerate
+ hypothyroidism better than men.
+
+
+ In hypothyroidism and diabetes, respiration is impaired, and lactic acid is formed even at rest, and
+ relatively little carbon dioxide is produced. To compensate for the metabolic inefficiency of
+ hypothyroidism, adrenalin and noradrenalin are secreted in very large amounts. Adrenalin causes free
+ fatty acids to circulate at much higher levels, and the lactic acid, adrenalin, and free fatty
+ acids all stimulate hyperventilation. The already deficient carbon dioxide is reduced even
+ more, producing respiratory alkalosis. Free fatty acids, especially unsaturated fats, increase
+ permeability of blood vessels, allowing proteins and fats to enter the endothelium and smooth muscle
+ cells of the blood vessels. Lactic acid itself promotes an inflammatory state, and in combination with
+ reduced CO2 and respiratory alkalosis, contributes to the hyponatremia (sodium deficiency) that is
+ characteristic of hypothyroidism. This sodium deficiency and osmotic dilution causes cells to take up
+ water, increasing their volume.
+
+
+ In hyperventilation, the heart’s ability to work is decreased, and the work it has to do is increased,
+ because peripheral resistance is increased, raising blood pressure. One component of peripheral
+ resistance is the narrowing of the channels in blood vessels caused by endothelial swelling. In the
+ heart, a similarly waterlogged state makes complete contraction and complete relaxation impossible.
+
+
+ Estrogen itself intensifies all of these changes of hypothyroidism, increasing perrmeability and edema,
+ and decreasing the force of the heart-beat, impairing the diastolic relaxation. Besides its direct
+ actions, and synergism with hypothyroidism, estrogen also chronically increases growth hormone, which
+ causes chronic exposure of the blood vessels to higher levels of free fatty acids (with a bias
+ toward unsaturated fatty acids), and promotes edema and vascular leakage. Hyperestrogenism,
+ like hypothyroidism, tends to produce dilution of the body fluids, and is associated with increased
+ bowel permeability, leading to endotoxemia; both dilution of the plasma and endotoxemia
+ impair heart function.
+
+
+ Progesterone’s effects are antagonistic to estrogen’s:. Progesterone decreases the
+ formation of nitric oxide, decreasing edema; it strengthens the heart beat, by
+ improving venous return and increasing stroke volume, but at the same time it reduces peripheral
+ resistance by relaxing arteries (by inhibiting calcium entry but also by other effects, and
+ independently of the endothelium) and decreasing edematous swelling.
+
+
+ The effects of progesterone on the heart and blood vessels are paralleled by those of carbon
+ dioxide: Increased carbon dioxide increases perfusion of the heart muscle, increases its stroke
+ volume, and reduces peripheral resistance.
+ The physical and chemical properties of carbon dioxide that I have written about previously
+ include protective anti-excitatory and energy-sustaining functions that explain these effects. Since
+ these effects have been known for many years, I think it is obvious that the obsessive interest in
+ explaining these functions in terms of other molecules, such as nitric oxide, is motivated by the desire
+ for new drugs, not by a desire to understand the physiology with which the researchers are pretending to
+ deal.
+
+
+ Although women, because of estrogen’s antithyroid actions, are much more likely to suffer from
+ hypothyroidism than men are, until menopause they have much higher levels of progesterone than men do.
+ The effects of hyperestrogenism and hypothyroidism, with lower carbon dioxide production, are offset by
+ high levels of progesterone. After menopause, women begin to have heart attacks at a rapidly increasing
+ rate.
+
+
+ During the years that men are beginning to have a considerable risk of heart attacks, with declining
+ thyroid function indicated by lower T3, their testosterone and progesterone are declining, while their
+ estrogen is rising. Men who have heart attacks have much higher levels of estrogen than men at the same
+ age who haven’t had a heart attack.
+
+
+ Whether the issue is free radical damage, vascular permeability with fat deposition, vascular spasm,
+ edema, decreased heart efficiency, or blood clotting, the effects of chronic estrogen exposure are
+ counter-adaptive. Progesterone, by opposing estrogen, is universally protective against vascular
+ and heart disease.
+
+
+ So far, the rule in most estrogen/progesterone research has been to devise experiments so that claims of
+ benefit can be made for estrogen, with the expectation that they will meet an uncritical audience. In
+ some studies, it’s hard to tell whether idiocy or subterfuge is responsible for the way the experiment
+ was designed and described, for example when synthetic chemicals with anti-progesterone activity are
+ described as “progesterone.” Since one estrogen-funded researcher who supposedly found progesterone to
+ be ineffective as treatment for premenstrual syndrome practically admitted to me in conversation an
+ intent to mislead, I think it is reasonable to discount idiocy as the explanation for the tremendous
+ bias in published research. With the vastly increased resources in the estrogen industry, resulting from
+ the product promotion “for the prevention of heart disease,” I think we should expect the research fraud
+ to become increasingly blatant.
+
+
+ Rather than being “heart protective,” estrogen is highly heart-toxic, and it is this that makes its most
+ important antagonist, progesterone, so important in protecting the heart and circulatory system.
+
+
+ REFERENCES
+
+ JAMA 1998 Aug 19;280(7):605-13.
+ Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in
+ postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.
+ Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E University of California, San
+ Francisco 94143, USA. CONTEXT: Observational studies have found lower rates of coronary heart disease
+ (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has
+ not been confirmed in clinical trials. OBJECTIVE: To determine if estrogen plus progestin therapy alters
+ the risk for CHD events in postmenopausal women with established coronary disease. DESIGN: Randomized,
+ blinded, placebo-controlled secondary prevention trial. SETTING: Outpatient and community settings at 20
+ US clinical centers. PARTICIPANTS: A total of 2763 women with coronary disease, younger than 80 years,
+ and postmenopausal with an intact uterus. Mean age was 66.7 years. INTERVENTION: Either
+ 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily
+ (
. Follow-up averaged 4.1 years;
+ 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end
+ of 3 years. MAIN OUTCOME MEASURES: The primary outcome was the occurrence of nonfatal
+ myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included
+ coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest,
+ stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also
+ considered. RESULTS: Overall, there were no significant differences between groups in the primary
+ outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women
+ in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI],
+ 0.80-1.22). The lack of an overall effect
+ occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher
+ high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each
+ P<.001). Within the overall null effect, there was a statistically significant time trend, with more
+ CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5.
+ More women in the hormone group than in the placebo group experienced venous thromboembolic
+ events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH,
+ 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for
+ which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH,
+ 1.08; 95% CI, 0.84-1.38). CONCLUSIONS: During an average follow-up of 4.1 years,
+ treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the
+ overall rate of CHD events in postmenopausal women with established coronary disease. The treatment
+ did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no
+ overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do
+ not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the
+ favorable pattern of CHD
+
+
+ Am J Med 1982 Dec;73(6):872-81. Serum estrogen levels in men with acute myocardial
+ infarction. Klaiber EL, Broverman DM, Haffajee CI, Hochman JS, Sacks GM, Dalen JE Serum
+ estradiol and serum estrone levels were assessed in 29 men in 14 men in whom myocardial infarction was
+ ruled out; in 12 men without apparent coronary heart disease but hospitalized in an intensive care unit;
+ and in 28 men who were not hospitalized and who acted as control subjects. (The 12 men who were
+ hospitalized but who did not have coronary heart disease were included to control for physical and
+ emotional stress of a severe medical illness.) Ages ranged from 21 to 56 years. Age, height, and weight
+ did not differ significantly among groups. Blood samples were obtained in the patient groups on each of
+ the first three days of hospitalization. The serum estrone level was significantly elevated in all four
+ patient groups when compared with that in the control group. Estrone level, then, did not differentiate
+ patients with and without coronary heart disease. Serum estradiol levels were significantly
+ elevated in the groups with myocardial infarction, unstable angina, and in the group in
+ whom myocardial infarction was ruled out. However, estradiol levels were not significantly elevated in
+ the group in the intensive care unit without coronary heart disease when compared to the level in the
+ normal control group. Serum estradiol levels, then, were elevated in men with confirmed or
+ suspected coronary heart disease but were not elevated in men without coronary heart
+ disease even under the stressful conditions found in an intensive care unit. Serum estradiol levels were significantly and positively correlated (p less than 0.03) with serum total creatine
+ phosphokinase levels in the patients with myocardial infarction. The five patients with
+ myocardial infarction who died within 10 days of admission had markedly elevated serum estradiol levels.
+ The potential significance of these serum estradiol elevations is discussed in terms of estradiol's
+ ability to enhance adrenergic neural activity and the resultant increase in myocardial oxygen demand.
+
+
+ JAMA 1978 Apr 3;239(14):1407-9.
+ Noncontraceptive estrogens and nonfatal myocardial infarction. Jick H, Dinan B, Rothman KJ
+ We obtained information on 107 women younger than 46 years discharged from a hospital with a diagnosis
+ of acute myocardial infarction. In the series there were 17 women aged 39 to 45 years who were otherwise
+ apparently healthy and had had a natural menopause, hysterectomy, or tubal ligation or whose spouse had
+ had a vasectomy. Among them, nine (53%) were taking noncontraceptive estrogens just prior to admission.
+ Among 34 control women, four (12%) were taking estrogens. The relative risk estimate, comparing
+ estrogen users with nonusers, is 7.5, with 90% confidence limits of 2.4 and 24. All but one
+ of the 17 ml subjects were cigarette smokers. While this illness is rare in most healthy young women,
+ the risk in women older than about 38 years who both smoke and take estrogens appears to be substantial.
+
+
+ JAMA 1978 Apr 3;239(14):1403-6.
+ Oral contraceptives and nonfatal myocardial infarction. Jick H, Dinan B, Rothman KJ We
+ obtained information on 107 women younger than 46 years who were discharged from a hospital with a
+ diagnosis of acute myocardial infarction. In the series 26 women were otherwise apparently healthy and
+ potentially childbearing. Among these 26 women, 20 (77%) were taking oral contraceptives just
+ prior to admission, and one was taking conjugated estrogens. Among 59 control women, 14 (24%) were
+ taking oral contraceptives and one was taking conjugated estrogens. The relative risk
+ estimate, comparing oral contraceptive users with nonusers, is 14 with 90% confidence
+ limits of 5.5 and 37. All but two of the 26 women were cigarette smokers. While this illness is rare in
+ most healthy young women, the risk in women older than about 37 years who both smoke and take oral
+ contraceptive appears to be high.
+
+
+ M. Karmazyn, et al., "Changes in coronary vascular resistance associated with prolonged hypoxia
+ in isolated rat hearts: A possible role of prostaglandins,"
+ Life Sciences 25, 1991-1999, 1979. "if...hypoxic perfusion is prolonged, the initial dilatation
+ passes off and an intense vasoconstriction results." "The constriction could be prevented by
+ progesterone but not by estradiol or testosterone." "There is increasing evidence that
+ angina pectoris and myocardiaol infarction may often be due to active caronary constriction."
+ "Inhibitors of PG synthesis at high concentrations prevented or reversed the constriction." (Besides
+ aspirin) "Chloroquine, procaine and propranolol can all behave as PG antagonists...." "The failure of
+ estradiol or testosterone to have any effect and the complete prevention of the constriction by
+ physiological levels of progesterone suggest that more attention should be paid to this last steroid."
+ "...hypoxia can cause coronary constriction and...the effect does not occur in young or
+ progesterone-treated hearts...."
+
+
+ Am J Epidemiol 1996 May 15;143(10):971-8.
+ Prior to use of estrogen replacement therapy, are users healthier than nonusers? Matthews
+ KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Observational studies have demonstrated that women who
+ have used postmenopausal estrogen replacement therapy (ERT) are at reduced risk of coronary heart
+ disease. The authors examined whether
+ premenopausal women who subsequently elected to use ERT during menopause had a better cardiovascular
+ risk factor profile prior to use than did nonusers. A total of 541 premenopausal women had
+
+
+ Prior to use of ERT, in comparison with nonusers, subsequent users reported on standardized
+ questionnaires that they often exhibited Type A behavior, more aware of their feelings, motives, and
+ symptoms, and had more symptoms of stress. Women who elect to use ERT have a better cardiovascular
+ risk factor profile prior to the use of ERT than do women who subsequently do not use this treatment
+ during the menopause, which supports the hypothesis that part of the apparent benefit associated
+ with the use of ERT is due to preexisting characteristics of women who use ERT. This study
+ underscores the widely recognized importance of randomized clinical trials to estimate the
+ direct benefit of postmenopausal ERT for protecting women from cardiovascular disease.
+
+
+ "Effects of androgens on haemostasis," Winkler UH, Maturitas, 1996 Jul, 24:3, 147-55.
+ "Androgen deficiency is associated with an increased incidence of cardiovascular disease. There
+ is evidence that thromboembolic disease as well as myocardial infarction in hypogonadic males are
+ mediated by low baseline fibrinolytic activity. Hypogonadism in males is associated with an
+ enhancement of fibrinolytic inhibition via increased synthesis of the plasminogen activator inhibitor
+ PAI 1.”
+
+
+ M. Mabry White, et al., “Estrogen, progesterone, and vascular reactivity: Potential cellular
+ mechanisms," Endocrine Reviews 16(6), 739, 1995. "Female hormones are broadly recognized as
+ affecting susceptibility to vascular disease...." Migraines, Raynaud's phenomena, primary pulmonary
+ hypertension are mentioned as vascular disorders with a female predominance.
+
+
+ J. Boczkowski, et al., "Induction of diaphragmatic nitric oxide synthase after endotoxin
+ administration in rats; role on diaphragmatic contractile dysfunction," J. Clin. Invest.
+ 98, 1550-1559, 1996. "We conclude that iNOS [inducible nitric oxide synthase] was induced..." by
+ endotoxin.
+
+
+ Arch Int Pharmacodyn Ther 1986 May;281(1):57-65. Effects of 17 beta-estradiol on the isolated
+ rabbit heart. Raddino R, Manca C, Poli E, Bolognesi R, Visioli O. We have studied the
+ effects of 17 beta-estradiol on the left ventricular pressure and on the coronary perfusion pressure in
+ isolated rabbit heart, in order to evaluate the action of this hormone on the myocardial contractility
+ and on the coronary resistances. 17 beta-Estradiol has induced a negative inotropic effect
+ starting from a concentration of 10(-6) M and a vasodilation starting from 10(-7) M when
+ administered on a vasopressin-induced coronary spasm. These effects are not related to sex or to alpha-,
+ beta-adrenergic, histaminergic, anaesthetic-like mechanisms, but seem to interfere with calcium
+ transport.
+
+
+ Med Hypotheses 1997 Aug;49(2):183-5.
+ Coronary artery spasm: a hypothesis on prevention by progesterone. Kanda I, Endo M.
+ Department of Surgery, Heart Institute of Japan, Tokyo Women's Medical College, Japan. The
+ mechanism of coronary artery spasm has been hypothesized as follows: the dormant gene of the smooth
+ muscle of the human coronary artery is identical or similar to the active gene of the smooth muscle
+ of ductus arteriosus, but can be activated by estrogen. The activation could be preventable by
+ progesterone. The prevention is due to the reduction of the number of estrogen receptors of the
+ smooth muscle of the coronary artery.
+
+
+
+ J. Bolanos, et al., "Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in
+ cultured astrocytes," J. Neurochem. 63, 910-916, 1994.
+
+
+ M. Cleeter, et al., "Reversible inhibition of cytochrome C oxidase, the terminal enzyme of the
+ mitochondrial respiratory chain, by nitric oxide," FEBS Lett. 345, 50-54, 1994.
+
+
+ Ann Thorac Surg 1999 Sep;68(3):925-30. Coronary perfusate composition influences diastolic
+ properties, myocardial water content, and histologic characteristics of the rat left
+ ventricle. Starr JP, Jia CX, Amirhamzeh MM, Rabkin DG, Hart JP, Hsu DT, Fisher PE, Szabolcs
+ M, Spotnitz HM. “Recent studies found that edema, histology, and left ventricular diastolic
+ compliance exhibit quantitative relationships in rats. Edema due to low osmolarity coronary
+ perfusates increases myocardial water content and histologic edema score and decreases left
+ ventricular filling. The present study examined effects of perfusate osmolarity and
+ chemical composition on rat hearts.” “Myocardial water content reflected perfusate osmolarity, being
+ lowest in Stanford and University of Wisconsin solutions (p<0.05 versus other groups) and highest in
+ dilute Plegisol (p<0.05). Left ventricular filling volumes were smallest in dilute Plegisol and
+ Plegisol (p<0.05).” “Perfusate osmolarity determined myocardial water content and left ventricular
+ filling volume. However, perfusate chemical composition influenced the histologic appearance of edema.
+ Pathologic grading of edema can be influenced by factors other than osmolarity alone.”
+
+
+ Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide
+ production in murine macrophages. Miller L; et al J Leukoc Biol, 59(3):442-50 1996 Mar. The
+ purpose of this study was to determine whether the female hormones estradiol-l7 beta (E2) and
+ progesterone (P4) influence inducible nitric oxide synthase (iNOS) and the production of nitric oxide
+ (NO) by interferon gamma (IFN-gamma) and lipopolysaccharide (LPS)-activated mouse macrophages. Treatment
+ with P4 alone caused a time- and dose-dependent inhibition of NO production by macrophage cell lines
+ (RAW 264.7, J774) and mouse bone marrow culture-derived macrophages as assessed by nitrite accumulation.
+ RAW 264.7 cells transiently transfected with an iNOS gene promoter/luciferase reporter-gene construct
+ that were stimulated with IFN-gamma/LPS in the presence of P4 displayed reduced luciferase activity and
+ NO production. Analysis of RAW 264.7 cells by Northern blot hybridization revealed concurrent
+ P4-mediated reduction in iNOS mRNA. These observations suggest that P4-mediated inhibition of NO may be
+ an important gender-based difference within females and males that relates to macrophage-mediated host
+ defense.
+
+
+ Testosterone relaxes rabbit coronary arteries and aorta. Yue P; Chatterjee K; Beale C;
+ Poole-Wilson PA; Collins P Department of Cardiac Medicine, National Heart and Lung Institute, London,
+ UK. Circulation, 1995 Feb 15, 91:4, 1154-60 “Testosterone induces endothelium-independent
+ relaxation in isolated rabbit coronary artery and aorta, which is neither mediated by prostaglandin
+ I2 or cyclic GMP. Potassium conductance and potassium channels but not ATP-sensitive
+ potassium channels may be involved partially in the mechanism of testosterone-induced relaxation. The
+ in vitro relaxation is independent of sex and of a classic receptor. The coronary
+ artery is significantly more sensitive to relaxation by testosterone than the aorta. Testosterone is a
+ more potent relaxing agent of rabbit coronary artery than other testosterone analogues.”
+
+
+ J. Nakamura, et al., "Estrogen regulates vascular endothelial growth permeability factor
+ expression in 7,12-dimethyl- benz(a)anthracene-induced rat mammary tumors,"
+ Endocrinology 137(12_, 5589-5596, 1996. ("...one mechanism by which estrogen
+ acts as a mammary tumor promotor is by stimulating VEG/PF, leading to increased tumor angiogenesis
+ and/or permeability of the microvessels to allow tumor cell migration.")
+
+
+ D. A. Barber, et al., "Endothelin receptors are modulated in association with endogenous
+ fluctuations in estrogen," Amer. J. of Physiology--Heart and Circulatory Physiology 40(5),
+ H1999-H2006, 1996. ("...contractions to endothelin-1 but not endothelin-3 or sarafotoxin S6c were
+ significantly greater in coronary arterial rings from female comparred with male pigs...." "In
+ addition, independent of endogenous estrogen status, coronary arteries from female pigs generate
+ significantly greater contractions to endothelin-1 compared with male pigs. This phenomenon occurs
+ at the level of smooth muscle and is not dependent on the endothelium or synthesis of nitric oide or
+ prostaglandins."
+
+
+
+ T. M. Chou, et al, "Testosterone induces dilation of canine coronary conductance and resistance
+ arteries in vivo," Circulation 94(10), 2614-2619, 1996.
+
+
+ K. Sudhir, et al., "Estrogen enhances basal nitric oxide release in the forearm vasculature in
+ perimenopausal women," Hypertension 28(3), 330-334, 1996.
+
+
+ G. Sitzler, et al., "Investigation of the negative inotropic effects of 17-beta-oestradiol in
+ human isolated myocardial tissues," British J. of Pharmacology 119(1), 43-48, 1996.
+
+
+ S. M. Hyder, et al., "Uterine expression of vascular endothelial growth factor is increased by
+ estradiol and tamoxifen," Cancer Research 56(17), 3954-3960, 1996. ("These findings raise
+ the possibility that estrogen and antiestrogen effects on uterine edema, proliferation, and tumor
+ incidence may involve local increases in tissue VEGF production.")
+
+
+ N. Ferrara and T. Davis-Smyth, "The biology of vascular endothelial growth factor,"
+ Endocrine Reviews 18(1), 4-19,? 1997. "...induces vasodilatation in vitro in a
+ dose-dependent fashion and produces transient tachycardia, hypotension, and a decrease in cardiac output
+ when injected intravenously in conscious...rats. Such effects appear to be caused by a decrease
+ in venous return, mediated primarily by endothelial cell-derived nitric oxide...."
+ "Recently, elevation of VEGF in the peritoneal fluid of patients with endometriosis has been
+ reported.""...it has been suggested that VEGF up-regulation plays a pathogenic role in the capillary hyperpermeability that characterizes ovarian hyperstimulation syndrome as well as in
+ the dysfunctional endothelium of preeclampsia."
+
+
+ B. Jilma, et al, "Sex differences in concentrtions of exhaled nitric oxide and plasma
+ nitrate," Life Sciences 58*6), 469-476, 1996. ("Nitric oxide is generally considered as an
+ endogenous vasoprotective agent." "...men exhaled 50% more NO and had 99% higher (nitrate) NO3 levels
+ than women."
+
+
+
+ Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide production in
+ murine macrophages. Miller L; et al J Leukoc Biol, 59(3):442-50 1996 Mar. “Treatment with
+ P4 alone caused a time- and dose-dependent inhibition of NO production by macrophage
+ cell lines (RAW 264.7, J774) and mouse bone marrow culture-derived macrophages as assessed by nitrite
+ accumulation. RAW 264.7 cells transiently transfected with an iNOS gene promoter/luciferase
+ reporter-gene construct that were stimulated with IFN-gamma/LPS in the presence of P4 displayed reduced
+ luciferase activity and NO production. Analysis of RAW 264.7 cells by Northern blot hybridization
+ revealed concurrent P4-mediated reduction in iNOS mRNA. These observations suggest that P4-mediated
+ inhibition of NO may be an important gender-based difference within females and males that relates to
+ macrophage-mediated host defense.”
+
+
+ Int J Epidemiol 1990 Jun;19(2):297-302. Relationship of menopausal status and sex hormones to
+ serum lipids and blood pressure. Wu ZY, Wu XK, Zhang YW. “Conditional logistic
+ regression analysis found that progesterone is a protective factor only and testosterone is one of
+ the risk factors for hypertension.”
+
+
+
+ Pharmacol Biochem Behav 1990 Oct;37(2):325-7. Steroid sex hormones and cardiovascular function
+ in healthy males and females: a correlational study.
+
+ Positive correlations were also found between estradiol and SBP and HR in women.”
+
+
+ Scand J Clin Lab Invest 1993 Jul;53(4):353-8. Effects of ovarian stimulation on blood pressure
+ and plasma catecholamine levels. Tollan A, Oian P, Kjeldsen SE, Holst N, Eide I.
of the sympathetic nervous tone due to a decrease in blood pressure, or may indicate
+ reduced neuronal re-uptake of released noradrenaline. The mechanisms behind the strong
+ correlation between adrenaline and blood pressure are unclear, but may be induced by the
+ supraphysiological oestradiol levels.”
+
+
+ J Mol Cell Cardiol 1986 Dec;18(12):1207-18. Post-ischemic cardiac chamber stiffness and coronary
+ vasomotion: the role of edema and effects of dextran. Vogel WM, Cerel AW, Apstein CS.
+ “Contributions of edema to left ventricular (LV) chamber stiffness and coronary resistance after
+ ischemia were studied in isolated buffer-perfused rabbit hearts, with constant LV chamber volume,
+ subjected to 30 min global ischemia and 60 min reperfusion. During reperfusion hearts were perfused with
+ standard buffer or with 3% dextran to increase oncotic pressure and decrease water content.” “Coronary
+ resistance in untreated ischemic hearts increased by 26% from 2.0 +/- 0.06 to 2.6 +/- 0.06 mmHg/ml/min
+ after 60 min reperfusion. In treated hearts coronary resistance increased by 16% from 1.9 +/- 0.09 to
+ 2.2 +/- 0.09 mm/Hg/ml/min (P less than 0.01 v. untreated ischemic). To determine whether the decrease in
+ coronary
+ resistance with dextran could be ascribed to active vasodilation, dilator responses to 2 min hypoxia
+ or 10(-4)M adenosine were tested in nonischemic and reperfused ischemic hearts. Dilator responses
+ were stable in nonischemic hearts or hearts reperfused after 15 min ischemia but after 30 min
+ ischemia the dilator response to hypoxia was reduced by 72% (P less than 0.025) and the dilator
+ response to adenosine was eliminated (P less than 0.02). Thus the response to dextran was unlike
+ that of a direct vasodilator. These data suggest that myocardial edema plays a significant role in
+ maintaining increased ventricular chamber stiffness and coronary resistance during reperfusion after
+ ischemia.”
+
+
+
+ Experientia 1980 Dec 15;36(12):1402-3.
+ Bilinear correlation between tissue water content and diastolic stiffness of the ventricular
+ myocardium. Pogatsa G. In oedematous and dehydrated canine hearts a close bilinear
+ correlation was demonstrated between myocardial water content and diastolic stiffness (characterized
+ by the passive elastic modulus) with an optimal minimum of stiffness at normal myocardial water
+ content.
+
+
+
+ S Afr Med J 1975 Dec 27;49(55):2251-4. Effect of natural oestrogens on blood pressure and weight
+ in postmenopausal women. Notelovitz M. “An investigation of the effect of conjugated
+ oestorgens (USP) on the blood pressure and weight gain of postmenopausal women was undertaken. Fifty-one
+ unselected women were treated for one year with cyclically administered conjugated oestrogen. Both the
+ mean systolic and diastolic blood pressures of
+ those in the group increased, but only the diastolic was significantly elevated.”
+ “The significance of the change in blood pressure is commented upon, and the recommendation
+ that postmenopausal women on oestrogen replacement therapy should have their blood pressure measured
+ every 6 months is made.”
+
+
+ Am J Hypertens 1995 Mar;8(3):249-53.
+ Ambulatory blood pressure in mild hypertensive women taking oral contraceptives. A case-control
+ study. Narkiewicz K, Graniero GR, D'Este D, Mattarei M, Zonzin P, Palatini P. “Both daytime
+ and nighttime systolic
+ blood pressure values were significantly higher in oral contraceptive users. There was an average
+ 8.3 mm
+
+
+
+ Am J Surg Pathol 1995 Apr;19(4):454-62.
+ Reversible ischemic colitis in young women. Association with oral contraceptive use. Deana
+ DG, Dean PJ. .”Ischemic colitis, a condition of middle-aged to elderly patients, occurs uncommonly in
+ younger persons.” “Ten women (59%) were using low-dose estrogenic oral contraceptive agents, compared
+ with the 1988 national average of 18.5% oral contraceptive users among females aged 15 to 44
+ years.
+ The calculated odds ratio yielded a greater than sixfold relative risk for the occurrence of
+ ischemic colitis among oral contraceptive users. In addition, four women not currently on
+ hormonal contraceptive therapy had a past history of oral contraceptive use; the three remaining women
+ were taking estrogen as replacement therapy after oophorectomy. In one patient, documented reversible
+ ischemic colitis recurred on resumption of oral contraceptive use....” “...spontaneous ischemic colitis
+ is a disorder found almost exclusively in women and is associated with the clinical use of exogenous
+ estrogenic agents.”
+
+
+ J Clin Endocrinol Metab 1993 Jun;76(6):1542-7.
+ Differential changes in serum concentrations of androgens and estrogens (in relation with cortisol)
+ in postmenopausal women with acute illness.
+ Spratt DI, Longcope C, Cox PM, Bigos ST, Wilbur-Welling C. “We evaluated relationships between
+ changes in serum levels of cortisol (F), androgens, estrogens, and gonadotropins in 20 postmenopausal
+ women with acute critical illness to determine if changes in adrenal androgens and estrogens paralleled
+ gonadal axis suppression or adrenal stimulation.
“The decreased serum T levels
+ suggest inhibition of 17 beta-OH-dehydrogenase and/or increased aromatization to
+ estradiol.
+ The marked increase in serum estrogen levels also suggests increased aromatization. The
+ absence of increases in DHEA and DHEA-S suggest enhanced activity of 3 beta-hydroxysteroid dehydrogenase
+ and/or inhibition of C17,20-lyase activity of P-450c17.”.
+
+
+
+
+
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+
+
+
+
+
+
+ The dark side of stress (learned helplessness)
+
+
+ Acetylcholine is the "neurotransmitter" of cholinergic nerves, including the parasympathetic system.
+ Cholinesterase (or acetylcholinesterase) is an enzyme that destroys acetylcholine, limiting the action of the
+ cholinergic nerves. Attaching a phosphate group to the cholinesterase enzyme inactivates it, prolonging and
+ intensifying the action of cholinergic stimulation.
+
+
+ The autonomic nervous system has traditionally been divided into the sympathetic-adrenergic system, and the
+ parasympathetic-cholinergic system, with approximately opposing functions, intensifying energy expenditure and
+ limiting energy expenditure, respectively. The hormonal system and the behavioral system interact with these
+ systems, and each is capable of disrupting the others. Disruptive factors in the environment have increased in
+ recent decades.
+
+
+ Living is development; the choices we make create our individuality. If genetically identical mice grow up in a
+ large and varied environment, small differences in their experience will affect cell growth in their brains,
+ leading to large differences in their exploratory behavior as they age (Freund, et al., 2013). Geneticists used
+ to say that "genes determine our limits," but this experiment shows that an environment can provide both
+ limitations and opportunities for expanding the inherited potential. If our environment restricts our choices,
+ our becoming human is thwarted, the way rats' potentials weren't discovered when they were kept in the standard
+ little laboratory boxes. An opportunity to be complexly involved in a complex environment lets us become more of
+ what we are, more humanly differentiated. A series of experiments that started at the University of California
+ in 1960 found that rats that lived in larger spaces with various things to explore were better at learning and
+ solving problems than rats that were raised in the standard little laboratory cages (Krech, et al., 1960).
+ Studying their brains, they found that the enzyme cholinesterase, which destroys the neurotransmitter,
+ acetylcholine, was increased. They later found that the offspring of these rats were better learners than their
+ parents, and their brains contained more cholinesterase. Their brains were also larger, with a considerable
+ thickening of the cortex, which is considered to be the part mainly responsible for complex behavior, learning
+ and intelligence. These processes aren't limited to childhood. For example, London taxi drivers who learn all
+ the streets in the city develop a larger hippocampus, an area of the brain involved with memory. The 1960s
+ research into environmental enrichment coincided with political changes in the US, but it went against the
+ dominant scientific ideas of the time. Starting in 1945, the US government had begun a series of projects to
+ develop techniques of behavior modification or mind control, using drugs, isolation, deprivation, and torture.
+ In the 1950s, psychiatry often used lobotomies (about 80,000, before they were generally discontinued in the
+ 1980s) and electroconvulsive "therapy," and university psychologists tortured animals, often as part of
+ developing techniques for controlling behavior. The CIA officially phased out their MKultra program in 1967, but
+ that was the year that Martin Seligman, at the University of Pennsylvania, popularized the idea of "learned
+ helplessness." He found that when an animal was unable to escape from torture, even for a very short time, it
+ would often fail to even try to escape the next time it was tortured. Seligman's lectures have been attended by
+ psychologists who worked at Guantanamo, and he recently received a no-bid Pentagon grant of $31,000,000, to
+ develop a program of "comprehensive soldier fitness," to train marines to avoid learned helplessness. Curt
+ Richter already in 1957 had described the "hopelessness" phenomenon in rats (“a reaction of hopelessness is
+ shown by some wild rats very soon after being grasped in the hand and prevented from moving. They seem literally
+ to give up,”) and even how to cure their hopelessness, by allowing them to have an experience of escaping once
+ (Richter, 1957, 1958). Rats which would normally be able to keep swimming in a tank for two or three days,
+ would often give up and drown in just a few minutes, after having an experience of "inescapable stress." Richter
+ made the important discovery that the hearts of the hopeless rats slowed down before they died, remaining
+ relaxed and filled with blood, revealing the dominant activity of the vagal nerve, secreting acetylcholine. The
+ sympathetic nervous system (secreting noradrenaline) accelerates the heart, and is usually activated in stress,
+ in the "fight or flight" reaction, but this radically different (parasympathetic) nervous activity hadn't
+ previously been seen to occur in stressful situations. The parasympathetic, cholinergic, nervous system had been
+ thought of as inactive during stress, and activated to regulate processes of digestion, sleep, and repair.
+ Besides the cholinergic nerves of the parasympathetic system, many nerves of the central nervous system also
+ secrete acetylcholine, which activates smooth muscles, skeletal muscles, glands, and other nerves, and also has
+ some inhibitory effects. The parasympathetic nerves also secrete the enzyme, cholinesterase, which destroys
+ acetylcholine. However, many other types of cell (red blood cells, fibroblasts, sympathetic nerves, marrow
+ cells), maybe all cells, can secrete cholinesterase. Because cholinergic nerves have been opposed to the
+ sympathetic, adrenergic, nerves, there has been a tendency to neglect their nerve exciting roles, when looking
+ at causes of excitotoxicity, or the stress-induced loss of brain cells. Excessive cholinergic stimulation,
+ however, can contribute to excitotoxic cell death, for example when it's combined with high cortisol and/or
+ hypoglycemia. Drugs that block the stimulating effects of acetylcholine (the anticholinergics) as well as
+ chemicals that mimic the effects of acetylcholine, such as the organophosphate insecticides, can impair the
+ ability to think and learn. This suggested to some people that age-related dementia was the result of the
+ deterioration of the cholinergic nerves in the brain. Drugs to increase the stimulating effects of acetylcholine
+ in the brain (by inactivating cholinesterase) were promoted as treatment for Alzheimer's disease. Although
+ herbal inhibitors were well known, profitable new drugs, starting with Tacrine, were put into use. It was soon
+ evident that Tacrine was causing serious liver damage, but wasn't slowing the rate of mental deterioration. As
+ the failure of the cholinergic drug Tacrine was becoming commonly known, another drug, amantadine (later, the
+ similar memantine) was proposed for combined treatment. In the 1950s, the anticholinergic drug atropine was
+ proposed a few times for treating dementia, and amantadine, which was also considered anticholinergic, was
+ proposed for some mental conditions, including Creutzfeldt-Jacob Disease (Sanders and Dunn, 1973). It must have
+ seemed odd to propose that an anticholinergic drug be used to treat a condition that was being so profitably
+ treated with a pro-cholinergic drug, but memantine came to be classified as an anti-excitatory "NMDA blocker,"
+ to protect the remaining cholinergic nerves, so that both drugs could logically be prescribed simultaneously.
+ The added drug seems to have a small beneficial effect, but there has been no suggestion that this could be the
+ result of its previously-known anticholinergic effects. Over the years, some people have suspected that
+ Alzheimer's disease might be caused partly by a lack of purpose and stimulation in their life, and have found
+ that meaningful, interesting activity could improve their mental functioning. Because the idea of a "genetically
+ determined hard-wired" brain is no longer taught so dogmatically, there is increasing interest in this therapy
+ for all kinds of brain impairment. The analogy to the Berkeley enrichment experience is clear, so the
+ association of increasing cholinesterase activity with improving brain function should be of interest. The
+ after-effect of poisoning by nerve gas or insecticide has been compared to the dementia of old age. The
+ anticholinergic drugs are generally recognized for protecting against those toxins. Traumatic brain injury, even
+ with improvement in the short term, often starts a long-term degenerative process, greatly increasing the
+ likelihood of dementia at a later age. A cholinergic excitotoxic process is known to be involved in the
+ traumatic degeneration of nerves (Lyeth and Hayes, 1992), and the use of anticholinergic drugs has been
+ recommended for many years to treat traumatic brain injuries (e.g., Ward, 1950: Ruge, 1954; Hayes, et al.,
+ 1986). In 1976 there was an experiment (Rosellini, et al.) that made an important link between the enrichment
+ experiments and the learned helplessness experiments. The control animals in the enrichment experiments were
+ singly housed, while the others shared a larger enclosure. In the later experiment, it was found that the rats
+ "who were reared in isolation died suddenly when placed in a stressful swimming situation," while the
+ group-housed animals were resistant, effective swimmers. Enrichment and deprivation have very clear biological
+ meaning, and one is the negation of the other. The increase of cholinesterase, the enzyme that destroys
+ acetylcholine, during enrichment, serves to inactivate cholinergic processes. If deprivation does its harm by
+ increasing the activity of the cholinergic system, we should expect that a cholinergic drug might substitute for
+ inescapable stress, as a cause of learned helplessness, and that an anticholinergic drug could cure learned
+ helplessness. Those tests have been done: "Treatment with the anticholinesterase, physostigmine, successfully
+ mimicked the effects of inescapable shock." "The centrally acting anticholinergic scopolamine hydrobromide
+ antagonized the effects of physostigmine, and when administered prior to escape testing antagonized the
+ disruptive effects of previously administered inescapable shock." (Anisman, et al., 1981.) This kind of
+ experiment would suggest that the anticholinesterase drugs still being used for Alzheimer's disease treatment
+ aren't biologically helpful. In an earlier newsletter I discussed the changes of growth hormone, and its
+ antagonist somatostatin, in association with dementia: Growth hormone increases, somatostatin decreases. The
+ cholinergic nerves are a major factor in shifting those hormones in the direction of dementia, and the
+ anticholinergic drugs tend to increase the ratio of somatostatin to growth hormone. Somatostatin and
+ cholinesterase have been found to co-exist in single nerve cells (Delfs, et al., 1984). Estrogen, which was
+ promoted so intensively as prevention or treatment for Alzheimer's disease, was finally shown to contribute to
+ its development. One of the characteristic effects of estrogen is to increase the level of growth hormone in the
+ blood. This is just one of many ways that estrogen is associated with cholinergic activation. During pregnancy,
+ it's important for the uterus not to contract. Cholinergic stimulation causes it to contract; too much estrogen
+ activates that system, and causes miscarriage if it's excessive. An important function of progesterone is to
+ keep the uterus relaxed during pregnancy. In the uterus, and in many other systems, progesterone increases the
+ activity of cholinesterase, removing the acetylcholine which, under the influence of estrogen, would cause the
+ uterus to contract. Progesterone is being used to treat brain injuries, very successfully. It protects against
+ inflammation, and in an early study, compared to placebo, lowered mortality by more than half. It's instructive
+ to consider its anticholinergic role in the uterus, in relation to its brain protective effects. When the brain
+ is poisoned by an organophosphate insecticide, which lowers the activity of cholinesterase, seizures are likely
+ to occur, and treatment with progesterone can prevent those seizures, reversing the inhibition of the enzyme
+ (and increasing the activity of cholinesterase in rats that weren't poisoned) (Joshi, et al., 2010). Similar
+ effects of progesterone on cholinesterase occur in menstrually cycling women (Fairbrother, et al., 1989),
+ implying that this is a general function of progesterone, not just something to protect pregnancy. Estrogen,
+ with similar generality, decreases the activity of cholinesterase. DHEA, like progesterone, increases the
+ activity of cholinesterase, and is brain protective (Aly, et al., 2011). Brain trauma consistently leads to
+ decreased activity of this enzyme (Östberg, et al., 2011; Donat, et al., 2007), causing the acetylcholine
+ produced in the brain to accumulate, with many interesting consequences. In 1997, a group (Pike, et al.) created
+ brain injuries in rats to test the idea that a cholinesterase inhibitor would improve their recovery and ability
+ to move through a maze. They found instead that it reduced the cognitive ability of both the injured and normal
+ rats. An anticholinergic drug, selegeline (deprenyl) that is used to treat Parkinson's disease and, informally,
+ as a mood altering antiaging drug, was found by a different group (Zhu, et al., 2000) to improve cognitive
+ recovery from brain injuries. One of acetylcholine's important functions, in the brain as elsewhere, is the
+ relaxation of blood vessels, and this is done by activating the synthesis of NO, nitric oxide. (Without NO,
+ acetylcholine constricts blood vessels; Librizzi, et al., 2000.) The basic control of blood flow in the brain is
+ the result of the relaxation of the wall of blood vessels in the presence of carbon dioxide, which is produced
+ in proportion to the rate at which oxygen and glucose are being metabolically combined by active cells. In the
+ inability of cells to produce CO2 at a normal rate, nitric oxide synthesis in blood vessels can cause them to
+ dilate. The mechanism of relaxation by NO is very different, however, involving the inhibition of mitochondrial
+ energy production (Barron, et al., 2001). Situations that favor the production and retention of a larger amount
+ of carbon dioxide in the tissues are likely to reduce the basic "tone" of the parasympathetic nervous system, as
+ there is less need for additional vasodilation. Nitric oxide can diffuse away from the blood vessels, affecting
+ the energy metabolism of nerve cells (Steinert, et al., 2010). Normally, astrocytes protect nerve cells from
+ nitric oxide (Chen, et al., 2001), but that function can be altered, for example by bacterial endotoxin absorbed
+ from the intestine (Solà, et al., 2002) or by amyloid-beta (Tran, 2001), causing them to produce nitric oxide
+ themselves. Nitric oxide is increasingly seen as an important factor in nerve degeneration (Doherty, 2011).
+ Nitric oxide activates processes (Obukuro, et al., 2013) that can lead to cell death. Inhibiting the production
+ of nitric oxide protects against various kinds of dementia (Sharma & Sharma, 2013; Sharma & Singh,
+ 2013). Brain trauma causes a large increase in nitric oxide formation, and blocking its synthesis improves
+ recovery (Hüttemann, et al., 2008; Gahm, et al., 2006). Organophosphates increase nitric oxide formation, and
+ the protective anticholinergic drugs such as atropine reduce it (Chang, et al., 2001; Kim, et al., 1997).
+ Stress, including fear (Campos, et al., 2013) and isolation (Zlatković & Filipović, 2013) can activate the
+ formation of nitric oxide, and various mediators of inflammation also activate it. The nitric oxide in a
+ person's exhaled breath can be used to diagnose some diseases, and it probably also reflects the level of their
+ emotional well-being. The increase of cholinesterase by enriched living serves to protect tissues against an
+ accumulation of acetylcholine. The activation of nitric oxide synthesis by acetylcholine tends to block energy
+ production, and to activate autolytic or catabolic processes, which are probably involved in the development of
+ a thinner cerebral cortex in isolated or stressed animals. Breaking down acetylcholine rapidly, the tissue
+ renewal processes are able to predominate in the enriched animals. Environmental conditions that are favorable
+ for respiratory energy production are protective against learned helplessness and neurodegeneration, and other
+ biological problems that involve the same mechanisms. Adaptation to high altitude, which stimulates the
+ formation of new mitochondria and increased thyroid (T3) activity, has been used for many years to treat
+ neurological problems, and the effect has been demonstrated in animal experiments (Manukhina, et al., 2010).
+ Bright light can reverse the cholinergic effects of inescapable stress (Flemmer, et al., 1990). During the
+ development of learned helplessness, the T3 level in the blood decreases (Helmreich, et al., 2006), and removal
+ of the thyroid gland creates the "escape deficit," while supplementing with thyroid hormone before exposing the
+ animal to inescapable shock prevents its development (Levine, et al., 1990). After learned helplessness has been
+ created in rats, supplementing with T3 reverses it (Massol, et al., 1987, 1988). Hypothyroidism and excess
+ cholinergic tone have many similarities, including increased formation of nitric oxide, so that similar
+ symptoms, such as muscle inflammation, can be produced by cholinesterase inhibitors such as Tacrine, by
+ increased nitric oxide, or by simple hypothyroidism (Jeyarasasingam, et al., 2000; Franco, et al., 2006).
+ Insecticide exposure has been suspected to be a factor in the increased incidence of Alzheimer's disease
+ (Zaganas, et al., 2013), but it could be contributing to many other problems, involving inflammation, edema, and
+ degeneration. Another important source of organophosphate poisoning is the air used to pressurize airliners,
+ which can be contaminated with organophosphate fumes coming from the engine used to compress it. Possibly the
+ most toxic component of our environment is the way the society has been designed, to eliminate meaningful
+ choices for most people. In the experiment of Freund, et al., some mice became more exploratory because of the
+ choices they made, while others' lives became more routinized and limited. Our culture reinforces routinized
+ living. In the absence of opportunities to vary the way you work and live to accord with new knowledge that you
+ gain, the nutritional, hormonal and physical factors have special importance. Supplements of thyroid and
+ progesterone are proven to be generally protective against the cholinergic threats, but there are many other
+ factors that can be adjusted according to particular needs. Niacinamide, like progesterone, inhibits the
+ production of nitric oxide, and also like progesterone, it improves recovery from brain injury (Hoane, et al.,
+ 2008). In genetically altered mice with an Alzheimer's trait, niacinamide corrects the defect (Green, et al.,
+ 2008). Drugs such as atropine and antihistamines can be used in crisis situations. Bright light, without excess
+ ultraviolet, should be available every day. The cholinergic system is much more than a part of the nervous
+ system, and is involved in cell metabolism and tissue renewal. Most people can benefit from reducing intake of
+ phosphate, iron, and polyunsaturated fats (which can inhibit cholinesterase; Willis, et al., 2009), and from
+ choosing foods that reduce production and absorption of endotoxin. And, obviously, drugs that are intended to
+ increase the effects of nitric oxide (asparagine, zildenafil/Viagra, minoxidil/Rogaine) and acetylcholine
+ (bethanechol, benzpyrinium, etc.) should be avoided.
+
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+ modulation by progesterone and 4'-chlorodiazepam in rats. Joshi V, Arora T, Mehta AK, Sharma
+ AK, Rathor N, Mehta KD, Mahajan P, Mediratta PK, Banerjee BD, Sharma KK. Environ Toxicol Pharmacol. 1997 Feb
+ 15;3(1):53-6. A role of nitric oxide in organophosphate-induced convulsions. Kim YB,
+ Hur GH, Lee YS, Han BG, Shin S. J Comp Physiol Psychol. 1960 Dec;53:509-19. Effects of
+ environmental complexity and training on brain chemistry. Krech D, Rosenzweig MR, Bennett EL.
+ Physiol Behav. 1990 Jul;48(1):165-7. Thyroparathyroidectomy produces a progressive escape deficit
+ in rats. Levine JD, Strauss LR, Muenz LR, Dratman MB, Stewart KT, Adler NT. Neuroscience.
+ 2000;101(2):283-7. Nitric oxide synthase inhibitors unmask acetylcholine-mediated constriction of
+ cerebral vessels in the in vitro isolated guinea-pig brain. Librizzi L, Folco G, de Curtis M.
+ J Neurotrauma. 1992 May;9 Suppl 2:S463-74. Cholinergic and opioid mediation of traumatic brain
+ injury. Lyeth BG, Hayes RL. Neurosci Behav Physiol. 2010 Sep;40(7):737-43. Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer's disease by adaptation
+ to hypoxia. Manukhina EB, Goryacheva AV, Barskov IV, Viktorov IV, Guseva AA, Pshennikova MG,
+ Khomenko IP, Mashina SY, Pokidyshev DA, Malyshev IY. Eur J Pharmacol. 1987 Feb 24;134(3):345-8. Triiodothyroacetic acid-induced reversal of learned helplessness in rats. Massol J, Martin
+ P, Soubrié P, Simon P. Eur J Pharmacol. 1988 Aug 2;152(3):347-51. Triiodothyroacetic acid (TRIAC)
+ potentiation of antidepressant-induced reversal of learned helplessness in rats. Massol J,
+ Martin P, Soubrié P, Puech AJ. J Neurosci. 2013 Jul 31;33(31):12557-12568. Nitric Oxide Mediates
+ Selective Degeneration of Hypothalamic Orexin Neurons through Dysfunction of Protein Disulfide
+ Isomerase.Obukuro K, Nobunaga M, Takigawa M, Morioka H, Hisatsune A, Isohama Y, Shimokawa H,
+ Tsutsui M, Katsuki H. Neurology. 2011 Mar 22;76(12):1046-50. Cholinergic dysfunction after
+ traumatic brain injury: preliminary findings from a PET study. Östberg A, Virta J, Rinne JO,
+ Oikonen V, Luoto P, Någren K, Arponen E, Tenovuo O. 1. Eur J Neurosci. 2013 Jan;37(2):181-9. Regulation of acetylcholinesterase activity by nitric oxide in rat neuromuscular junction via
+ N-methyl-D-aspartate receptor activation. Petrov KA, Malomouzh AI, Kovyazina IV, Krejci E,
+ Nikitashina AD, Proskurina SE, Zobov VV, Nikolsky EE. Brain Res. 2005 Jul 5;1049(1):112-9. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Pettus EH, Wright DW, Stein DG, Hoffman SW. J Neurotrauma. 1997 Dec;14(12):897-905. Effect
+ of tetrahydroaminoacridine, a cholinesterase inhibitor, on cognitive performance following experimental
+ brain injury. Pike BR, Hamm RJ, Temple MD, Buck DL, Lyeth BG. Psychosom Med. 1957
+ May-Jun;19(3):191-8. On the phenomenon of sudden death in animals and man. Richter
+ CP. Psychosom Med. 1976 Jan-Feb;38(1):55-8. Sudden death in the laboratory rat. Rosellini RA, Binik YM, Seligman MP. J Neurosurg. 1954 Jan;11(1):77-83. The use of cholinergic
+ blocking agents in the treatment of cranio-cerebral injuries. RUGE D. J Neurosurg. 1950
+ Sep;7(5):398-402. Atropine in the treatment of closed head injury.
+ WARD A Jr. Toxicol Appl Pharmacol. 2013 Aug 3. pii: S0041-008X(13)00326-8. Arsenic toxicity induced
+ endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible
+ nitric oxide synthase inhibitors. Sharma B, Sharma PM. Pharmacol Biochem Behav. 2013
+ Feb;103(4):821-30. Pharmacological inhibition of inducible nitric oxide synthase (iNOS) and
+ nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, convalesce behavior and biochemistry of
+ hypertension induced vascular dementia in rats. Sharma B, Singh N. J Neurol Neurosurg
+ Psychiatry. 1973 Aug;36(4):581-4. Creutzfeldt-Jakob disease treated with amantidine. A report of
+ two cases. Sanders WL, Dunn TL. Neuroscientist. 2010 Aug;16(4):435-52. Nitric
+ oxide signaling in brain function, dysfunction, and dementia. Steinert JR, Chernova T,
+ Forsythe ID. FASEB J. 2001 Jun;15(8):1407-9. Amyloid beta-peptide induces nitric oxide production
+ in rat hippocampus: association with cholinergic dysfunction and amelioration by inducible nitric oxide
+ synthase inhibitors. Tran MH, Yamada K, Olariu A, Mizuno M, Ren XH, Nabeshima T. Genes Nutr.
+ 2009 December; 4(4): 309–314. Dietary polyunsaturated fatty acids improve cholinergic transmission
+ in the aged brain Willis LM, Shukitt-Hale B, Joseph JA. Toxicology. 2013 May
+ 10;307:3-11. Linking pesticide exposure and dementia: what is the evidence? Zaganas
+ I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF, Tsatsakis AM. Exp Neurol. 2000
+ Nov;166(1):136-52. Postinjury administration of L-deprenyl improves cognitive function and enhances
+ neuroplasticity after traumatic brain injury. Zhu J, Hamm RJ, Reeves TM, Povlishock JT,
+ Phillips LL. Neurochem Int. 2013 Sep;63(3):172-9. Chronic social isolation induces NF-κB activation
+ and upregulation of iNOS protein expression in rat prefrontal cortex. Zlatković J, Filipović
+ D. J Biol Chem. 2006 Feb 24;281(8):4779-86. Hypothyroid phenotype is contributed by mitochondrial
+ complex I inactivation due to translocated neuronal nitric-oxide synthase. Franco MC, Antico
+ Arciuch VG, Peralta JG, Galli S, Levisman D, López LM, Romorini L, Poderoso JJ, Carreras MC. Laboratory of
+ Oxygen Metabolism, University Hospital, Facultad de Medicina, University of Buenos Aires, 1120-Buenos Aires,
+ Argentina. Although transcriptional effects of thyroid hormones have substantial influence on oxidative
+ metabolism, how thyroid sets basal metabolic rate remains obscure.
+ Compartmental localization of nitric-oxide synthases is important for nitric
+ oxide signaling. We therefore examined liver neuronal nitric-oxide synthase-alpha
+ (nNOS) subcellular distribution as a putative mechanism for thyroid effects on
+ rat metabolic rate. At low 3,3',5-triiodo-L-thyronine levels, nNOS mRNA increased
+ by 3-fold, protein expression by one-fold, and nNOS was selectively
+ translocated to mitochondria without changes in other isoforms. In contrast, under thyroid hormone
+ administration, mRNA level did not change and nNOS remained predominantly localized in cytosol. In
+ hypothyroidism, nNOS translocation resulted in enhanced mitochondrial nitric-oxide synthase activity with
+ low O2 uptake. In this context, NO utilization increased active O2 species and peroxynitrite yields and
+ tyrosine nitration of complex I proteins that reduced complex activity. Hypothyroidism was also associated
+ to high phospho-p38 mitogen-activated protein kinase and decreased phospho-extracellular signal-regulated kinase
+ 1/2 and cyclin D1 levels.
+ Similarly to thyroid hormones, but without changing thyroid status, nitric-oxide
+ synthase inhibitor N(omega)-nitro-L-arginine methyl ester increased basal
+ metabolic rate, prevented mitochondrial nitration and complex I derangement, and
+ turned mitogen-activated protein kinase signaling and cyclin D1 expression back
+ to control pattern. We surmise that nNOS spatial confinement in mitochondria is a
+ significant downstream effector of thyroid hormone and hypothyroid phenotype.
+
+ Toxicology. 2013 May 10;307:3-11. Linking pesticide exposure and dementia: what is the
+ evidence? Zaganas I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF,
+ Tsatsakis AM. J Pharmacol Exp Ther. 2000 Oct;295(1):314-20. Nitric oxide is involved in
+ acetylcholinesterase inhibitor-induced myopathy in rats. Jeyarasasingam G, Yeluashvili M, Quik
+ M. Neuroreport. 2000 Apr 27;11(6):1173-6. Tacrine, a reversible acetylcholinesterase inhibitor,
+ induces myopathy. Jeyarasasingam G, Yeluashvili M, Quik M. Biochem Biophys Res Commun. 2002
+ Jan 11;290(1):97-104. NO synthesis, unlike respiration, influences intracellular oxygen tension. Coste J, Vial
+ JC, Faury G, Deronzier A, Usson Y, Robert-Nicoud M, Verdetti J. We have developed a new phosphorescent probe,
+ PdTCPPNa(4), whose luminescence properties are affected by local variations of intracellular oxygen tension
+ (PO(2)). Spectrofluorometric measurements on living human umbilical venous endothelial cells loaded with this
+ molecule show that a decrease in extracellular oxygen tension induces a decrease of PO(2), illustrating the
+ phenomenon of oxygen diffusion and validating the use of this probe in living cells. Moreover, KCN- or
+ 2,4-dinitrophenol-induced modifications of respiration do not lead to detectable PO(2) variations, probably
+ because O(2) diffusion is sufficient to allow oxygen supply. On the contrary, activation by
+ acetylcholine or endothelial nitric oxide synthase (eNOS), which produces NO while consuming oxygen, induces
+ a significant decrease in PO(2), whose amplitude is dependent on the acetylcholine dose, i.e., the eNOS
+ activity level. Hence, activated cytosolic enzymes could consume high levels of oxygen which
+ cannot be supplied by diffusion, leading to PO(2) decrease. Other cell physiology mechanisms leading to PO(2)
+ variations can now be studied in living cells with this probe. Science. 1984 Jan 6;223(4631):61-3. Coexistence of acetylcholinesterase and somatostatin-immunoreactivity in neurons cultured from rat
+ cerebrum. Delfs JR, Zhu CH, Dichter MA. Genes Nutr. 2009 December; 4(4): 309–314. Dietary polyunsaturated fatty acids improve cholinergic transmission in the aged brain Willis LM, Shukitt-Hale B, Joseph JA. Toxicology. 2013 May 10;307:3-11. Linking pesticide exposure and
+ dementia: what is the evidence? Zaganas I, Kapetanaki S, Mastorodemos V, Kanavouras K, Colosio C, Wilks MF,
+ Tsatsakis AM. s sufficient for oxidative phosphorylation (references in ref. 1). These findings indicate that,
+ in execution of these tasks, the involved brain tissue switches to aerobic glycolysis. Acta Neurochir Suppl.
+ 1997;70:130-3. Topical application of insulin like growth factor-1 reduces edema and upregulation of neuronal
+ nitric oxide synthase following trauma to the rat spinal cord. Sharma HS, Nyberg F, Gordh T, Alm P, Westman J.
+ Toxicol Appl Pharmacol. 2013 Aug 3. pii: S0041-008X(13)00326-8. Arsenic toxicity induced
+ endothelial dysfunction and dementia: Pharmacological interdiction by histone deacetylase and inducible
+ nitric oxide synthase inhibitors. Sharma B, Sharma PM. 2. Pharmacol Biochem Behav. 2013
+ Feb;103(4):821-30. Pharmacological inhibition of inducible nitric oxide synthase (iNOS) and
+ nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, convalesce behavior and biochemistry of
+ hypertension induced vascular dementia in rats. Sharma B, Singh N. CNS and CVS Research Lab.,
+ Pharmacology Division, Department of Pharmaceutical Sciences and Drug Research, Faculty of Medicine, Punjabi
+ University, Patiala 147002, Punjab, India. bhupeshresearch@gmail.com
+ Cognitive disorders are likely to increase over the coming years (5-10). Vascular dementia (VaD) has
+ heterogeneous pathology and is a challenge for clinicians. Current Alzheimer's disease drugs have had limited
+ clinical efficacy in treating VaD and none have been approved by major regulatory authorities specifically
+ for this disease. Role of iNOS and NADPH-oxidase has been reported in various pathological conditions but
+ there role in hypertension (Hypt) induced VaD is still unclear. This research work investigates the salutiferous
+ effect of aminoguanidine (AG), an iNOS inhibitor and 4'-hydroxy-3'-methoxyacetophenone (HMAP), a NADPH oxidase
+ inhibitor in Hypt induced VaD in rats. Deoxycorticosterone acetate-salt (DOCA-S) hypertension has been used for
+ development of VaD in rats. Morris water-maze was used for testing learning and memory. Vascular system
+ assessment was done by testing endothelial function. Mean arterial blood pressure (MABP), oxidative stress
+ [aortic superoxide anion, serum and brain thiobarbituric acid reactive species (TBARS) and brain
+ glutathione (GSH)], nitric oxide levels (serum nitrite/nitrate) and cholinergic activity (brain acetyl
+ cholinesterase activity-AChE) were also measured. DOCA-S treated rats have shown increased MABP with impairment
+ of endothelial function, learning and memory, reduction in serum nitrite/nitrate & brain GSH levels
+ along with increase in serum & brain TBARS, and brain AChE activity. AG as well as HMAP significantly
+ convalesce Hypt induced impairment of learning, memory, endothelial function, and alterations in various
+ biochemical parameters. It may be concluded that AG, an iNOS inhibitor and HMAP, a NADPH-oxidase inhibitor
+ may be considered as potential agents for the management of Hypt induced VaD. Copyright © 2012 Elsevier
+ Inc. All rights reserved. [Curr Pharm Des. 2010;16(25):2837-50. Nitric oxide: target for therapeutic strategies
+ in Alzheimer's disease. Fernandez AP, Pozo-Rodrigalvarez A, Serrano J, Martinez-Murillo R. "data
+ implicating nitric oxide (NO) in the progression of the disease. The three isoforms of the NO-synthesizing
+ enzyme (NOS) operate as central mediators of amyloid beta-peptide (Aβ) action, giving rise to elevated
+ levels of NO that contributes to the maintenance, self-perpetuation and progression of the disease. "] J Neuropathol Exp Neurol. 2007 Apr;66(4):272-83. Nitric oxide synthase 3-mediated neurodegeneration
+ after intracerebral gene delivery. de la Monte SM, Jhaveri A, Maron BA, Wands JR. "increased nitric
+ oxide synthase 3 (NOS3) expression correlates with apoptosis in cortical neurons and colocalizes with
+ amyloid precursor protein (APP)-amyloid beta (Abeta) deposits in the brain."
+
+ Neuroscience. 2000;101(2):283-7. Nitric oxide synthase inhibitors unmask acetylcholine-mediated
+ constriction of cerebral vessels in the in vitro isolated guinea-pig brain. Librizzi L, Folco
+ G, de Curtis M. Pharmacology. 2000 Feb;60(2):82-9. Choline is a full agonist in inducing activation of neuronal
+ nitric oxide synthase via the muscarinic M1 receptor. Carriere JL, El-Fakahany EE. Glia. 2003 Jan
+ 15;41(2):207-11. Alzheimer's disease is associated with a selective increase in alpha7 nicotinic acetylcholine
+ receptor immunoreactivity in astrocytes. Teaktong T, Graham A, Court J, Perry R, Jaros E, Johnson M, Hall R,
+ Perry E. 16. Neuroscientist. 2010 Aug;16(4):435-52.
+ Nitric oxide signaling in brain function, dysfunction, and dementia.
+ Steinert JR, Chernova T, Forsythe ID. Neurotoxicity at the Synaptic Interface, MRC Toxicology Unit, University
+ of Leicester, Leicester, UK. Nitric oxide (NO) is an important signaling molecule that is widely used in the
+ nervous system. With recognition of its roles in synaptic plasticity (long-term potentiation, LTP; long-term
+ depression, LTD) and elucidation of calcium-dependent, NMDAR-mediated activation of neuronal nitric oxide
+ synthase (nNOS), numerous molecular and pharmacological tools have been used to explore the physiology and
+ pathological consequences for nitrergic signaling. In this review, the authors summarize the current
+ understanding of this subtle signaling pathway, discuss the evidence for nitrergic modulation of ion
+ channels and homeostatic modulation of intrinsic excitability, and speculate about the pathological consequences
+ of spillover between different nitrergic compartments in contributing to aberrant signaling in neurodegenerative
+ disorders. Accumulating evidence points to various ion channels and particularly voltage-gated potassium
+ channels as signaling targets, whereby NO mediates activity-dependent control of intrinsic neuronal
+ excitability; such changes could underlie broader mechanisms of synaptic plasticity across neuronal networks. In
+ addition, the inability to constrain NO diffusion suggests that spillover from
+ endothelium (eNOS) and/or immune compartments (iNOS) into the nervous system
+ provides potential pathological sources of NO and where control failure in these
+ other systems could have broader neurological implications. Abnormal NO signaling could
+ therefore contribute to a variety of neurodegenerative pathologies such as stroke/excitotoxicity,
+ Alzheimer's disease, multiple sclerosis, and Parkinson's disease. Neurosci Bull. 2011 Dec;27(6):366-82. Nitric
+ oxide in neurodegeneration: potential benefits of non-steroidal anti-inflammatories. Doherty GH.18.
+ Neuroscience. 2010 Dec 15;171(3):859-68. Low energy laser light (632.8 nm) suppresses amyloid-β peptide-induced
+ oxidative and inflammatory responses in astrocytes. Yang X, Askarova S, Sheng W, Chen JK, Sun AY, Sun GY, Yao G,
+ Lee JC. Neurosci Behav Physiol. 2010 Sep;40(7):737-43. Prevention of neurodegenerative damage to
+ the brain in rats in experimental Alzheimer's disease by adaptation to hypoxia. Manukhina EB,
+ Goryacheva AV, Barskov IV, Viktorov IV, Guseva AA, Pshennikova MG, Khomenko IP, Mashina SY, Pokidyshev DA,
+ Malyshev IY. Physiol Behav. 1990 Jul;48(1):165-7.
+ Thyroparathyroidectomy produces a progressive escape deficit in rats.
+ Levine JD, Strauss LR, Muenz LR, Dratman MB, Stewart KT, Adler NT. Department of Anatomy, University of
+ Pennsylvania, Philadelphia. Abnormal thyroid status and affective disorders have been associated in the human
+ clinical literature. It has recently been shown that pretreatment with thyroid
+ hormone can prevent escape deficits produced by inescapable shock in an animal
+ analogue of depression. In this report we provide evidence that hypothyroid
+ status can produce an escape deficit in rats. While sham-operated rats improved their
+ performance on a simple escape task over three days of testing, thyroparathyroidectomized rats showed a
+ pronounced decrease in their responses. Markov transition analysis was used to obtain conditional probabilities
+ of escaping given a prior escape or failure to escape for the two groups. This analysis shows that the structure
+ of the data set may be similar for the two groups. These results suggest that if intact rats learn to escape,
+ then hypothyroid rats may learn not to escape. 1. Pharmacol Biochem Behav. 1990 Aug;36(4):775-8.
+ Bright light blocks the capacity of inescapable swim stress to supersensitize a
+ central muscarinic mechanism.
+ Flemmer DD, Dilsaver SC, Peck JA. Department of Psychiatry, Ohio State University. Clinical and basic
+ researchers have proposed that muscarinic cholinergic mechanisms mediate some effects of chronic stress. Chronic
+ inescapable (forced) swim stress depletes brain biogenic amines and is used to produce learned helplessness in
+ rats. Behavioral and biochemical characteristics of animals in the state of learned helplessness lead some
+ investigators to believe this condition provides a useful animal model of depression. Inescapable
+ swim stress
+ also produces supersensitivity to the hypothermic effect of the muscarinic
+ agonist oxotremorine in the rat. The authors previously demonstrated that bright
+ light potently induces subsensitivity of a central muscarinic mechanism involved in the regulation of core
+ temperature under a variety of circumstances. They now report using a repeated measures design that
+ inescapable swim stress of five days duration produces supersensitivity to oxotremorine (increase in thermic
+ response of 405%). This supersensitivity is reversed within five days by treatment
+ with
+ bright light, despite continuation of daily swim stress. Daily inescapable swim
+ stress was continued beyond cessation of treatment with bright light. Five days later,
+ supersensitivity to the hypothermic effect of oxotremorine was once again evident. Pharmacol Biochem
+ Behav. 1986 Aug;25(2):415-21. Neurochemical and behavioral consequences of mild, uncontrollable shock:
+ effects of PCPA. Edwards E, Johnson J, Anderson D, Turano P, Henn FA. The present experiments
+ examined the role of the serotonergic system in the behavioral deficit produced by uncontrollable shock.
+ In Experiment 1: Establishment of model, the behavioral potential of the Sprague-Dawley rat was
+ defined. When exposed to mild uncontrollable stress such as a 0.8 mA electric footshock, a significant
+ percentage of rats developed a shock escape deficit which was evident when subsequently placed in a shock
+ escape paradigm. Serotonin depletion was produced by chronic treatment with p-chlorophenylalanine.
+ Biogenic amine levels and 5-HT levels were monitored in various brain areas using HPLC. Following
+ chronic treatment with PCPA, the shock escape capability of the Sprague-Dawley rat was
+ assessed. The severe depletion of 5-HT in various brain
+ regions was highly correlated with a dramatic improvement in the shock escape
+ scores. Thus, the detrimental effects of exposure to a mild course of inescapable
+ shock can be prevented by chronic treatment with PCPA. These experiments implicate the
+ serotonergic system as a possible mediator of the "learned helplessness" phenomenon. Biol
+ Psychiatry. 1985 Sep;20(9):1023-5. Triiodothyronine-induced reversal of learned helplessness in
+ rats. Martin P, Brochet D, Soubrie P, Simon P. Pharmacol Biochem Behav. 1982 Nov;17(5):877-83.
+ Evidence for a serotonergic mechanism of the learned helplessness phenomenon. Brown L, Rosellini RA,
+ Samuels OB, Riley EP. The present experiments examined the role of the serotonergic system in the
+ learned helplessness phenomenon. In Experiment 1, a 200 mg/kg dose of 1-tryptophan injected 30 min prior
+ to testing disrupted acquisition of Fixed Ratio 2 shuttle escape behavior. In Experiment 2, a 100 mg/kg
+ dose of 5-HTP produced interference with the acquisition of the escape response. Furthermore, this
+ interference was prevented by treatment with the serotonergic antagonist methysergide. In Experiment 3,
+ animals were pretreated with a subeffective dose of 1-tryptophan in combination with subeffective exposure
+ to inescapable shock. These animals showed a deficit in the acquisition of FR-2 shuttle escape. In
+ Experiment 4, combined exposure to a subeffective dose of 5-HTP and inescapable shock (40 trials) resulted
+ in an acquisition deficit. This deficit was reversed by methysergide. Experiment 5 showed that the
+ detrimental effects of exposure to prolonged (80 trials) of inescapable shock can be prevented by
+ treatment with methysergide. These studies implicate the serotonergic system as a possible mediator
+ of the learned helplessness phenomenon. 45. Med Hypotheses. 2004;63(2):308-21. Brain cholinesterases: II.
+ The molecular and cellular basis of Alzheimer's disease. Shen ZX. 2436 Rhode Island Avenue #3, Golden valley, MN
+ 55427-5011, USA.
+ zhengxshen@yahoo.com
+ Currently available evidence demonstrates that cholinesterases (ChEs), owing to their powerful enzymatic and
+ non-catalytic actions, unusually strong electrostatics, and exceptionally ubiquitous presence and
+ redundancy in their
+ capacity as the connector, the organizer and the safeguard of the brain, play fundamental
+ role(s) in the well-being of cells, tissues, animal and human lives, while they present themselves
+ adequately in quality and quantity. The widespread intracellular and extracellular membrane networks of
+ ChEs in the brain are also subject to various insults, such as aging, gene anomalies, environmental hazards,
+ head trauma, excessive oxidative stress, imbalances and/or deficits of organic constituents. The loss and the
+ alteration of ChEs on the outer surface membranous network may initiate the formation of extracellular senile
+ plaques and induce an outside-in cascade of Alzheimer's disease (AD). The alteration in ChEs on the
+ intracellular compartments membranous network may give rise to the development of intracellular neurofibrillary
+ tangles and induce an inside-out cascade of AD. The abnormal patterns of glycosylation and configuration changes
+ in ChEs may be reflecting their impaired metabolism at the molecular and cellular level and causing the
+ enzymatic and pharmacodynamical modifications and neurotoxicity detected in brain tissue and/or CSF of patients
+ with AD and in specimens in laboratory experiments. The inflammatory reactions mainly arising from
+ ChEs-containing neuroglial cells may facilitate the pathophysiologic process of AD. It is proposed that brain
+ ChEs may serve as a central point rallying various hypotheses regarding the etio-pathogenesis of AD. 3.
+ Neurology. 2011 Mar 22;76(12):1046-50. doi: 10.1212/WNL.0b013e318211c1c4. Cholinergic dysfunction after
+ traumatic brain injury: preliminary findings from a PET study. Östberg A, Virta J, Rinne JO, Oikonen V, Luoto P,
+ Någren K, Arponen E, Tenovuo O. Department of Neurology, University of Turku and Turku University Central
+ Hospital, Turku, Finland. OBJECTIVE: There is evidence that the cholinergic system is frequently involved in the
+ cognitive consequences of traumatic brain injury (TBI). We studied whether the brain cholinergic function is
+ altered after TBI in vivo using PET. METHODS: Cholinergic function was assessed with
+ [methyl-(11)C]N-methylpiperidyl-4-acetate, which reflects the acetylcholinesterase (AChE) activity, in 17
+ subjects more than 1 year after a TBI and in 12 healthy controls. All subjects had been without any centrally
+ acting drugs for at least 4 weeks. RESULTS: The AChE activity was significantly lower in subjects with TBI
+ compared
+
+ 0.004). CONCLUSIONS: Patients with chronic cognitive symptoms after TBI show widely lowered AChE activity across
+ the neocortex. © 2011 by AAN Enterprises, Inc. 9. Brain Inj. 2007 Sep;21(10):1031-7. Alterations of
+ acetylcholinesterase activity after traumatic brain injury in rats. Donat CK, Schuhmann MU, Voigt C, Nieber K,
+ Schliebs R, Brust P. Institute of Interdisciplinary Isotope Research, Permoserstasse 15, 04318 Leipzig,
+ Germany. donat@iif-leipzig.de
+ OBJECTIVE: The cholinergic system is highly vulnerable to traumatic brain injury (TBI). However, limited
+ information is available to what extent the degrading enzyme acetylcholinesterase (AChE) is involved. The
+ present study addresses this question. METHOD: Thirty-six anaesthetized Sprague-Dawley rats were subjected
+ to sham operation or to TBI using controlled cortical impact (CCI). The AChE activity was histochemically
+ determined in frozen brain slices at 2, 24 and 72 hours after TBI. RESULTS: High enzyme activity was observed in
+ regions rich in cholinergic innervation such as the olfactory tubercle, basal forebrain, putamen and superior
+ colliculi. Low activity was found in the cortex, cerebellum and particularly in
+ the white matter. A decrease of AchE activity (20-35%) was found in the
+ hippocampus and hypothalamus already at 2 hours after TBI. An increase of approximately
+ 30% was found in the basal forebrain at 2 and 24 hours. No changes occurred at 72 hours. CONCLUSION: The
+ findings are consistent with impairment of the cholinergic neurotransmission after TBI and suggest the
+ involvement of the AChE in short-term regulatory mechanisms. 35. Res Commun Chem Pathol Pharmacol. 1990
+ Jun;68(3):391-4. Increase of muscarinic receptor following kainic acid lesions of the nucleus basalis
+ magnocellularis in rat brain: an autoradiographic study. Katayama S, Kito S, Yamamura Y. Third Department of
+ Internal Medicine, Hiroshima University School of Medicine, Japan. We observed changes in cholinergic markers in
+ rat brain seven days after lesioning the nucleus basalis magnocellularis (nbm) with kainic acid. In
+ histochemical preparations stained for acetylcholinesterase (AChE), there was a
+ marked loss of large AChE reactive neurons within and beneath the nbm on the
+ injected side, and the AChE positive fibers were greatly decreased particularly
+ in the IV-VI layers of the frontal and parietal cortices ipsilateral to the
+ kainate lesion. Using in vitro receptor autoradiography, we found a significant increase (about 25%) in 3H-QNB
+ binding sites in the I-IV layers of the ipsilateral frontal and parietal cortices (p 0.05, Student's
+ t-test). The area
+ with decreased AChE activity and increased density in 3H-QNB binding sites corresponded to
+ the innervation of the cholinergic system arising from the nbm. The increase of density in 3H-QNB binding sites
+ was considered to reflect the postsynaptic denervation supersensitivity. 36. Hum Exp Toxicol. 1992
+ Nov;11(6):517-23. Long-term study of brain lesions following soman, in comparison to DFP and metrazol poisoning.
+ Kadar T, Cohen G, Sahar R, Alkalai D, Shapira S. Department of Pharmacology, Israel Institute for Biological
+ Research, Ness-Ziona, Israel. The long-term histopathological effects of acute lethal (95 micrograms kg-1)
+ and sublethal (56 micrograms kg-1) doses of soman were studied in rats and were compared to lesions caused
+ by equipotent doses of either another cholinesterase (ChE) inhibitor, DFP (1.8 mg kg-1), or a
+ non-organophosphorus convulsant, metrazol (100 mg kg-1). Severe toxic signs were noted following one LD50 dose
+ administration of all the compounds, yet only soman induced brain lesions. Moreover, even when administered at a
+ sublethal dose (0.5 LD50), soman induced some histological changes without any clinical signs of intoxication.
+ Soman-induced brain lesions were assessed quantitatively using a computerized image analyser. The analysis was
+ carried out for up to 3 months following administration, and a dynamic pattern of pathology was shown. The
+ cortical thickness and area of CA1 and CA3 cells declined significantly as early as 1 week post-exposure. No
+ pathological findings were detected following DFP and metrazol administration. It is therefore suggested
+ that brain lesions are not common for all ChE inhibitors and that convulsions per se are not the only factor
+ leading to brain damage following the administration of soman. The degenerative process (found also with the
+ sublethal dose of soman) might be due to a secondary effect, unrelated to soman's clinical toxicity, but leading
+ to long-term brain injuries. 42. J Neurotrauma. 1997 Dec;14(12):897-905. Effect of
+ tetrahydroaminoacridine, a cholinesterase inhibitor, on cognitive performance following experimental brain
+ injury. Pike BR, Hamm RJ, Temple MD, Buck DL, Lyeth BG. Department of Psychology, Virginia
+ Commonwealth University, Medical College of Virginia, Richmond 23284-2018, USA. An emerging literature exists in
+ support of deficits in cholinergic neurotransmission days to weeks following experimental traumatic brain injury
+ (TBI). In addition, novel cholinomimetic therapeutics have been demonstrated to improve cognitive outcome
+ following TBI in rats. We examined the effects of repeated postinjury administration of a cholinesterase
+ inhibitor, tetrahydroaminoacridine (THA), on cognitive performance following experimental TBI. Rats were either
+ injured at a moderate level of central fluid percussion TBI (2.1+/-0.1 atm) or were surgically prepared but not
+ delivered a fluid pulse (sham injury). Beginning 24 h after TBI or sham injury, rats were injected (IP) daily
+ for 15 days with an equal volume (1.0 ml/kg) of either 0.0, 1.0, 3.0, or 9.0
+
+ respectively). Cognitive performance was assessed on Days 11-15 after injury in a Morris water maze
+ (MWM). Analysis of maze latencies over days indicated that
+ chronic administration of THA produced a dose-related impairment in MWM
+ performance in both the injured and sham groups, with the 9.0 mg/kg dose
+ producing the largest deficit. The 1.0 and 3.0 mg/kg doses of THA impaired MWM
+ performance without affecting swimming speeds. Thus, the results of this investigation do not support the use of
+ THA as a cholinomimetic therapeutic for the treatment of cognitive deficits following TBI. 43. Toxicol Lett.
+ 1998 Dec 28;102-103:527-33. Chronic effects of low level exposure to anticholinesterases--a mechanistic review.
+ Ray DE. Medical Research Council Toxicology Unit, Leicester, UK. der2@le.ac.uk
+ High dose exposure to anticholinesterases which results in symptomatic poisoning can have lasting
+ consequences due to the trauma of intoxication, excitotoxicity, secondary hypoxic damage, and (for some
+ agents) a delayed onset polyneuropathy (OPIDN). The potential effects of low level exposure are less well
+ defined. The most reliable data comes from controlled clinical trials with specific agents. A single dose
+ of sarin or repeated doses of metrifonate or mevinphos, have produced only transient adverse effects at doses
+ causing substantial acetylcholinesterase inhibition. Other data comes from epidemiological surveys. These
+ have often used more sensitive indices than the clinical studies, but are less reliable due to the
+ difficulty of defining exposure and matching control and exposed populations. Subtle, mainly cognitive,
+ differences between exposed and non-exposed populations are sometimes seen. Low level exposure can cause a
+ reversible down-regulation of cholinergic systems, and a range of non-cholinesterase effects that are
+ structure-specific, and do not always parallel acute toxicity. Novel protein targets sensitive to low level
+ exposure to some organophosphates are known to exist in the brain, but their functional significance is not yet
+ understood. 44. Exp Neurol. 2000 Nov;166(1):136-52. Postinjury administration of L-deprenyl improves cognitive
+ function and enhances neuroplasticity after traumatic brain injury. Zhu J, Hamm RJ, Reeves TM, Povlishock
+ JT, Phillips LL. Department of Anatomy, Medical College of Virginia, Richmond, Virginia 23298-0709, USA. The rat
+ model of combined central fluid percussion traumatic brain injury (TBI) and bilateral entorhinal cortical lesion
+ (BEC) produces profound, persistent cognitive deficits, sequelae associated with human TBI. In contrast to
+ percussive TBI alone, this combined injury induces maladaptive hippocampal plasticity. Recent reports suggest a
+ potential role for dopamine in CNS plasticity after trauma. We have examined the effect of the dopamine enhancer
+ l-deprenyl on cognitive function and neuroplasticity following TBI. Rats received fluid percussion TBI, BEC
+ alone, or combined TBI + BEC lesion and were treated once daily for 7 days with l-deprenyl, beginning 24 h after
+ TBI alone and 15 min after BEC or TBI + BEC. Postinjury motor assessment showed no effect of l-deprenyl
+ treatment. Cognitive performance was assessed on days 11-15 postinjury and brains from the same cases examined
+ for dopamine beta-hydroxylase immunoreactivity (DBH-IR) and acetylcholinesterase (AChE) histochemistry.
+ Significant cognitive improvement relative to untreated injured cases was observed in both TBI groups following
+ l-deprenyl treatment; however, no drug effects were seen with BEC alone. l-Deprenyl attenuated injury-induced
+ loss in DBH-IR over CA1 and CA3 after TBI alone. However, after combined TBI + BEC, l-deprenyl was only
+ effective in protecting CA1 DBH-IR. AChE histostaining in CA3 was significantly elevated with l-deprenyl
+ in both injury models. After TBI + BEC, l-deprenyl also increased AChE
+ in the dentate molecular layer relative to untreated injured cases. These results
+ suggest that dopaminergic/noradrenergic enhancement facilitates cognitive
+ recovery after brain injury and that noradrenergic fiber integrity is correlated with enhanced synaptic
+ plasticity in the injured hippocampus. Copyright 2000 Academic Press. J Neurotrauma. 1992 May;9 Suppl
+ 2:S463-74. Cholinergic and opioid mediation of traumatic brain injury. Lyeth BG,
+ Hayes RL. Psychosom Med. 1976 Jan-Feb;38(1):55-8. Sudden death in the laboratory rat. Rosellini RA, Binik YM, Seligman MP. Vulnerability to sudden death was produced in laboratory rats by
+ manipulating their developmental history. Rats who were reared in isolation died suddenly when placed in a
+ stressful swimming situation. Handling of these singly-housed rats from 25 to 100 days of age potentiated the
+ phenomenon. However, animals who were group housed did not die even when they had been previously handled.
+ J Neurol Neurosurg Psychiatry. 1973 Aug;36(4):581-4. Creutzfeldt-Jakob disease treated with amantidine. A report
+ of two cases. Sanders WL, Dunn TL. The treatment of two cases of Creutzfeldt-Jakob disease with amantidine is
+ described. The first case made a remarkable initial improvement which was sustained for two months, but then
+ deteriorated and died. Histological examination of the brain showed changes consistent with early
+ Creutzfeldt-Jakob disease. The second case which was clinically one of Creutzfeldt-Jakob disease has now been
+ followed for 30 months since the start of treatment and appears to be cured. It is considered that amantidine
+ has a definite effect in this disease and it is suggested that its mode of action, though unknown, is more
+ likely to be metabolic than antiviral. Free PMC Article Arch Int Pharmacodyn Ther. 1986 Mar;280(1):136-44.
+ Effect of stress and glucocorticoids on the gastrointestinal cholinergic enzymes. Oriaku ET, Soliman KF.
+ (Glucocorticoids lower AChE) Cardiovasc Res. 1990 Apr;24(4):335-9. Sympathectomy alters acetylcholinesterase
+ expression in adult rat heart. Nyquist Battie C, Moran N. Harris LW, Garry VF, Jr, Moore RD. Biosynthesis
+ of cholinesterase in rabbit bone marrow cells in culture. Biochem Pharmacol. 1974 Aug;23(15):2155–2163.
+ Heller M, Hanahan DJ. Human erythrocyte membrane bound enzyme acetylcholinesterase. Biochim
+ Biophys Acta. 1972 Jan 17;255(1):251–272. J Cell Biol. 1976 June 1; 69(3): 638–646. Bartos EM. Properties
+ of growth-related acetylcholinesterase in a cell line of fibroblastic origin Behav Brain Res 2000
+ Jul;112(1-2):33-41 Impaired escape performance and enhanced conditioned fear in rats following exposure to an
+ uncontrollable stressor are mediated by glutamate and nitric oxide in the dorsal raphe nucleus. Grahn RE,
+ Watkins LR, Maier SF. Department of Psychology, Connecticut College, Box 5275, 270 Mohegan Avenue, 06320-4196,
+ New London, CT 06320-4196, USA. regra@conncoll.edu
+ Exposure to uncontrollable aversive events produces a variety of behavioral consequences that do not occur if
+ the aversive event is controllable. Accumulating evidence suggests that exaggerated excitation of serotonin
+ (5-HT) neurons in the dorsal raphe nucleus (DRN) is sufficient to cause these same behaviors, such as poor
+ shuttlebox escape performance and enhanced conditioned fear that occur 24 h after exposure to inescapable
+ tailshock (IS). The aim of the present studies was to explore the possibility that N-methyl-D-aspartate (NMDA)
+ receptor activation and nitric oxide (NO) formation within the DRN might be involved in mediating the behavioral
+ consequences of IS. To this end, either the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV) or
+ the nitric oxide synthase inhibitor Nw-nitro-L-arginine methyl ester (L-NAME), was microinjected into the DRN
+ before IS or before testing 24 h later. Blocking NMDA receptors with APV in the DRN during IS prevented the
+ usual impact of IS on escape responding and conditioned fear. However, injection of APV at the time of testing
+ only reduced these effects. The DRN was shown to be the critical site mediating blockade of these behavioral
+ changes since injection of APV lateral to the DRN did not alter the behavioral consequences of IS. Conversely,
+ L-NAME was most effective in reversing the effects of IS when administered at the time of testing. These results
+ suggest that there is glutamatergic input to the DRN at the time of IS that produces long-lasting changes in DRN
+ sensitivity. This plasticity in the DRN is discussed as a possible mechanism by which IS leads to changes in
+ escape performance and conditioned fear responding. and prolonged depression causes shrinkage of this area. The
+ high cortisol associated with depression is undoubtedly one of the factors causing brain shrinkage during
+ stress. Cushing's disease, in which the adrenal glands produce far too much cortisol, causes shrinkage of the
+ brain, and when the disease is cured by normalizing the level of cortisol, the brain size is restored. There are
+ two very different kinds of stress reaction. The best known "fight or flight reaction" could be called more
+ accurately "struggle to adapt." Another, less discussed kind, might appear to be a "give up and die or get
+ depressed" reaction, but it involves many processes that are protective and adaptive in certain circumstances.
+ tone and heart rate; drown easily. The role of acetylcholine, (Anisman, et al., 1981). A situation of
+ extreme restraint causes very rapid damage to the tissues, with bleeding ulcers of the stomach and intestine,
+ shrinking of the thymus gland, and, if the animal survives for a while, atrophy of the brain. (Doi, et al.,
+ 1991; Gatón, et al., 1993) LH, somatotropin, GH, Ach. caffeine progest Behav Brain Res. 2012 Mar
+ 17;228(2):294-8. doi: 10.1016/j.bbr.2011.11.036. Epub 2011 Dec 8. Parental enrichment and offspring development:
+ modifications to brain, behavior and the epigenome. Mychasiuk R, Zahir S, Schmold N, Ilnytskyy S, Kovalchuk O,
+ Gibb R. University of Lethbridge, Canadian Centre for Behavioural Neuroscience, Canada.
+ r.mychasiuk@uleth.ca
+
+ 4. Biomed Pharmacother. 2012 Jun;66(4):249-55. doi: 10.1016/j.biopha.2011.11.005. Epub 2011 Dec 21.
+ Cholinesterase activities and biochemical determinations in patients with prostate cancer: influence of Gleason
+ score, treatment and bone metastasis. Battisti V, Bagatini MD, Maders LD, Chiesa J, Santos KF, Gonçalves JF,
+ Abdalla FH, Battisti IE, Schetinger MR, Morsch VM. Departamento de Química, Centro de Ciências Naturais e
+ Exatas, Universidade Federal de Santa Maria, Campus Universitário, 97105-900 Santa Maria, RS, Brazil.
+ battistivanessa@gmail.com
+ Prostate cancer (PCa) is the sixth most common type of cancer worldwide. Cholinesterase is well known as having
+ non-cholinergic functions such as cellular proliferation and differentiation, suggesting a possible influence of
+ cholinesterase in tumorogenesis. Thus, the aim of this study was to investigate the whole blood
+ acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE) activities and some biochemical parameters
+ in PCa patients. This study was performed in 66 PCa patients and 40 control subjects. AChE and BChE activities
+ were determined in PCa patients and the influence of the Gleason score; bone metastasis and treatment in the
+ enzyme activities were also verified. Furthermore, we also analyzed possible biochemical alterations in these
+ patients.
+ AChE and BChE activities decreased in PCa patients in relation to the control
+ group and various biochemical changes were observed in these patients. Moreover,
+ Gleason score, metastasis and treatment influenced cholinesterase activities and
+ biochemical determinations. Our results suggest that cholinesterases activities
+ and biochemical parameters are altered in PCa. These facts support the idea that
+ the drop in the cholinesterase activity and the consequent increased amount of acetylcholine
+ could lead to a cholinergic overstimulation and increase the cell proliferation in PCa. Copyright © 2011
+ Elsevier Masson SAS. All rights reserved. 4. Biomed Pharmacother. 2012 Jun;66(4):249-55. doi:
+ 10.1016/j.biopha.2011.11.005. Epub 2011 Dec 21. Cholinesterase activities and biochemical determinations in
+ patients with prostate cancer: influence of Gleason score, treatment and bone metastasis. Battisti V, Bagatini
+ MD, Maders LD, Chiesa J, Santos KF, Gonçalves JF, Abdalla FH, Battisti IE, Schetinger MR, Morsch VM.
+ Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Campus
+ Universitário, 97105-900 Santa Maria, RS, Brazil.
+ battistivanessa@gmail.com
+ Prostate cancer (PCa) is the sixth most common type of cancer worldwide. Cholinesterase is well known as having
+ non-cholinergic functions such as cellular proliferation and differentiation, suggesting a possible influence of
+ cholinesterase in tumorogenesis. Thus, the aim of this study was to investigate the whole blood
+ acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE) activities and some biochemical parameters
+ in PCa patients. This study was performed in 66 PCa patients and 40 control subjects. AChE and BChE activities
+ were determined in PCa patients and the influence of the Gleason score; bone metastasis and treatment in the
+ enzyme activities were also verified. Furthermore, we also analyzed possible biochemical alterations in these
+ patients. AChE and BChE activities decreased in PCa patients in relation to the control group and various
+ biochemical changes were observed in these patients. Moreover, Gleason score, metastasis and treatment
+ influenced cholinesterase activities and biochemical determinations. Our results suggest that
+ cholinesterases activities and biochemical parameters are altered in PCa. These facts support the idea
+ that the drop in the cholinesterase activity and the consequent increased amount of acetylcholine could
+ lead to a cholinergic overstimulation and increase the cell proliferation in PCa. Copyright © 2011 Elsevier
+ Masson SAS. All rights reserved. 1. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2012 May;28(3):253-4, 262.
+ [Progesterone exerts neuroprotective effect on hypoxic-ischemic encephalopathy-induced brain damage via
+ inhibition expression of inducible nitric oxide synthase and nitric oxide production]. [Article in Chinese] Wang
+ XY, Li XJ, Li DL, Wang CR, Guo XP.
+ wxyinwxyin@163.com
+
+ 2. Mol Reprod Dev. 2012 Oct;79(10):689-96. doi: 10.1002/mrd.22075. Epub 2012 Sep 11. Roles of cytokines and
+ progesterone in the regulation of the nitric oxide generating system in bovine luteal endothelial cells.
+ Yoshioka S, Acosta TJ, Okuda K. Laboratory of Reproductive Physiology, Graduate School of Natural Science and
+ Technology, Okayama University, Okayama, Japan. Nitric oxide (NO) produced by luteal endothelial cells (LECs)
+ plays important roles in regulating corpus luteum (CL) function, yet the local mechanism regulating NO
+ generation in bovine CL remains unclear. The purpose of the present study was to elucidate if tumor necrosis
+ factor-α (TNF), interferon γ (IFNG), and/or progesterone (P4) play roles in regulating NO generating system in
+ LECs. Cultured bovine LECs obtained from the CL at the mid-luteal stage (Days 8-12 of the cycle) were treated
+ for 24 hr with TNF (2.9 nM), IFNG (2.5 nM), or P4 (0.032-32 µM). NO production was increased by TNF and IFNG,
+ but decreased by P4 (P < 0.05). TNF and IFNG stimulated the relative steady-state amounts of inducible nitric
+ oxide synthase (iNOS) mRNA and iNOS protein expression (P < 0.05), whereas P4 inhibited relative steady-state
+ amounts of iNOS mRNA and iNOS protein expression (P < 0.05). In contrast, endothelial nitric oxide synthase
+ (eNOS) expression was not affected by any treatment. TNF and IFNG stimulated NOS activity (P < 0.05) and
+ 1400W, a specific inhibitor of iNOS, reduced NO production stimulated by TNF and IFNG in LECs
+ (P < 0.05). Onapristone,
+ a specific P4 receptor antagonist, blocked the inhibitory effect of P4 on NO
+ production in LECs (P < 0.05). The overall findings suggest that TNF and IFNG accelerate luteolysis by
+ increasing NO production via stimulation of iNOS expression and NOS activity in bovine LECs. P4, on the other
+ hand, may act in maintaining CL function by suppressing iNOS expression in bovine LECs. Mol. Reprod. Dev. 79:
+ 689-696, 2012. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc. 3. J Neurochem. 2012
+ Jul;122(1):185-95. doi: 10.1111/j.1471-4159.2012.07753.x. Progesterone prevents mitochondrial dysfunction in the
+ spinal cord of wobbler mice. Deniselle MC, Carreras MC, Garay L, Gargiulo-Monachelli G, Meyer M, Poderoso
+ JJ, De Nicola AF. Laboratory of Neuroendocrine Biochemistry, Instituto de Biologia y Medicina
+ Experimental-CONICET, Buenos Aires, Argentina. In the Wobbler mouse, a mutation of the Vps54 protein increases
+ oxidative stress in spinal motoneurons, associated to toxic levels of nitric oxide and hyperactivity of
+ nitric oxide synthase (NOS). Progesterone neuroprotection has been reported for several CNS diseases, including
+ the Wobbler mouse neurodegeneration. In the present study, we analyzed progesterone effects on
+ mitochondrial-associated parameters of symptomatic Wobbler mice. The activities of mitochondrial respiratory
+ chain complexes I, II-III and IV and protein levels of mitochondrial and cytosolic NOS were determined in
+ cervical and lumbar cords from control, Wobbler and Wobbler mice receiving a progesterone implant for 18 days.
+ We found a significant reduction of complex I and II-III activities in mitochondria and increased protein levels
+ of mitochondrial, but not cytosolic nNOS, in the cervical cord of Wobbler mice. Progesterone
+ treatment prevented the
+ reduction of complex I in the cervical region and the increased level of
+ mitochondrial nNOS. Wobbler motoneurons also showed accumulation of amyloid precursor
+ protein immunoreactivity and decreased activity and immunostaining of MnSOD. Progesterone treatment avoided
+ these abnormalities. Therefore, administration of progesterone to clinically afflicted Wobblers (i) prevented
+ the abnormal increase of mitochondrial nNOS and normalized respiratory complex I; (ii) decreased amyloid
+ precursor protein accumulation, a sign of axonal degeneration, and (iii) increased superoxide dismutation. Thus,
+ progesterone neuroprotection decreases mitochondriopathy of Wobbler mouse cervical spinal cord. © 2012 The
+ Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry. Comp Biochem Physiol C. 1993
+ Sep;106(1):125-9. The role of the neurotransmitters acetylcholine and noradrenaline in the
+ pathogenesis of stress ulcers. Gatón J, Fernández de la Gándara F, Velasco A. People with
+ Cloninger's "harm avoidance" personality trait, which is closely associated with serotonin (Hansenne, et al.,
+ 1999), are more likely to develop dementia (Clément, et al., 2010). These observations are consistent with the
+ stress-susceptibility of people with high serotonin exposure, and to the effects of cortisol on nerves and
+ glucose-derived energy production. Jpn J Surg. 1991 Jan;21(1):43-9.
+ Participation of the parasympathetic nervous system in the development of
+ activity-stress ulcers.
+ Doi K, Iwahashi K, Tsunekawa K.17. J Auton Nerv Syst. 1987 Oct;20(3):265-8. Adrenergic modulation of gastric
+ stress pathology in rats: a cholinergic link. Ray A, Sullivan RM, Henke PG. Department of Psychology, St.
+ Francis Xavier University, Antigonish, Nova Scotia, Canada. The effects of some adrenergic drugs were evaluated
+ on cold restraint-induced gastric ulcers in rats. The beta-adrenergic antagonist, (+/-)-propranolol (1 and
+ 10 mg/kg), as well as the beta-agonist, isoproterenol (0.05 and 0.5 mg/kg) potentiated the gastric pathology. On
+ the other hand, the alpha-agonist, clonidine (0.5 mg/kg) attenuated and the alpha-antagonist, yohimbine (1
+ mg/kg) aggravated stress ulcer development. The anticholinergic agent, atropine methylnitrate (1 mg/kg), reduced
+ both the frequency and severity of stress ulcers and also antagonized the potentiating effects of
+ (+/-)-propranolol, isoproterenol and yohimbine. The results suggest a cholinergic role in the adrenergic
+ modulation of gastric stress pathology. Psychopharmacology (Berl). 1981;74(1):81-7.
+ Cholinergic influences on escape deficits produced by uncontrollable stress.
+ Anisman H, Glazier SJ, Sklar LS. A series of experiments assessed the potential role of acetylcholine (ACh) in
+ the escape interference produced by inescapable shock. Treatment with the
+ anticholinesterase, physostigmine, successfully mimicked the effects of
+ inescapable shock. That is, the drug disrupted performance when escape was prevented for 6
+ s on any given trial, thereby necessitating sustained active responding. When escape was possible upon shock
+ onset, the drug treatment did not influence performance. The centrally acting anticholinergic
+ scopolamine
+ hydrobromide antagonized the effects of physostigmine, and when administered
+ prior to escape testing antagonized the disruptive effects of previously
+ administered inescapable shock. In contrast, the peripherally acting agent scopolamine
+ methylbromide did not influence the effects of these treatments, suggesting that the effects of physostigmine
+ and inescapable shock involved central ACh changes. Scopolamine hydrobromide administered prior to inescapable
+ shock did not prevent the escape interference from subsequently appearing, but this effect could not be
+ attributed to state dependence. It was argued that the interference of escape following uncontrollable stress
+ was due to non-associative motor deficits. Alterations of the escape deficits by scopolamine were due to
+ elimination of the motor disruption. Curr Opin Oncol. 2005 Jan;17(1):55-60. DNA methylation and cancer therapy:
+ new developments and expectations. Esteller M. Cancer Epigenetics Laboratory, Spanish National Cancer Centre
+ (CNIO) Madrid, Spain. mesteller@cnio.es
+ PURPOSE OF REVIEW: In addition to having genetic causes, cancer can also be considered an epigenetic disease.
+ The main epigenetic modification is DNA methylation, and patterns of aberrant DNA methylation are now recognized
+ to be a common hallmark of human tumors. One of the most characteristic features is the inactivation of
+ tumor-suppressor genes by CpG-island hypermethylation of the CpG islands located in their promoter
+ regions. These sites, among others, are the targets of DNA-demethylating agents, the promising chemotherapeutic
+ drugs that are the focus of this article. RECENT FINDINGS: Four exciting aspects have recently arisen at the
+ forefront of the advancements in this field: first, the development of new compounds with DNA-demethylating
+ capacity that are less toxic (for example, procaine) and may be administered orally (for example,
+ zebularine); Science. 2013 May 10;340(6133):756-9.
+ Emergence of individuality in genetically identical mice.
+ Freund J, Brandmaier AM, Lewejohann L, Kirste I, Kritzler M, Krüger A, Sachser N, Lindenberger U, Kempermann G.
+ CRTD-DFG Research Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.
+ Comment in Science. 2013 May 10;340(6133):695-6. Brain plasticity as a neurobiological reflection
+ of individuality is difficult to capture in animal models. Inspired by behavioral-genetic investigations of
+ human monozygotic twins reared together, we obtained dense longitudinal activity data on 40 inbred mice
+ living in one large enriched environment. The exploratory activity of the mice diverged over time, resulting in
+ increasing individual differences with advancing age. Individual differences in cumulative roaming entropy,
+ indicating the active coverage of territory, correlated positively with individual differences in adult
+ hippocampal neurogenesis. Our results show that factors unfolding or emerging during development contribute to
+ individual differences in structural brain plasticity and behavior. The paradigm introduced here serves as
+ an animal model for identifying mechanisms of plasticity underlying nonshared environmental contributions to
+ individual differences in behavior. Neurobiol Aging. 1995 Jul-Aug;16(4):523-30. Delayed onset of Alzheimer's
+ disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs. Breitner JC, Welsh KA, Helms MJ,
+ Gaskell PC, Gau BA, Roses AD, Pericak-Vance MA, Saunders AM. If each opportunity we have to choose expands
+ our curiosity, we go beyond our inheritance to become something unique but also universal, that is, more
+ fully human. J Neurobiol. 1976 Jan;7(1):75-85. Effects of environment on morphology of rat cerebral cortex and
+ hippocampus. Diamond MC, Ingham CA, Johnson RE, Bennett EL, Rosenzweig MR. … strains of rats. KRECH D,
+ ROSENZWEIG MR, BENNETT EL.… 19. Pharmacol Biochem Behav. 1986 Sep;25(3):521-6. Cholinergic function and memory:
+ extensive inhibition of choline acetyltransferase fails to impair radial maze performance in rats. Wenk G,
+ Sweeney J, Hughey D, Carson J, Olton D. The present study investigated the effects of a potent inhibitor of
+ choline acetyltransferase (ChAT), BW813U, on the choice accuracy of rats in the radial arm maze. BW813U (100
+ mg/kg, IP) produced a rapid (within 1 hour) and substantial decrease in ChAT activity throughout the brain,
+ ranging from 66% (hippocampus) to 80% (caudate nucleus) that lasted up to 5 days. A single
+ injection (50 mg/kg, IP)
+ into rats with lesions (using ibotenic acid) in the nucleus basalis
+ magnocellularis and medial septal area, decreased ChAT activity by 75% and 60% in
+ the cortex and hippocampus, respectively. Lesioned and unlesioned rats were
+ trained on the radial arm maze until they reached a criterion level of
+ performance. Each rat then received an injection of BW813U (50 or 100 mg/kg, IP). Choice
+ accuracy was not impaired at any time following the injection. The lack of effect on performance may be due to 2
+ possible factors: The radial maze retention paradigm chosen may not be sufficiently difficult, or the decrease
+ in acetylcholine production was not sufficient to affect behavior. Compensation by non-cholinergic neural
+ systems might account for the insensitivity of the rats to significant cholinergic depletion. Psychol Aging.
+ 1988 Dec;3(4):399-406. Genotype-environment interaction in personality development: identical twins reared
+ apart. Bergeman CS, Plomin R, McClearn GE, Pedersen NL, Friberg LT. Center for Developmental and Health
+ Genetics, Pennsylvania State University, University Park 16802. The focus of this study is to identify specific
+ genotype-environment (GE) interactions as they contribute to individual differences in personality in later
+ life. In behavioral genetics, GE interaction refers to the possibility that individuals of different genotypes
+ may respond differently to specific environments. A sample of 99 pairs of identical twins reared apart, whose
+ average age is 59 years, has been studied as part of the Swedish Adoption/Twin Study of Aging (SATSA).
+ Hierarchical multiple regression was used to detect interactions between personality and environmental measures
+ after the main effects of genotype and environment were removed. Analyses yield evidence for 11 significant
+ interactions that provide the first evidence for GE interaction in human development using specific
+ environmental measures. Thus, in addition to the main-effect contributions of heredity and environment, GE
+ interactions contribute to individual differences in personality as measured in the second half of the life
+ course.
+
+ Wikipedia:
+ Excitability and inhibition
+ [edit source | editbeta]
+
+ Acetylcholine also has other effects on neurons. One effect is to cause a slow depolarization
+ [citation needed] by blocking a tonically active K+
+ current, which increases neuronal excitability. Alternatively, acetylcholine can activate
+ non-specific cation conductances to directly excite neurons.[10] An effect upon postsynaptic M4-muscarinic ACh receptors is to open inward-rectifier potassium ion channel (Kir) and cause
+ inhibition.[11] The influence of acetylcholine on specific neuron types can be dependent upon the
+ duration of cholinergic stimulation. For instance, transient exposure to acetylcholine (up to several
+ seconds) can inhibit cortical pyramidal neurons via M1 type muscarinic receptors that are linked to Gq-type
+ G-protein alpha subunits. M1 receptor activation can induce calcium-release from intracellular
+ stores, which then activate a calcium-activated potassium conductance which inhibits pyramidal neuron firing.[12] On the other hand, tonic M1 receptor activation is strongly
+ excitatory. Thus, ACh acting at one type of receptor can have multiple effects on the same
+ postsynaptic neuron, depending on the duration of receptor activation.[13] Recent experiments in behaving animals have demonstrated that cortical neurons
+ indeed experience both transient and persistent changes in local acetylcholine levels during cue-detection
+ behaviors.[14]
+
+
+ In the cerebral cortex, tonic ACh inhibits layer 4 medium spiny neurons, the main targets of thalamocortical inputs while excitingpyramidal cells in layers 2/3 and layer 5.[11] This filters out weak sensory inputs in layer 4 and amplifies inputs that reach
+ the layers 2/3 and layer L5 excitatory microcircuits. As a result, these layer-specific effects of ACh might
+ function to improve the signal noise ratio of cortical processing.[11] At the same time, acetylcholine acts through nicotinic receptors to excite
+ certain groups of inhibitory interneurons in the cortex, which further dampen down cortical activity.[15]
+
+
+ Role in decision making
+ [edit source | editbeta]
+
+
+ One well-supported function of acetylcholine (ACh) in cortex is increased responsiveness to sensory stimuli,
+ a form of attention.Phasic increases of ACh during visual,[16] auditory [17] and somatosensory [18] stimulus presentations have been found to increase the firing rate of neurons in
+ the corresponding primary sensory cortices. When cholinergic neurons in the basal forebrain are lesioned,
+ animals' ability to detect visual signals was robustly and persistently impaired.[19] In that same study, animals' ability to correctly reject non-target trials was
+ not impaired, further supporting the interpretation that phasic ACh facilitates responsiveness to stimuli.
+ Looking at ACh's effect on thalamocortical connections, a known pathway of sensory information, in vitro
+ application of cholinergic agonist carbachol to mouse auditory cortex enhanced thalamocortical activity.[20] In addition, Gil et al. (1997) applied a different cholinergic agonist, nicotine, and found that activity was enhanced at thalamocortical synapses.[21]This finding provides further evidence for a facilitative role of ACh in transmission
+ of sensory information from the thalamus to selective regions of cortex.
+
+
+ An additional suggested function of ACh in cortex is suppression of intracortical information transmission.
+ Gil et al. (1997) applied the cholinergic agonist muscarine to neocortical layers and found that excitatory post-synaptic potentials between intracortical synapses were depressed.[21] In vitro application of cholinergic agonist carbachol to mouse auditory cortex
+ suppressed intracortical activity as well.[20] Optical recording with a voltage-sensitive dye in rat visual cortical slices
+ demonstrated significant suppression in intracortical spread of excitement in the presence of ACh.[22]
+
+
+ Some forms of learning and plasticity in cortex appear dependent on the presence of acetylcholine. Bear et
+ al. (1986) found that the typical synaptic remapping in striate cortex that occurs during monocular deprivation is reduced when there is a depletion of cholinergic projections
+ to that region of cortex.[23] Kilgard et al. (1998) found that repeated stimulation of the basal forebrain, a primary source of ACh neurons, paired with presentation of a tone at a
+ specific frequency, resulted in remapping of the auditory cortex to better suit processing of that tone.[24]Baskerville et al. (1996) investigated the role of ACh in experience-dependent plasticity by depleting cholinergic inputs to the barrel cortex of rats.[25] The cholinergic depleted animals had a significantly reduced amount of
+ whisker-pairing plasticity. Apart from the cortical areas, Crespo et al. (2006) found that the activation of
+ nicotinic and muscarinic receptors in the nucleus accumbens is necessary for the acquisition of an appetitive task.[26]
+
+
+ ACh has been implicated in the reporting of expected uncertainty in the environment [27] based both on the suggested functions listed above and results recorded while
+ subjects perform a behavioral cuing task. Reaction time difference between correctly cued trials and incorrectly cued
+ trials, called the cue validity, was found to vary inversely with ACh levels in primates with pharmacologically (e.g. Witte et al., 1997) and surgically (e.g. Voytko
+ et al., 1994) altered levels of ACh.[28]
+ [29] The result was also found in Alzheimer's disease patients (Parasuraman et al., 1992) and smokers after nicotine
+ (an ACh agonist) consumption.[30]
+ [31] The inverse covariance is consistent with the interpretation of ACh as representing expected
+ uncertainty in the environment, further supporting this claim.
+
+
+
+ 12•.^ Gulledge, AT; Stuart, GJ (2005). "Cholinergic inhibition of
+ neocortical pyramidal neurons". Journal of Neuroscience 25 (44):
+ 10308–20. doi:10.1523/JNEUROSCI.2697-05.2005. PMID 16267239.
+
+
+ ^
+ Gulledge, AT; Bucci, DJ; Zhang, SS; Matsui, M; Yeh, HH (2009). "M1 Receptors Mediate Cholinergic Modulation of Excitability in Neocortical Pyramidal Neurons". Journal of Neuroscience 29 (31): 9888–902. doi:10.1523/JNEUROSCI.1366-09.2009.PMC 2745329. PMID 19657040.
+
+
+ ^
+ Parikh, V; Kozak, R; Martinez, V; Sarter, M (2007). "Prefrontal acetylcholine release controls cue detection on multiple time scales". Neuron 56 (1): 141–54. doi:10.1016/j.neuron.2007.08.025.PMC 2084212. PMID 17920021.
+
+
+ ^ Gulledge, AT; Park, SB; Kawaguchi, Y; Stuart, GJ (2007). "Heterogeneity
+ of phasic cholinergic signaling in neocortical neurons".Journal of neurophysiology 97 (3): 2215–29. doi:10.1152/jn.00493.2006.PMID 17122323.
+
+
+ ^
+ Spehlmann R, Daniels JC, Smathers CC (1971). "Acetylcholine and the synaptic transmission of specific impulses to the visual cortex". Brain 94 (1): 125–38. doi:10.1093/brain/94.1.125. PMID 4324030.
+
+
+ ^
+ Foote SL, Freedman R, Oliver AP (March 1975). "Effects of putative neurotransmitters on neuronal activity in monkey auditory cortex". Brain Res. 86 (2): 229–42. doi:10.1016/0006-8993(75)90699-X.PMID 234774.
+
+
+ ^
+ Stone TW (September 1972). "Cholinergic mechanisms in the rat somatosensory cerebral cortex". J. Physiol. (Lond.) 225 (2): 485–99. PMC 1331117. PMID 5074408.
+
+
+ ^
+ McGaughy J, Kaiser T, Sarter M (April 1996). "Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: selectivity of
+ the behavioral impairment and relation to cortical AChE-positive fiber density". Behav.
+ Neurosci. 110 (2): 247–65.doi:10.1037/0735-7044.110.2.247. PMID 8731052.
+
+
+ ^ a b Hsieh CY, Cruikshank SJ, Metherate R (October
+ 2000). "Differential modulation of auditory thalamocortical and intracortical synaptic transmission by
+ cholinergic agonist". Brain Res. 880 (1–2): 51–64.doi:10.1016/S0006-8993(00)02766-9.PMID 11032989.
+
+
+ ^ a b Gil Z, Connors BW, Amitai Y (September 1997). "Differential regulation of neocortical synapses by neuromodulators and activity". Neuron 19 (3): 679–86. doi:10.1016/S0896-6273(00)80380-3.PMID 9331357.
+
+
+ ^
+ Kimura F, Fukuda M, Tsumoto T (October 1999). "Acetylcholine suppresses the spread of excitation in the visual cortex revealed by optical recording:
+ possible differential effect depending on the source of input". Eur. J. Neurosci. 11 (10): 3597–609.doi:10.1046/j.1460-9568.1999.00779.x. PMID 10564367.
+
+
+ ^ Bear MF, Singer W (1986). "Modulation of visual cortical plasticity by acetylcholine and
+ noradrenaline". Nature 320 (6058): 172–6.doi:10.1038/320172a0. PMID 3005879.
+
+
+ ^ Kilgard MP, Merzenich MM (March 1998). "Cortical map reorganization enabled by nucleus
+ basalis activity". Science 279 (5357): 1714–8. doi:10.1126/science.279.5357.1714. PMID 9497289.
+
+
+ ^
+ Baskerville KA, Schweitzer JB, Herron P (October 1997). "Effects of cholinergic depletion on experience-dependent plasticity in the cortex of the rat". Neuroscience 80 (4): 1159–69. doi:10.1016/S0306-4522(97)00064-X. PMID 9284068.
+
+
+ ^
+ Crespo JA, Sturm K, Saria A, Zernig G (May 2006). "Activation of muscarinic and nicotinic acetylcholine receptors in the nucleus accumbens core is
+ necessary for the acquisition of drug reinforcement".J. Neurosci. 26 (22): 6004–10.doi:10.1523/JNEUROSCI.4494-05.2006. PMID 16738243.
+
+
+ ^
+ Yu & Dayan 2005
+
+
+ ^
+ Witte EA, Marrocco RT (August 1997). "Alteration of brain noradrenergic activity in rhesus monkeys affects the alerting component of covert
+ orienting". Psychopharmacology (Berl.) 132 (4):
+ 315–23.doi:10.1007/s002130050351. PMID 9298508.
+
+
+ ^ Voytko ML, Olton DS, Richardson RT, Gorman LK, Tobin JR, Price DL (January 1994). "Basal forebrain lesions in monkeys disrupt attention but not learning and memory". J. Neurosci. 14 (1): 167–86.PMID 8283232.
+
+
+ 1. Pharmacol Res. 2011 Jun;63(6):525-31. Endothelin receptor antagonists: potential in Alzheimer's
+ disease. Palmer J, Love S. Dementia Research Group, Institute of Clinical Neurosciences, School of
+ Clinical Sciences, University of Bristol, Frenchay Hospital, Bristol BS16 1LE, United Kingdom. jen.palmer@bristol.ac.uk
+ Alzheimer's disease (AD) is believed to be initiated by the accumulation of neurotoxic forms of Aβ peptide
+ within the brain. AD patients show reduction of cerebral blood flow (CBF), the extent of the reduction
+ correlating with the impairment of cognition. There is evidence that cerebral hypoperfusion
+ precedes
+ and may even trigger the onset of dementia in AD. Cerebral hypoperfusion impairs
+ neuronal function, reduces the clearance of Aβ peptide and other toxic
+ metabolites from the brain, and upregulates Aβ production. Studies in animal
+ models of AD have shown the reduction in CBF to be more than would be expected
+ for the reduction in neuronal metabolic activity. Aβ may contribute to the
+ reduction in CBF in AD, as both Aβ₁₋₄₀ and Aβ₁₋₄₂ induce cerebrovascular
+ dysfunction. Aβ₁₋₄₀ acts directly on cerebral arteries to cause cerebral smooth muscle cell
+ contraction. Aβ₁₋₄₂ causes increased neuronal production and release of endothelin-1
+ (ET-1), a potent vasoconstrictor, and upregulation of endothelin-converting enzyme-2 (ECE-2), the enzyme which
+ cleaves ET-1 from its inactive precursor. ET-1 and ECE-2 are also elevated in AD, making it likely that
+ upregulation of the ECE-2-ET-1 axis by Aβ₁₋₄₂ contributes to the chronic reduction of CBF in
+ AD. At present, only a few symptomatic treatment options exist for AD. The involvement of ET-1 in the
+ pathogenesis of endothelial dysfunction associated with elevated Aβ indicates the potential for endothelin
+ receptor antagonists in the treatment of AD. It has already been demonstrated that the endothelin receptor
+ antagonist bosentan, preserves aortic and carotid endothelial function in Tg2576 mice, and our findings suggest
+ that endothelin receptor antagonists may be beneficial in maintaining CBF in AD. Copyright © 2011 Elsevier Ltd.
+ All rights reserved. Fiziol Zh SSSR Im I M Sechenova. 1975 Oct;61(10):1466-72. [Amine receptors in brain
+ vessels]. [Article in Russian] Edvinsson L, Owman Ch. Isolated middle cerebral arteries from cats and pial
+ arteries from humans (obtained during lobe resection) were studied in a sensitive in vitro system allowing a
+ detailed pharmacological characterization of various amine receptors and related dissociation constants. It was
+ found that the adrenergic receptors comprise contractile (alpha) and dilatory (beta) receptors. Acetylcholine induced
+ dilation (at low doses) as well as constriction (at high doses) both responses
+ being inhibited in a comparative way by atropine. Experiments with selective inhibitors
+ showed the presence of specific histamine H2 (dilatory) receptors; at
+ high doses histamine contracted the vessels in a non-specific way.
+ 5-Hydroxytryptamine was the most efficient vasoconstrictor agent, and the
+ response could be blocked by the serotonin-antagonist, methysergide. Behav Neurosci. 2007 Jun;121(3):491-500.
+ Exposure to enriched environment improves spatial learning performances and enhances cell density but not choline acetyltransferase activity in the hippocampus of ventral subicular-lesioned rats.
+ Dhanushkodi A, Bindu B, Raju TR, Kutty BM. Department of NeurophysiologyNational Institute of Mental Health and
+ Neuro Sciences (NIMHANS Deemed University), Bangalore, India. The authors demonstrated the efficacy of enriched
+ housing conditions in promoting the behavioral recovery and neuronal survival following subicular lesion in
+ rats. Chemical lesioning of the ventral subiculum impaired the spatial learning performances in rats. The lesion
+ also induced a significant degree of neurodegeneration in the CA1 and CA3 areas of the hippocampus and
+ entorhinal cortex. Exposure to enriched housing conditions improved the behavioral performance and partially
+ attenuated the neurodegeneration in the hippocampus. The choline acetyl transferase (ChAT) activity in the
+ hippocampus remained unchanged following ventral subicular lesion and also following exposure to an enriched
+ environment. The study implicates the effectiveness of activity-dependent neuronal plasticity induced by
+ environmental enrichment in adulthood following brain insult. Copyright (c) 2007 APA, all rights reserved. Horm
+ Behav. 2013 Jul 27. pii: S0018-506X(13)00139-6. Progesterone and vitamin D: Improvement after traumatic brain
+ injury in middle-aged rats. Tang H, Hua F, Wang J, Sayeed I, Wang X, Chen Z, Yousuf S, Atif F, Stein DG.
+ Department of Emergency Medicine, Emory University, Atlanta, GA 30322, USA. Progesterone (PROG) and vitamin D
+ hormone (VDH) have both shown promise in treating traumatic brain injury (TBI). Both modulate apoptosis,
+ inflammation, oxidative stress, andexcitotoxicity. We investigated whether 21days of VDH
+ deficiency would alter cognitive behavior after TBI and whether combined PROG and VDH would improve behavioral
+ and morphological outcomes more than either hormone alone in VDH-deficient middle-aged rats given bilateral
+ contusions of the medial frontal cortex. PROG (16mg/kg) and VDH (5μg/kg) were injected intraperitoneally 1h
+ post-injury. Eight additional doses of PROG were injected subcutaneously over 7days post-injury. VDH deficiency
+ itself did not significantly reduce baseline behavioral functions or aggravate impaired cognitive outcomes.
+ Combination therapy showed moderate improvement in preserving spatial and reference memory but was not
+ significantly better than PROG monotherapy. However, combination therapy significantly reduced neuronal loss and
+ the proliferation of reactive astrocytes, and showed better efficacy compared to VDH or PROG alone in preventing
+ MAP-2 degradation. VDH+PROG combination therapy may attenuate some of the potential long-term, subtle,
+ pathophysiological consequences of brain injury in older subjects. © 2013. KEYWORDS: Yang, glutamate stimulates
+ DNA repair; methylation of dna during stress, hydrophobic Life Sci 1998;62(17-18):1717-21 Induction of
+ inducible nitric oxide synthase and heme oxygenase-1 in rat glial cells. Kitamura Y, Matsuoka Y, Nomura Y,
+ Taniguchi T Department of Neurobiology, Kyoto Pharmaceutical University, Japan. Recent observations
+ suggest a possible interaction between the nitric oxide (NO)/NO synthases and carbon monoxide (CO)/heme
+ oxygenases systems. We examined the effects of lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), and NO
+ donor such as S-nitroso-N-acetylpenicillamine (SNAP) on induction of inducible NO synthase (iNOS) and heme
+ oxygenase-1 (HO-1) in mixed glial cells and in rat hippocampus. In in vitro glial cells, treatment with LPS
+ induced the expression of 130-kDa iNOS after 6 h, and NO2- accumulation and enhancement of the protein level of
+ 33-kDa HO-1 after 12 h. In addition, treatment with SNAP induced HO-1 expression after 6 h. Although a NOS
+ inhibitor, such as N(G)-nitro-L-arginine (NNA), did not change LPS-induced iNOS expression, the inhibitor
+ suppressed both NO2- accumulation and the enhancement of HO-1. Immunocytochemistry showed
+ that LPS-treatment induced iNOS-immunoreactivity predominantly in microglia, while this treatment induced
+ HO-1-immunoreactivity in both microglia and astrocytes. These results suggest that endogenous NO production by
+ iNOS in microglia causes autocrine- and paracrine-induction of HO-1 protein in microglia and astrocytes in rat
+ brain.
+
+
+ 4. Proc Soc Exp Biol Med. 1994 Oct;207(1):43-7. Dietary restriction modulates the norepinephrine content and
+ uptake of the heart and cardiac synaptosomes. Kim SW, Yu BP, Sanderford M, Herlihy JT. Department of
+ Physiology, University of Texas Health Science Center at San Antonio 78284. The present study was designed to
+ examine the effects of long-term dietary restriction on cardiac sympathetic nerves and neurotransmitter. The
+ food intake of male, 6-week-old Fischer 344 rats was reduced to 60% of the intake of control rats fed ad
+ libitum. The body and heart weights of rats diet restricted for 4.5 months were less than those of the ad
+ libitum fed animals, while the heart weight to body weight ratios were higher. The norepinephrine (NE)
+ content of hearts from
+ restricted rats (1073 +/- 84 ng/g wet wt) was higher than controls (774 +/- 38
+ ng/g wet wt), although the total amount of NE per heart was unchanged. Similarly, the cardiac
+ synaptosomal P2 fraction from restricted rats possessed a higher NE content (24.1 +/- 2.4 ng/mg protein) than
+ the P2 fraction of ad libitum fed controls (13.7 +/- 1.3 ng/mg protein). The desmethylimipramine-sensitive
+ norepinephrine uptake of the P2 fraction from restricted rats was significantly higher than that of control rats
+ (9.44 +/- 1.33 vs 4.75 +/- 0.35 ng/mg protein/hr). The NE uptakes of the two groups were similar when uptake was
+ normalized to endogenous NE levels. These results demonstrate that long-term dietary restriction affects cardiac
+ sympathetic nerve endings and suggest that part of the beneficial action of life-long dietary restriction on the
+ age-related decline in cardiovascular regulation may be related to changes in cardiac sympathetic nerves. Int J
+ Cancer. 1985 Apr 15;35(4):493-7. Muscarinic cholinergic receptors in pancreatic acinar carcinoma of rat. Taton
+ G, Delhaye M, Swillens S, Morisset J, Larose L, Longnecker DS, Poirier GG. The active enantiomer of tritiated
+ quinuclidinyl benzilate (3H(-)QNB) was used as a ligand to evaluate the muscarinic receptors. The 3H(-)QNB
+ binding characteristics of muscarinic cholinergic receptors obtained from normal and neoplastic tissues were
+ studied to determine changes in receptor properties during neoplastic transformation. Saturable and
+ stereospecific binding sites for 3H(-)QNB are present in homogenates of rat pancreatic adenocarcinoma. The
+ proportions of high- and low-affinity agonist binding sites are similar for neoplastic and normal tissues. The
+ density of muscarinic receptors is higher in neoplastic (200 femtomoles/mg protein) than in normal pancreatic
+ homogenates (80 femtomoles/mg protein). The muscarinic binding sites of the neoplastic and fetal
+ pancreas show similar KD values which are higher than those observed for normal pancreas. 17: Cancer Res. 1986
+ Nov;46(11):5706-14. Muscarinic receptor coupling to intracellular calcium release in rat pancreatic acinar
+ carcinoma. Chien JL, Warren JR. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of
+ cholinergic receptor protein affinity labeled with the muscarinic antagonist [3H]propylbenzilylcholine mustard
+ revealed a major polypeptide with molecular weight of 80,000-83,000 in both acinar carcinoma and normal acinar
+ cells of rat pancreas. Muscarinic receptor protein is therefore conserved in pancreatic acinar carcinoma. A
+ small but significant difference was detected in the affinity of carcinoma cell receptors (Kd approximately 0.6
+ nM) and normal cell receptors (Kd approximately 0.3 nM) for reversible binding of the muscarinic
+ antagonist drug, N-methylscopolamine. In addition, carcinoma cell muscarinic receptors displayed homogeneous
+ binding of the agonist drugs carbamylcholine (Kd approximately 31 microM) and oxotremorine (Kd approximately 4
+ microM), whereas normal cell receptors demonstrated heterogeneous binding, with a minor receptor population
+ showing high affinity binding for carbamylcholine (Kd approximately 3 microM) and oxotremorine (Kd approximately
+ 160 nM), and a major population showing low affinity binding for carbamylcholine (Kd approximately 110 microM)
+ and oxotremorine (Kd approximately 18 microM). Both carcinoma and normal cells exhibited concentration-dependent
+ carbamylcholine-stimulated increases in cytosolic free Ca2+, as measured by 45Ca2+ outflux assay and
+ intracellular quin 2 fluorescence. However, carcinoma cells were observed to be more sensitive to Ca2+
+ mobilizing actions of submaximal carbamylcholine concentrations, demonstrating 50% maximal stimulation of
+ intracellular Ca2+ release at a carbamylcholine concentration (approximately 0.4 microM) approximately one order
+ of magnitude below that seen for normal cells. These results indicate altered muscarinic receptor coupling to
+ intracellular Ca2+ release in acinar carcinoma cells, which manifests as a single activated receptor state
+ for agonist binding, and increased sensitivity of Ca2+ release in response to muscarinic receptor stimulation.
+ 1: Anticancer Drugs. 2008 Aug;19(7):655-71. Neurotransmission and cancer: implications for prevention and
+ therapy. Schuller HM. Experimental Oncology Laboratory, Department of Pathobiology, College of Veterinary
+ Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. hmsch@utk.edu
+ Published evidence compiled in this review supports the hypothesis that the development, progression, and
+ responsiveness to prevention and therapy of the most common human cancers is strongly influenced, if not
+ entirely orchestrated, by an imbalance in stimulatory and inhibitory neurotransmission. The neurotransmitters
+ acetylcholine, adrenaline, and noradrenaline of the autonomic nervous system act as powerful upstream regulators
+ that orchestrate numerous cell and tissue functions, by releasing growth factors, angiogenesis factors and
+ metastasis factors, arachidonic acid, proinflammatory cytokines, and local neurotransmitters from cancer cells
+ and their microenvironment. In addition, they modulate proliferation, apoptosis, angiogenesis, and metastasis of
+ cancer directly by intracellular signaling downstream of neurotransmitter receptors. Nicotine and the
+ tobacco-specific nitrosamines have the documented ability to hyperstimulate neurotransmission by both branches
+ of the autonomic nervous system. The expression and function of these neurotransmitter pathways are cell type
+ specific. Lifestyle, diet, diseases, stress, and pharmacological treatments modulate the expression and
+ responsiveness of neurotransmitter pathways. Current preclinical testing systems fail to incorporate the
+ modulating effects of neurotransmission on the responsiveness to anticancer agents and should be amended
+ accordingly. The neurotransmitter gamma-aminobutyric acid has a strong inhibitory function on sympathicus-driven
+ cancers whereas stimulators of cyclic adenosine monophosphate/protein kinase A signaling have strong inhibitory
+ function on parasympathicus-driven cancers. Marker-guided restoration of the physiological balance in
+ stimulatory and inhibitory neurotransmission represents a promising and hitherto neglected strategy for
+ the prevention and therapy of neurotransmitter-responsive cancers. Psychological stress in IBD: new insights
+ into pathogenic and ...
+ www.ncbi.nlm.nih.gov › Journal List › Gut ›
+ v.54(10); Oct 2005 by JE Mawdsley - 2005 - Cited by 255 - Related articles Psychological stress has long been
+ reported anecdotally to increase disease ..... atropine and was more marked in cholinesterase deficient
+ Wistar-Kyoto rats. Neuropsychopharmacology. 2002 May;26(5):672-81. Sexual diergism of
+ hypothalamo-pituitary-adrenal cortical responses to low-dose physotigmine in elderly vs. young women and men.
+ Rubin RT, Rhodes ME, O'Toole S, Czambel RK. Center for Neurosciences Research, MCP Hahnemann University School
+ of Medicine, Allegheny General Hospital, Pittsburgh, PA 15212, USA. rubin@wpahs.org
+ We previously demonstrated that the reversible cholinesterase inhibitor, physostigmine (PHYSO), administered to
+ normal young adult women and men (average age 35 years) at a dose that produced few or no side effects, resulted
+ in a sex difference (sexual diergism) in hypothalamo-pituitary-adrenal cortical (HPA) axis responses:
+ Plasma ACTH(1-39), cortisol, and arginine vasopressin (AVP)
+ concentrations increased to a significantly greater extent in the men than in
+ the women. To explore the effect of age on these sexually diergic hormone responses, in
+ the present study we used the same dose of PHYSO (8 microg/kg IV) to stimulate ACTH(1-39), cortisol, and AVP
+ secretion in normal elderly, non-estrogen-replaced women and elderly men (average ages 73 years and 70 years,
+ respectively). The subjects underwent three test sessions 5-7 days apart: PHYSO, saline control, and a second
+ session of PHYSO. Serial blood samples were taken for hormone analyses before and after pharmacologic
+ challenge.As with the previously studied younger subjects, PHYSO administration produced no side effects in
+ about half the elderly subjects and mild side effects in the other half, with no significant female-male
+ differences. The hormone responses were
+ 2-5 fold greater in the elderly subjects than in the younger subjects, but in
+ contrast to the younger subjects, the elderly men did not have significantly greater hormone responses to PHYSO
+ administration than did the elderly women. The ACTH(1-39) and AVP responses to PHYSO for the two sessions were
+ significantly positively correlated in the men (+0.96, +0.91) but not in the women. None of the hormone
+ responses was significantly correlated with the presence or absence of side effects in either group of
+ subjects.These results indicate a greater sensitivity of the HPA axis to low-dose PHYSO, and
+ a loss of
+ overall sex differences in hormone responses, in elderly compared with younger
+ subjects. The lack of a difference in side effects between the elderly women
+ and men and the lack of significant correlations between presence or absence of side effects and hormone
+ responses suggest that the increase in hormone responses with aging is due to correspondingly increased
+ responsiveness of central cholinergic systems and/or the HPA axis, and not to a nonspecific stress response.
+ Horm Behav. 2013 Feb;63(2):284-90. Progesterone and neuroprotection. Singh M, Su C. Department of
+ Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, Center FOR HER, University
+ of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA. meharvan.singh@unthsc.edu
+ Numerous studies aimed at identifying the role of estrogen on the brain have used the ovariectomized rodent as
+ the experimental model. And while estrogen intervention in these animals has, at least partially, restored
+ cholinergic, neurotrophin and cognitive deficits seen in the ovariectomized animal, it is worth considering that
+ the removal of the ovaries results in the loss of not only circulating estrogen but of circulating progesterone
+ as well. As such, the various deficits associated with ovariectomy may be attributed to the loss of progesterone
+ as well. Similarly, one must also consider the fact that the human menopause results in the precipitous decline
+ of not just circulating estrogens, but in circulating progesterone as well and as such, the increased risk for
+ diseases such as Alzheimer's disease during the postmenopausal period could also be contributed by this loss of
+ progesterone. In fact, progesterone has been shown to exert neuroprotective effects, both in cell models, animal
+ models and in humans. Here, we review the evidence that supports the neuroprotective effects of
+ progesterone and discuss the various mechanisms that are thought to mediate these protective
+ effects. We also discuss the receptor pharmacology of progesterone's neuroprotective effects
+ and present a conceptual model of progesterone action that supports the complementary effects of
+ membrane-associated and classical intracellular progesterone receptors. In addition, we discuss
+ fundamental differences in the neurobiology of progesterone and the clinically used, synthetic progestin,
+ medroxyprogesterone acetate that may offer an explanation for the negative findings of the combined
+ estrogen/progestin arm of the Women's Health Initiative-Memory Study (WHIMS) and suggest that the type of
+ progestin used may dictate the outcome of either pre-clinical or clinical studies that addresses brain
+ function.
+
+ Brain Res. 2005 Jul 5;1049(1):112-9. Progesterone treatment inhibits the inflammatory agents that
+ accompany traumatic brain injury. Pettus EH, Wright DW, Stein DG, Hoffman SW. Department of
+ Cell Biology, Emory University, Atlanta, GA 30322, USA. Progesterone given after traumatic brain injury (TBI)
+ has been shown to reduce the initial cytotoxic surge of inflammatory factors. We used Western blot techniques to
+ analyze how progesterone might affect three inflammation-related factors common to TBI: complement factor C3
+ (C3), glial fibrillary acidic protein (GFAP), and nuclear factor kappa beta (NFkappaB). One hour after bilateral
+ injury to the medial frontal cortex, adult male rats were given injections of progesterone (16 mg/kg) for 2
+ days. Brains were harvested 48 h post-TBI, proteins were extracted from samples, each of which contained tissue
+ from both the contused and peri-contused areas, then measured by Western blot densitometry. Complete C3, GFAP,
+ and NFkappaB p65 were increased in all injured animals. However, in animals given progesterone post-TBI, NFkappaB p65 and the
+ inflammatory metabolites of C3 (9 kDa and 75 kDa) were decreased in comparison to
+ vehicle-treated animals. J Leukoc Biol 1996 Mar;59(3):442-50 Progesterone inhibits inducible nitric oxide
+ synthase gene expression and nitric oxide production in murine macrophages. Miller L, Alley EW, Murphy WJ,
+ Russell SW, Hunt JS Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas
+ City, USA. The purpose of this study was to determine whether the female hormones estradiol-l7 beta (E2)
+ and progesterone (P4) influence inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO)
+ by interferon-gamma(IFN-gamma)-and lipopolysaccharide (LPS)-activated mouse macrophages. Treatment with P4 alone
+ caused a time- and dose-dependent inhibition of NO production by macrophage cell lines (RAW 264.7, J774) and
+ mouse bone marrow culture-derived macrophages as assessed by nitrite accumulation. RAW 264.7 cells transiently
+ transfected with an iNOS gene promoter/luciferase reporter-gene construct that were stimulated with
+ IFN-gamma/LPS in the presence of P4 displayed reduced luciferase activity and NO production. Analysis of RAW
+ 264.7 cells by Northern blot hybridization revealed concurrent P4-mediated reduction in iNOS mRNA. These
+ observations suggest that P4-mediated inhibition of NO may be an important gender-based difference within
+ females and males that relates to macrophage-mediated host defense. J Reprod Immunol 1997 Nov
+ 15;35(2):87-99 Female steroid hormones regulate production of pro-inflammatory molecules in uterine
+ leukocytes. Hunt JS, Miller L, Roby KF, Huang J, Platt JS, DeBrot BL Department of Anatomy and Cell Biology,
+ University of Kansas Medical Center, Kansas City 66160-7400, USA. jhunt@kumc.edu Estrogens and progesterone could be among the environmental signals that govern
+ uterine immune cell synthesis of pro-inflammatory substances. In order to investigate this possibility, we first
+ mapped expression of the inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha)
+ genes in the leukocytes of cycling and pregnant mouse uteri, then tested the ability of estradiol-17 beta (E2)
+ and progesterone to influence gene expression. Immunohistochemistry, in situ hybridization, and other
+ experimental approaches, revealed that the iNOS and TNF-alpha genes are expressed in mouse uterine mast cells,
+ macrophages and natural killer cells (uNK). Gene expression in each cell type was noted to be dependent upon
+ stage of the cycle or stage of gestation, implying potential relationships with levels of female hormones and
+ state of cell differentiation or activation. Further in vivo and in vitro experiments showed that individual
+ hormones have cell type-specific effects on synthesis of iNOS and TNF-alpha that are exerted at the level of
+ transcription. In uterine mast cells, iNOS and TNF-alpha are promoted by E2 whereas preliminary studies in
+ macrophages suggest that transcription and translation of the two genes are unaffected by E2 but are inhibited
+ by progesterone. Hypothyroidism increases NO; T3, vs helpless; hypothyroid, escape deficit, Levine, et
+ 1990.
+ choline is increased in AD CSF Elble R;, Carriere;
+
+ Genes Nutr. 2009 December; 4(4): 309–314. Dietary polyunsaturated fatty acids improve cholinergic
+ transmission in the aged brain Willis LM, Shukitt-Hale B, Joseph JA. 28. Bloj B, Morero RD,
+ Farias RN, Trucco RE (1973) Membrane lipid fatty acids and regulation of membrane-bound enzymes. Allosteric
+ behaviour of erythrocyte Mg 2+-ATPase (Na++ K+)-ATPase and acetylcholinesterase from rats fed different
+ fat-supplemented diets. Biochim Biophys Acta 311:67–79. [PubMed] 29. Vajreswari A, Narayanareddy K (1992) Effect
+ of dietary fats on erythrocyte membrane lipid composition and membrane-bound enzyme activities. Metabolism
+ 41:352–358. [PubMed] 30. Vajreswari A, Rupalatha M, Rao PS (2002) Effect of altered dietary n-6-to-n-3 fatty
+ acid ratio on erythrocyte lipid composition and membrane-bound enzymes. J Nutr Sci Vitaminol 48:365–370.
+ [PubMed] 31. Foot M, Cruz TF, Clandinin MT (1983) Effect of dietary lipid on synaptosomal
+ acetylcholinesterase activity. Biochem J 211:507–509. [PMC free article] [PubMed] 33.
+ Srinivasarao P, Narayanareddy K, Vajreswari A, Rupalatha M, Prakash PS, Rao P (1997) Influence of dietary fat on
+ the activities of subcellular membrane-bound enzymes from different regions of the brain. Neuochem Int
+ 31:789–794. [PubMed]
+
+ The protective effect of anticholinergic drugs, such as atropine or scopolamine, against various
+ degenerative brain processes might lead a person to wonder whether the Berkeley enrichment experiments might
+ not have been neurologically exactly the opposite of the stress experiments of Richter and Seligman, that
+ is, reducing cholinergic processes with enrichment, increasing them with impoverishment of choices and
+ experience. A drug, pilocarpine,
+
+ USING THE BRAIN FOR LIFE Living is development; the choices we make create our individuality. If genetically
+ identical mice grow up in a large and varied environment, small differences in their experience will affect cell
+ growth in their brains, leading to large differences in their exploratory behavior as they age (Freund, et al.,
+ 2013). Geneticists used to say that "genes determine our limits," but this experiment shows that an environment
+ can provide both limitations and opportunities for expanding the inherited potential. If our environment
+ restricts our choices, our becoming human is thwarted, the way rats' potentials weren't discovered when they
+ were kept in the standard little laboratory boxes. An opportunity to be complexly involved in a complex
+ environment lets us become more of what we are, more humanly differentiated. A series of experiments that
+ started at the University of California in 1960 found that rats that lived in larger spaces with various things
+ to explore were better at learning and solving problems than rats that were raised in the standard little
+ laboratory cages (Rosenzweig, 1960). Studying their brains, they found that the enzyme cholinesterase, which
+ destroys the neurotransmitter, acetylcholine, was increased. They later found that the offspring of these rats
+ were better learners than their parents, and their brains contained more cholinesterase. Their brains were also
+ larger, with a considerable thickening of the cortex, which is considered to be the part mainly responsible for
+ complex behavior, learning and intelligence. These processes aren't limited to childhood. For example,
+ London taxi drivers who learn all the streets in the city develop a larger hippocampus, an area of the brain
+ involved with memory. The 1960s research into environmental enrichment coincided with political changes in
+ the US, but it went against the dominant scientific ideas of the time. Starting in 1945, the US government had
+ begun a series of projects to develop techniques of behavior modification or mind control, using drugs,
+ isolation, deprivation, and torture. In the 1950s, psychiatry often used lobotomies (about 80,000, before they
+ were generally discontinued in the 1980s) and electroconvulsive "therapy," and university psychologists tortured
+ animals, often as part of developing techniques for controlling behavior. The CIA officially phased out
+ their MKultra program in 1967, but that was the year that Martin Seligman, at the University of Pennsylvania,
+ popularized the idea of "learned helplessness." He found that when an animal was unable to escape from torture,
+ even for a very short time, it would often fail to even try to escape the next time it was tortured.
+ Seligman's lectures have been attended by psychologists who worked at Guantanamo, and he recently received a
+ no-bid Pentagon grant of $31,000,000, to develop a program of "comprehensive soldier fitness," to train marines
+ to avoid learned helplessness.
+
+ Curt Richter already in 1957 had described the "hopelessness" phenomenon in rats (“a reaction of hopelessness is
+ shown by some wild rats very soon after being grasped in the hand and prevented from moving. They seem literally
+ to give up,”) and even how to cure their hopelessness, by allowing them to have an experience of escaping once
+ (Richter, 1957). Rats which would normally be able to keep swimming in a tank for two or three days, would
+ often give up and drown in just a few minutes, after having an experience of "inescapable stress." Richter made
+ the important discovery that the hearts of the hopeless rats slowed down before they died, remaining relaxed and
+ filled with blood, revealing the dominant activity of the vagal nerve, secreting acetylcholine. The
+ sympathetic nervous system (secreting noradrenaline) accelerates the heart, and is usually activated in stress,
+ in the "fight or flight" reaction, but this radically different (parasympathetic) nervous activity hadn't
+ previously been seen to occur in stressful situations. The parasympathetic, cholinergic, nervous system had been
+ thought of as inactive during stress, and activated to regulate processes of digestion, sleep, and repair.
+ Besides the cholinergic nerves of the parasympathetic system, many nerves of the central nervous system also
+ secrete acetylcholine, which activates smooth muscles, skeletal muscles, glands, and other nerves, and also has
+ some inhibitory effects. The parasympathetic nerves also secrete the enzyme, cholinesterase, which destroys
+ acetylcholine. However, many other types of cell (red blood cells, fibroblasts, sympathetic nerves, marrow
+ cells), maybe all cells, can secrete acetylcholine. Because cholinergic nerves have been opposed to the
+ sympathetic, adrenergic, nerves, there has been a tendency to neglect their nerve exciting roles, when looking
+ at causes of excitotoxicity, or the stress-induced loss of brain cells. Excessive cholinergic stimulation,
+ however, can contribute to excitotoxic cell death, for example when it's combined with high cortisol and/or
+ hypoglycemia. Drugs that block the stimulating effects of acetylcholine (the anticholinergics) as well as
+ chemicals that mimic them, such as the organophosphate insecticides, can impair the ability to think and learn.
+ This suggested to some people that age-related dementia was the result of the deterioration of the cholinergic
+ nerves in the brain. Drugs to increase the stimulating effects of acetylcholine in the brain (by inactivating
+ cholinesterase) were promoted as treatment for Alzheimer's disease. Although herbal inhibitors were well
+ known, profitable new drugs, starting with Tacrine, were put into use. It was soon evident that Tacrine was
+ causing serious liver damage, but wasn't slowing the rate of mental deterioration. As the failure of the
+ cholinergic drug Tacrine was becoming commonly known, another drug, amantadine (later, the similar memantine)
+ was proposed for combined treatment. In the 1950s, the anticholinergic drug atropine was proposed a few times
+ for treating dementia, and amantadine, which was also considered anticholinergic, was proposed for some
+ mental conditions, including Creutzfeldt-Jacob Disease (Sanders and Dunn, 1973). It must have seemed odd to
+ propose that an anticholinergic drug be used to treat a condition that was being so profitably treated with a
+ pro-cholinergic drug, but memantine came to be classified as an anti-excitatory "NMDA blocker," to protect the
+ remaining cholinergic nerves, so that both drugs could be prescribed simultaneously. The added drug seems to
+ have a small beneficial effect, but there has been no suggestion that this could be the result of its
+ previously-known anticholinergic effects. Over the years, some people have suspected that Alzheimer's disease
+ might be caused partly by a lack of purpose and stimulation in their life, and have found that meaningful,
+ interesting activity could improve their mental functioning. Because the idea of a "genetically determined
+ hard-wired" brain is no longer taught so dogmatically, there is increasing interest in this therapy for all
+ kinds of brain impairment. The analogy to the Berkeley enrichment experience is clear, so the association of
+ increasing cholinesterase activity with improving brain function should be of interest. The after-effect of
+ poisoning by nerve gas or insecticide has been compared to the dementia of old age. The anticholinergic drugs
+ are generally recognized for protecting against those toxins. Traumatic brain injury, even with improvement in
+ the short term, often starts a long-term degenerative process, greatly increasing the likelihood of dementia at
+ a later age. A cholinergic excitotoxic process is known to be involved in the traumatic degeneration of nerves
+ (Lyeth and Hayes, 1992), and the use of anticholinergic drugs has been recommended for many years to treat
+ traumatic brain injuries (e.g., Ward, 1950: Ruge, 1954; Hayes, et al., 1986). In 1976 there was an experiment
+ (Rosellini, et al.) that made an important link between the enrichment experiments and the learned helplessness
+ experiments. The control animals in the enrichment experiments were singly housed, while the others shared a
+ larger enclosure. In the later experiment, it was found that the rats "who were reared in isolation died
+ suddenly when placed in a stressful swimming situation," while the group-housed animals were resistant,
+ effective swimmers. Enrichment and deprivation have very clear biological meaning, and one is the negation of
+ the other. The increase of acetylcholinesterase, the enzyme that destroys acetylcholine, during
+ enrichment, serves to inactivate cholinergic processes. If deprivation does its harm by increasing the activity
+ of the cholinergic system, we should expect that a cholinergic drug might substitute for inescapable stress, as
+ a cause of learned helplessness, and that an anticholinergic drug could cure learned helplessness. Those tests
+ have been done: "Treatment with the anticholinesterase, physostigmine, successfully mimicked the effects of
+ inescapable shock." "The centrally acting anticholinergic scopolamine hydrobromide antagonized the effects of
+ physostigmine, and when administered prior to escape testing antagonized the disruptive effects of previously
+ administered inescapable shock." (Anisman, et al., 1981.) This kind of experiment would suggest that the
+ anticholinesterase drugs still being used for Alzheimer's disease treatment aren't biologically helpful. In an
+ earlier newsletter I discussed the changes of growth hormone, and its antagonist somatostatin, in association
+ with dementia: Growth hormone increases, somatostatin decreases. The cholinergic nerves are a major factor in
+ shifting those hormones in the direction of dementia, and the anticholinergic drugs tend to increase the ratio
+ of somatostatin to growth hormone. Somatostatin and cholinesterase have been found to co-exist in single nerve
+ cells (Delfs, et al., 1984). Estrogen, which was promoted so intensively as prevention or treatment for
+ Alzheimer's disease, was finally shown to contribute to its development. One of the characteristic effects of
+ estrogen is to increase the level of growth hormone in the blood. This is just one of many ways that estrogen is
+ associated with cholinergic activation. During pregnancy, it's important for the uterus not to contract.
+ Cholinergic stimulation causes it to contract; too much estrogen activates that system, and causes miscarriage
+ if it's excessive. An important function of progesterone is to keep the uterus relaxed during pregnancy. In the
+ uterus, and in many other systems, progesterone increases the activity of cholinesterase, removing the
+ acetylcholine which, under the influence of estrogen, would cause the uterus to contract. Progesterone is being
+ used to treat brain injuries, very successfully. It protects against inflammation, and in an early study,
+ compared to placebo, lowered mortality by more than half. It's instructive to consider its anticholinergic role
+ in the uterus, in relation to its brain protective effects. When the brain is poisoned by an organophosphate
+ insecticide, which lowers the activity of cholinesterase, seizures are likely to occur, and treatment with
+ progesterone can prevent those seizures, reversing the inhibition of the enzyme (and increasing the activity of
+ cholinesterase in rats that weren't poisoned) (Joshi, et al., 2010). Similar effects of progesterone on
+ cholinesterase occur in women (Fairbrother, et al., 1989), implying that this is a general function of
+ progesterone, not just something to protect pregnancy. Estrogen, with similar generality, decreases the activity
+ of cholinesterase. DHEA, like progesterone, increases the activity of cholinesterase, and is brain protective
+ (Aly, et al., 2011). Brain trauma consistently leads to decreased activity of this enzyme (Östberg, et al.,
+ 2011; Donat, et al., 2007), causing the acetylcholine produced in the brain to accumulate, with many interesting
+ consequences. In 1997, a group (Pike, et al.) created brain injuries in rats to test the idea that a
+ cholinesterase inhibitor would improve their recovery and ability to move through a maze. They found instead
+ that it reduced the cognitive ability of both the injured and normal rats. An anticholinergic drug, selegeline
+ (deprenyl) that is used to treat Parkinson's disease and, informally, as a mood altering antiaging drug, was
+ found by a different group (Zhu, et al., 2000) to improve cognitive recovery from brain injuries. One of
+ acetylcholine's important functions, in the brain as elsewhere, is the relaxation of blood vessels, and this is
+ done by activating the synthesis of NO, nitric oxide. (Without NO, acetylcholine constricts blood vessels;
+ Librizzi, et al., 2000.) The basic control of blood flow in the brain is the result of the relaxation of the
+ wall of blood vessels in the presence of carbon dioxide, which is produced in proportion to the rate at which
+ oxygen and glucose are being metabolically combined by active cells. In the inability of cells to produce CO2 at
+ a normal rate, nitric oxide synthesis in blood vessels can cause them to dilate. The mechanism of relaxation by
+ NO is very different, however, involving the inhibition of mitochondrial energy production (Barron, et al.,
+ 2001). Situations that favor the production and retention of a larger amount of carbon dioxide in the tissues
+ are likely to reduce the basic "tone" of the parasympathetic nervous system, as there is less need for
+ additional vasodilation. Nitric oxide can diffuse away from the blood vessels, affecting the energy metabolism
+ of nerve cells (Steinert, et al., 2010). Normally, astrocytes protect nerve cells from nitric oxide (Chen, et
+ al., 2001), but that function can be altered, for example by bacterial endotoxin absorbed from the intestine
+ (Solà, et al., 2002) or by amyloid-beta (Tran, 2001), causing them to produce nitric oxide themselves. Nitric
+ oxide is increasingly seen as an important factor in nerve degeneration (Doherty, 2011). Nitric oxide activates
+ processes (Obukuro, et al., 2013) that can lead to cell death. Inhibiting the production of nitric oxide
+ protects against various kinds of dementia (Sharma & Sharma, 2013; Sharma & Singh, 2013). Brain trauma
+ causes a large increase in nitric oxide formation, and blocking its synthesis improves recovery (Hüttemann, et
+ al., 2008; Gahm, et al., 2006). Organophosphates increase nitric oxide formation, and the protective
+ anticholinergic drugs such as atropine reduce it (Chang, et al., 2001; Kim, et al., 1997). Stress, including
+ fear (Campos, et al., 2013) and isolation (Zlatković and Filipović, 2013) can activate the formation of nitric
+ oxide, and various mediators of inflammation also activate it. The nitric oxide in a person's exhaled breath can
+ be used to diagnose some diseases, and it probably also reflects the level of their emotional well-being. The
+ increase of cholinesterase by enriched living serves to protect tissues against an accumulation of
+ acetylcholine. The activation of nitric oxide synthesis by acetylcholine tends to block energy production, and
+ to activate autolytic or catabolic processes, which are probably involved in the development of a thinner
+ cerebral cortex in isolated or stressed animals. Breaking down acetylcholine rapidly, the tissue renewal
+ processes are able to predominate in the enriched animals. Environmental conditions that are favorable for
+ respiratory energy production are protective against learned helplessness and neurodegeneration, and other
+ biological problems that involve the same mechanisms. Adaptation to high altitude, which stimulates the
+ formation of new mitochondria and increased thyroid (T3) activity, has been used for many years to treat
+ neurological problems, and the effect has been demonstrated in animal experiments (Manukhina, et al., 2010).
+ Bright light can reverse the cholinergic effects of inescapable stress (Flemmer, et al., 1990). During the
+ development of learned helplessness, the T3 level in the blood decreases (Helmreich, et al., 2006), and removal
+ of the thyroid gland creates the "escape deficit," while supplementing with thyroid hormone before exposing the
+ animal inescapable shock prevents its development (Levine, et al., 1990). After learned helplessness has been
+ created in rats, supplementing with T3 reverses it (Massol, et al., 1987, 1988). Hypothyroidism and excess
+ cholinergic tone have many similarities, including increased formation of nitric oxide, so that similar
+ symptoms, such as muscle inflammation, can be produced by cholinesterase inhibitors such as Tacrine, by
+ increased nitric oxide, or by simple hypothyroidism (Jeyarasasingam, et al., 2000; Franco, et al., 2006).
+ Insecticide exposure has been suspected to be a factor in the increased incidence of Alzheimer's disease
+ (Zaganas, et al., 2013), but it could be contributing to many other problems, involving inflammation, edema, and
+ degeneration. Another important source of organophosphate poisoning is the air used to pressurize airliners,
+ which can be contaminated with organophosphate fumes coming from the engine used to compress it. Possibly
+ the most toxic component of our environment is the way the society has been designed, to eliminate meaningful
+ choices for most people. In the experiment of Freund, et al., some mice became more exploratory
+ because of the choices they made, while others' lives became more routinized and limited. Our culture reinforces
+ routinized living. In the absence of opportunities to vary the way you work and live to accord with new
+ knowledge that you gain, the nutritional, hormonal and physical factors have special importance. Supplements of
+ thyroid and progesterone are proven to be generally protective against the cholinergic threats, but there are
+ many other factors that can be adjusted according to particular needs. Niacinamide, like progesterone, inhibits
+ the production of nitric oxide, and also like progesterone, it improves recovery from brain injury (Hoane, et
+ al., 2008). In genetically altered mice with an Alzheimer's trait, niacinamide corrects the defect (Green, et
+ al., 2008). Drugs such as atropine and antihistamines can be used in crisis situations. Bright light, without
+ excess ultraviolet, should be available every day. The cholinergic system is much more than a part of the
+ nervous system, and is involved in cell metabolism and tissue renewal. Most people can benefit from reducing
+ intake of phosphate, iron, and polyunsaturated fats (which can inhibit cholinesterase; Willis, et al., 2009),
+ and from choosing foods that reduce production and absorption of endotoxin. And, obviously, drugs that are
+ intended to increase the effects of nitric oxide and acetylcholine should be avoided. © Ray Peat Ph.D. 2016. All
+ Rights Reserved. www.RayPeat.com
+
+
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+
+ Diabetes, scleroderma, oils and hormones
+
+
+ Diabetes, scleroderma, oils and hormones
+
+
+
+ The basic argument: Stress and aging make cells less responsive in many ways by damaging their ability to
+ produce energy and to adapt. The polyunsaturated fats are universally toxic to the energy producing system,
+ and act as a "misleading signal" channeling cellular adaptation down certain self-defeating pathways.
+ Diabetes is just one of the "terminal" diseases that can be caused by the polyunsaturated vegetable oils.
+ Coconut oil, in diabetes as in other degenerative diseases, is highly protective.
+
+
+ When the oral contraceptive pill was new (Enovid), it was found to produce signs of diabetes, including
+ decreased glucose tolerance. Spellacy and Carlson (1966) suggested that an elevation of circulating free
+ fatty acids might be responsible, and remarked that "Free fatty acids can block the Krebs cycle, with
+ relative insulin action resistance resulting." "The potential danger of the oral contraceptives is one of
+ prolonged pancreatic stimulation." Recent papers are reporting that the estrogen used to "treat menopause"
+ causes an increase in free fatty acids. Spellacy and Carlson suggested that estrogen's effect was mediated
+ by growth hormone, and that is now the consensus. Women are much more likely than men to develop diabetes.
+
+
+ Ephraim Racker observed that free unsaturated fatty acids inhibit mitochondrial respiration, and recent
+ studies are finding that free linoleic and linolenic acids act as intracellular regulators, stimulating the
+ protein kinase C (PKC) system, which is also stimulated by estrogen and the (cancer promoting) phorbol
+ esters. They stimulate the cell while blocking the energy it needs to respond.
+
+
+ Scleroderma, or systemic sclerosis, is a supposedly mysterious condition in which tissues harden, with an
+ excessive deposition of fibrous material. Besides hardening the skin, it can involve fibrosis of the heart
+ and other organs, and can cause changes in blood vessels of the kidneys like those seen in some types of
+ hypertension, and often involves Raynaud's phenomenon and osteoporosis of the fingers. (Silicone functions
+ as an adjuvant, making exposure to irritants, solvents or infections more harmful. This seems to be the
+ reason for the association between breast implants and scleroderma.) Another type of disease that involves
+ hardening of the skin is scleredema, in which the skin thickens with an accumulation of "mucin" between
+ collagen bundles, and in which fibroblasts are overactive in producing collagen. (Varga, et al.) This
+ condition is believed to often follow a "febrile illness" and is associated with diabetes. My interest in
+ these conditions comes from my awareness that estrogen promotes collagen formation, and that changes in the
+ connective tissue are deeply associated with the processes of stress and aging, following the ideas of
+ Metchnikov and Selye.
+
+
+ Many people are still committed to the various old theories of diabetes, though a few are showing ways in
+ which multiple causes can lead to diabetes. Increasingly, old age itself is seen to be "like diabetes
+ (Meneilly, et al.; Smith, et al.), and the situation is ripe for a recentering of our understanding of
+ diabetes around some of the general facts about aging and stress.
+
+
+
+ Diabetes mellitus, as named, refers to excessive urination and sugary urine, but it is now often diagnosed
+ in people who neither urinate excessively nor pass glucose in the urine, on the basis of a high level of
+ glucose in the blood. Many other signs (abnormal mucopolysaccharide metabolism with thickening of basement
+ membranes, leakage of albumin through capillary walls and into the urine, a high level of free fatty acids
+ in the blood, insensitivity of tissues to insulin, or reduced sensitivity of the beta cells to glucose) are
+ considered diagnostic by some people, who believe that the worst aspects of the disease can be prevented if
+ they can diagnose early and take preventive measures. This attitude derives largely from the genetic theory
+ of causation, though it incorporates a belief that (environmental) intervention can ameliorate the course of
+ the disease. When I wrote Nutrition for Women, I mentioned that the sudden appearance of diabetes in
+ non-European Jews when they moved to Isreal made the genetic theory of diabetes untenable, and since then
+ other studies have made the similar point that environmental factors seem crucial. (Shaltout, et al.) Many
+ people are arguing for the racial/genetic theory of diabetes, but they are failing to consider some simple
+ dietary factors, especially the high consumption of unsaturated seed oils and the combination of nutritional
+ deficiencies and environmental stress.
+
+
+ I have known adults and children who were diagnosed as diabetic, and given insulin (and indoctrinated with
+ the idea that they had a terminal degenerative disease) on the strength of a single test showing excessive
+ glucose. When I taught at the naturopathic medical school in Portland, I tried to make it clear that
+ "diabetes" (a term referring to excessive urination) is a function, and that a high level of glucose in the
+ blood or urine is also a function, and that the use of insulin should require a greater diagnostic
+ justification than the use of aspirin for a headache does, because insulin use itself constitutes a serious
+ health problem. (And we seldom hear the idea that "diabetes" might have a positive side [Robinson and
+ Johnston], for example that it reduces the symptoms of asthma [Vianna and Garcialeme], which get worse when
+ insulin is given. Normal pregnancy can be considered "diabetic" by some definitions based on blood sugar. I
+ got interested in this when I talked to a healthy "diabetic" woman who had a two year old child whose IQ
+ must have been over 200, judging by his spontaneous precocious hobbies. Old gynecologists told me that it
+ was common knowledge that "diabetic" women had intellectually precocious children.)
+
+
+
+ When non-diabetic apes were given insulin treatments, they developed some of the same "complications of
+ diabetes" that are seen in humans, and antibodies to insulin were found in their retinas, suggesting that
+ some "complications of diabetes" were complications of insulin treatment. Patients were seldom well informed
+ of the arguments against the use of insulin, but the justification for the new genetically engineered human
+ insulin is precisely that it avoids immunological damage.
+
+
+ Insulin was introduced into medicine in the 1920s. According to the Britannica Book of the Year for 1947,
+ page 265, "Mortality from diabetes in 1920 in the United States was 16.0 per 100,000, 14,062 deaths, but in
+ 1944, it was 26.4 per 100,000, 34,948 deaths."
+
+
+ One of the theories of the cause of diabetes is that a virus damages the beta cells in the pancreas, and the
+ main argument for that in the 1970s was that the onset of diabetes in children can often be dated to a time
+ shortly after a severe viral infection. It is true that intense sickness and a high fever (and high doses of
+ drugs given to treat the sickness) can cause very high levels of glucose in the blood, and even glucose in
+ the urine, but this is a fairly well recognized consequence of stress. High doses of cortisone (prednisone,
+ etc.) typically cause elevated glucose levels. Cushing's syndrome usually involves hyperglycemia. Normally,
+ this is just a functional response to an excess of glucocorticoids, but studies in dogs suggested that
+ intense and/or prolonged stress can damage the insulin-secreting cells in the pancreas. Dogs had half of
+ their pancreas removed, to increase the burden put on the remaining tissue, and after a large dose of
+ cortisone the dogs became (and remained) diabetic.
+
+
+ One of the problems associated with diabetes is the calcification of blood vessels, though now there is more
+ emphasis on fatty degeneration. Other blood vessel problems include hypertension, and poor circulation in
+ general, leading to gangrene of the feet, impotence, and degeneration of the retina. In muscles, and
+ probably in other tissues of diabetics, capillaries are more widely spaced, as if the basal oxidative
+ requirement were lower than normal. However, mitochondria contain more respiratory enzymes, as if to partly
+ compensate for the poor delivery of oxygen to the cells. Osteoporosis or osteopenia is a common complication
+ of diabetes, and seems to be associated with the calcification of soft tissues.
+
+
+ F. Z. Meerson's description of the stress-injured heart is very similar to the general changes that occur in
+ chronic diabetes. He found that the stressed heart becomes rigid and unable to contract completely, or to
+ relax completely. Excess calcium enters cells, and fatty acids are mobilized both locally and systemically,
+ and both of these tend to damage the mitochondria. In diabetes, fatty acids are mobilized and oxidized
+ instead of glucose, and calcium enters cells, increasing their rigidity and preventing relaxation of muscles
+ in blood vessels. (I'm not sure whether it is relevant to cell physiology, but the presence of an excess of
+ free unsaturated fatty acids, and of calcium, in cells makes me think of the insoluble soap that these
+ substances form in other situations, including the intestine. It seems that this could form a harmful
+ deposit in cells, blocking many metabolic processes.)
+
+
+
+ For many years, histologists have observed that calcium and iron tend to be deposited together in
+ "devitalized" tissues. Now we know that cell death from a great variety of causes involves the cell's
+ absorption of increased amounts of calcium. Simply the lack of energy increases the amount of calcium in a
+ cell, and stimulation or excitation does the same, creating or exaggerating a deficiency of energy. In low
+ thyroid people, many (if not all) tissues are very easily damaged. Since glucose is needed by liver cells to
+ produce the active (T3) form of thyroid, diabetes almost by definition will produce hypothyroidism, since in
+ diabetes glucose can't be absorbed efficiently by cells.
+
+
+
+ In the form of cell damage caused by the "excitotoxins," glutamic and aspartic acids, the damage seems to
+ require both stimulation, and difficulty in maintaining adequate energy production. This combination leads
+ to both calcium uptake and lipid peroxidation. When cells are de-energized, they tend to activate iron by
+ chemical reduction, producing lipid peroxidation. This could explain the presence of chemically active iron,
+ but an actual increase in the iron concentration suggests that there has been prolonged injury (oxidative
+ stress) to the cell, with increased production of the heme group, which binds iron.
+
+
+ Hans Selye found that he could produce scleroderma (hardening and calcification of the skin) in rats by
+ giving them a toxic dose of a heavy metal, and then irritating the skin a little by plucking hair. Iron is
+ now tending to be recognized as a factor in inflammation. Vitamin E was able to prevent the development of
+ scleroderma under Selye's experimental conditions, suggesting that the irritation allowed the heavy metal to
+ cause oxidative damage to the skin. Selye found other ways to cause calcification of tissues, including the
+ walls of arteries, but he directed most of his attention to the role of "pro-inflammatory" hormones. A
+ decreased blood supply was often used to predispose an organ to calcification. In diabetes, a characteristic
+ feature is that the blood supply is relatively remote from cells in muscle and skin, so the oxygen and
+ nutrients have to diffuse farther than in normal individuals, and the ATP level of cells is
+ characteristically lower than normal. In blood cells, both red (Garnier, et al.) and white cells are
+ probably more rigid in diabetes, because of lower ATP production, and higher intracellular calcium and
+ sodium.
+
+
+ Magnesium in the cell is largely associated with ATP, as the complex Mg-ATP. When ATP is "used" or converted
+ to ADP, this lower-energy substance associates with calcium, as Ca-ADP. In a hypothyroid state, the energy
+ charge can be depleted by stress, causing cells to lose magnesium. ATP is less stable when it isn't
+ complexed with magnesium, so the stress-induced loss of magnesium makes the cell more susceptible to stress,
+ by acting as a chronic background stimulation, forcing the cell to replace the ATP which is lost because of
+ its instability. In this state, the cell takes up an excess of calcium.
+
+
+
+ The picture that I think explains many of the features of diabetes is that an energy deficit produces an
+ alarm state, causing increased production of adrenalin and cortisol. Adrenalin mobilizes fat from storage,
+ and the free fatty acids create a chronic problem involving 1) blocked ATP production, 2) activation of the
+ protein kinase C system (increasing tension in blood vessels), 3) inhibition of thyroid function with its
+ energetic, hormonal, and tissue-structure consequences, 4) availability of fats for prostaglandin synthesis,
+ and 5) possibly a direct effect on clot dissolving, besides the PAI-1 (plasminogen activator inhibitor)
+ effect seen in diabetes (Ceriello, et al., Udvardy, et al., Vague, et al.). (Estrogen has many pro-clotting
+ effects, and one of them is a decreased activity of vascular plasminogen activator. K. E. Miller and S. V.
+ Pizzo, "Venous and arterial thromboembolic disease in women using oral contraceptives," Am. J. Obst. Gyn.
+ 144, 824, 1982. In 1968, D. G. Daniel et al., reported that estrogen promotes thromboembolism by increasing
+ clotting factor IX in the blood.)
+
+
+ Increased entry of calcium into cells is complexly related to increased exposure to unsaturated fatty acids,
+ decreased energy, and lipid peroxidation. Osteoporosis, calcification of soft tissues and high blood
+ pressure are promoted by multiple stresses, hypothyroidism, and magnesium deficiency. The particular
+ direction a disease takes--diabetes, scleroderma, lupus, Alzheimer's, stroke, etc.--probably results from
+ the balance between resources and demands within a particular organ or system. Calcium overload of cells
+ can't be avoided by avoiding dietary calcium, because the bones provide a reservoir from which calcium is
+ easily drawn during stress. (In fact, the reason calcium can temporarily help prevent muscle cramps seems to
+ be that it makes magnesium more available to the muscles.)
+
+
+ If we want to stop a disease that involves abnormal calcification or contraction of muscle (see Zenere, et
+ al.), we can increase our consumption of magnesium, and to cause cells to absorb and retain the magnesium,
+ we can increase our thyroid function. The use of coconut oil provides energy to stabilize blood sugar while
+ protecting mitochondria and the thyroid system from the harmful effects of unsaturated fats.
+
+
+ In 1947, B. A. Houssay found that a diet based on sugar as a source of energy was more protective against
+ diabetes than a diet based on lard, while the most protective diet was based on coconut oil. Lard reflects
+ the pigs' diet, and is usually extremely unsaturated, especially since it became standard to fatten them on
+ soybeans and corn. Essentially, his study seems to show that unsaturated (pork) fat permits diabetes to
+ develop, sugar is slightly protective, and coconut oil is very protective against the form of diabetes
+ caused by a poison.
+
+
+ At the same time, A. Lazarow was demonstrating that a low protein diet made animals more sensitive to
+ diabetes, and that cysteine, glutathione, and thioglycolic acid (antioxidants) are protective against
+ diabetes. The chelator of metals, BAL (British anti-lewisite), was also found to protect against diabetes.
+
+
+ Taken together, those studies suggest that the oxidizable unsaturated fats are involved in the process of
+ producing diabetes. At the same time, other studies were showing that the unsaturated oils suppress the
+ thyroid, and that coconut oil increases the metabolic rate, apparently by normalizing thyroid function.
+ Hypothyroidism is known to include deposition of mucopolysaccharides in tissues, increased permeability of
+ capillaries with leakage of albumin out of the blood, elevated adrenalin which can lead to increased
+ production of cortisol, decreased testosterone production, high risk of heart and circulatory disease,
+ including a tendency to ulceration of the extremities, and osteoporosis, all of which are recognized
+ "complications of diabetes." Broda Barnes gave all of his diabetic patients a thyroid supplement, and found
+ that none of them developed the expected complications of diabetes.
+
+
+ Recently, a high safflower oil diet was found to cause diabetes (Ikemoto, et al.), and obesity itself is
+ thought to be a factor in developing diabetes. The hormone patterns associated with obesity can be seen as
+ either cause or effect of the obesity (or both cause and effect), since, for example, low thyroid can
+ increase both estrogen and cortisol, which support the formation of fat, and the fat cells can become a
+ chronic source of estrogen synthesis.
+
+
+ On a diet lacking the "essential" unsaturated fatty acids, Benhamou (1995) found that nonobese diabetic mice
+ didn't develop diabetes, that is, the unsaturated fats themselves, without obesity, are sufficient to cause
+ diabetes. (Also see Girard; Golay, et al., and Kusunoki, et al.)
+
+
+
+ Estrogen and the polyunsaturated fatty acids (PUFA), linoleic and linolenic acid, alike activate the protein
+ kinase C (PKC) system of cellular activation. Many of the functions of PUFA are similar to the functions of
+ estrogen (e.g., antagonism to thyroid function, promotion of age pigment/lipofuscin), so this information
+ showing that they both act similarly on the same basic regulatory pathway is important. Estrogen increases
+ secretion of growth hormone (GH; it's closely associated with prolactin, also increased by estrogen), and GH
+ causes an increase in free fatty acids in the blood. Estrogen promotes iron retention, so it sets the stage
+ for oxidative stress. At least in some systems, both estrogen and PUFA promote the entry of calcium into the
+ cell.
+
+
+ In diabetes, there is a generalized excess activation of the PKC system. The starch-based diet, emphasizing
+ grains, beans, nuts, and vegetables, has been promoted with a variety of justifications. When people are
+ urged to reduce their fat and sugar consumption, they are told to eat more starch. Starch stimulates the
+ appetite, promotes fat synthesis by stimulating insulin secretion, and sometimes increases the growth of
+ bacteria that produce toxins. It is often associated with allergens, and according to Gerhard Volkheimer,
+ whole starch grains can be "persorbed" from the intestine directly into the blood stream where they may
+ block arterioles, causing widely distributed nests of cell-death. I have heard dietitians urge the use of
+ "complex carbohydrates" (starch) instead of sugar. In the first physiology lab I took, we fed rats a large
+ blob of moist cornstarch with a stomach tube, and then after waiting a few minutes, were told to dissect the
+ rat to find out "how far the starch had gone." In such a short time, we were surprised to find that not a
+ trace of the starch could be found. The professor's purpose was to impress us with the rapidity with which
+ starch is digested and absorbed. Various studies have demonstrated that starch (composed of pure glucose)
+ raises blood glucose more quickly than sucrose (half fructose, half glucose) does. The sudden increase of
+ blood glucose is sometimes thought to contribute to the development of diabetes, but if it does, it is
+ probably mediated by fat metabolism and the hormones other than just insulin.
+
+
+ Brewer's yeast has been used successfully to treat diabetes. In the l930s, my father had severe diabetes,
+ but after a few weeks of living on brewer's yeast, he recovered and never had any further evidence of
+ diabetes. Besides its high B-vitamin and protein content, yeast is an unusual food that should be sparingly
+ used, because of its high phosphorous/calcium ratio, high potassium to sodium ratio, and high estrogen
+ content. The insulin-producing beta cells of the pancreas have estrogen receptors, but I don't know of any
+ new research investigating this aspect of yeast therapy. In rabbit studies, diabetes produced by alloxan
+ poisoning, which kills the beta cells, was cured by DHEA treatment, and beta cells were found to have
+ regenerated in the pancreatic islets.
+
+
+ I think the basic anti-aging diet is also the best diet for prevention and treatment of diabetes,
+ scleroderma, and the various "connective tissue diseases." This would emphasize high protein, low
+ unsaturated fats, low iron, and high antioxidant consumption, with a moderate or low starch consumption. In
+ practice, this means that a major part of the diet should be milk, cheese, eggs, shellfish, fruits and
+ coconut oil, with vitamin E and salt as the safest supplements. It should be remembered that amino acids,
+ especially in eggs, stimulate insulin secretion, and that this can cause hypoglycemia, which in turn causes
+ cortisol secretion. Eating fruit (or other carbohydrate), coconut oil, and salt at the same meal will
+ decrease this effect of the protein. Magnesium carbonate and epsom salts can also be useful and safe
+ supplements, except when the synthetic material causes an allergic bowel reaction..
+
+
+ Although I started this newsletter with the thought of discussing the Mead acids--the unsaturated (n-9) fats
+ that are formed under certain conditions, especially when the dietary polyunsaturated fatty acids are
+ "deficient"--and their prostaglandin derivatives as a distinct anti-stress, anti-aging system, the loss of
+ which makes us highly susceptible to injury, I will save that argument for a future time, leaving this
+ newsletter as an addition to the view that an excess of the polyunsaturated fats is central to the
+ development of degenerative diseases: Cancer, heart disease, arthritis, immunodeficiency, diabetes,
+ hypertension, osteoporosis, connective tissue disease, and calcification.
+
+
+
+ REFERENCES WITH EXCERPTS AND COMMENTS
+
+
+
+
+ A. A. Alzaid, et al., "Effects of insulin on plasma magnesium in noninsulin-dependent diabetes mellitus:
+ Evidence for insulin resistance," J. of Clin. Endocr. and Metab. 80(4), 1376-1381, 1995. "...insulin
+ resistance in subjects with NIDDM impairs the ability of insulin to stimulate magnesium as well as glucose
+ uptake."
+
+
+ A. B. Akella, et al., "Diminished Ca++ sensitivity of skinned cardiac muscle contractility coincident with
+ troponin T-band shifts in the diabetic rat," Circulation Research 76(4), 600-606, 1995.D. A. Antonetti, et
+ al., "Increased expression of mitochondrial-encoded genes in skeletal muscle of humans with diabetes
+ mellitus--Rapid publication," J. of Clinical Investigation 95(3), 1383-1388, 1995. "The increased
+ mitochondrial gene expression may contribute to the increase in mitochondrial respiration observed in
+ uncontrolled diabetes." (Low ATP with high respiration would suggest uncoupling; unsaturated fatty acids are
+ known uncouplers of respiration from energy production.)
+
+
+
+ S. Asakuma, et al., "The effects of antianginal drugs on energy expernditure during exercise in normal
+ subjects," Japanese Circulation Journal--English Edition 59(3), 137-145, 1995. "RQ (carbohydrate consumption
+ relative to fat consumption) during exercise was significantly increased and VO2 was decreased after
+ propranolol, metoprolol and amosulalol." "These data suggest that propranolol, metoprolol and amosulalol
+ [beta-blockers] increase the efficiency of energy expenditure during ordinary physical activity by
+ increasing the utilization of carbohydrate and by decreasing the utilization of fat."
+
+
+ M. Bardicef, et al., "Extracellular and intracellular magnesium depletion in pregnancy and gestational
+ diabetes," Amer. J. of Obst. and Gyn. 172(3), 1009-1013, 1995.
+
+
+ P. E. Beales, et al., "Baclofen, a gamma-aminobutyric acid-b receptor agonist, delays diabetes onset in the
+ non-obese diabetic mouse," Acta Diabetologica 32(1), 53-56, 1995.
+
+
+
+ P. Y. Benhamou, et al., :"Essential fatty acid deficiency prevents autoimmune diabetes in nonobese diabetic
+ mice through a positive impact on antigen-presenting cells and Th2 lymphocytes," Pancreas 11(1), 26-37,
+ 1995.
+
+
+ C. D. Berdanier, "Diet, autoimmunity, and insulin-dependent diabetes mellitus: A controversy," Proc. Soc.
+ Exp. Biol. Med. 209(3), 223-230, 1995. "The majority of the genetic mutations that result in the phenotypic
+ expression of the insulin-dependent diabetes mellitus genotype are in the immune system." Antibodies to milk
+ protein can be found in the patient, but these probably represent antigen mimicry, resulting from the loss
+ of antibody specificity which is a feature of autoimmune disease.
+
+
+ G. Bianchi, et al., "Thyroid volume in type 1 diabetes patients without overt thyroid disease," Acta
+ Diabetologica 32(1), 49-52, 1995. "An association between insulin-dependent diabetes mellitus (type 1) and
+ thyroid diseases has long been reported...."
+
+
+ P. Bjorntorp, "Insulin resistance: The consequence of a neuroendocrine disturbance?" Int. J. Obes. 19(Suppl.
+ 1), S6-S10, 1995. "The decreased capillary density may...be of importance for the apparent insulin
+ resistance."
+
+
+ R. Bouillon, et al., "Influence of age, sex, and insulin on osteoblast function: Osteoblast dysfunction in
+ diabetes mellitus," J. of Clin. Endocr. and Metab. 80(4), 1194-1202, 1995. "...the osteoblast function is
+ significantly decreased in diabetic patients...."
+
+
+
+ A. Ceriello, et al., "The defence against free radicals protects endothelial cells from
+ hyperglycaemia-induced plasminogen activator inhibitor 1 over-production," Blood Coagulation &
+ Fibrinolysis 6(2), 133-137, 1995. "The hypothesis that oxidative stress may play an important role in the
+ pathogenesis of diabetic complications is ... supported by this study." [GSH reduced PAI-1.]
+
+
+ V. Coiro, et al., "Low-dose ovine corticotropin-releasing hormone stimulation test in diabetes mellitus with
+ or without neuropathy," Metabolism--Clinical and Experimental 44(4), 538-542, 1995. "...basal and
+ CRH-induced cortisol levels were significantly higher in diabetics than in normal controls." "...even
+ uncomplicated diabetes mellitus is associated with adrenal hyperfunction."
+
+
+
+ S. R. Colberg, et al., "Skeletal muscle utilization of free fatty acids in women with visceral obesity," J.
+ Clin. Invest. 95(4), 1846-1853, 1995. "Visceral obesity is strongly associated with insulin resistance."
+ "...visceral adiposity is clearly associated with skeletal muscle insulin resistance but this is not due to
+ glucose-FFA [free fatty acid] substrate competition. Instead, women with visceral obesity have reduced
+ postabsorptive FFA utilization by muscle."
+
+
+ G. A. Colditz, et al., "Weight gain as a risk factor for clinical diabetes mellitus in women," Annals of
+ Internal Medicine 122(7), 481-486, 1995.
+
+
+ C. Douillet and M. Ciavatti, "Effect of vitamin E treatment on tissue fatty acids and cholesterol content in
+ experimental diabetes," J. Nutr. Biochem. 6(6), 319-326, 1995. "Diabetes induced a decrease of
+ monounsaturated fatty acids and particularly palmitoleic acid in all studied tissues: liver, aorta, plasma."
+ C18:3 n-6 and C20:4 n-6 were increased by diabetes.
+
+
+ M. Garnier, et al., "Red blood cell sodium conent in NID diabetic patients with hemorheological
+ abnormalities," Clinical Hemorheology 15(3), 325-333, 1995.
+
+
+ K. D. Gerbitz, et al., "Mitochondrial diabetes mellitus: A review," BBA--Mol. Basis Dis. 1271(1), 253-260,
+ 1995. This particular kind of diabetes, which is combined with deafness in 60% of the patients, involves a
+ variant mitochondrial gene and occurs in about 1.5% of diabetics. "The underlying pathomechanism is probably
+ a delayed insulin secretion due to an impaired mitochondrial ATP production in consequence of the mtDNA
+ defect." To know the "causal" value of this gene we have to know how often it occurs in people who never
+ develop diabetes. It is interesting that it is suggested to operate by way of impaired ATP production, which
+ can be the result of so many factors, such as excess unsaturated fats, low thyroid, low magnesium, low
+ copper, etc. Pages 141-151 of the same journal as an article by D. C. Wallace, et al., "Mitochondrial DNA
+ mutations in human degenerative diseases and aging," which makes the point that "Generally, individuals
+ inheriting these mitochondrial diseases are relatively normal in early life, develop symptoms during
+ childhood, mid-life, or old age depending on the severity of the ... mutation; and then undergo a
+ progressive decline." Their energy-producing systems are supposedly more susceptible to the effects of
+ aging.
+
+
+
+ J. Girard, "Role of free fatty acids in insulin resistance of subjects with non-insulin-dependent diabetes,"
+ Diabetes Metab. 21(2), 79-88, 1995. "Studies performed in the rat suggest that impaired glucose-induced
+ insulin secretion could also be related to chronic exposure of pancreatic beta cells to elevated plasma free
+ fatty acid levels." [This direct effect of free fatty acids on the beta cells is extremely important.
+ Estrogen--probably via GH--increases free fatty acids, and adrenalin--which is elevated in
+ hypothyroidism--increases the release of free fatty acids from storage. Free fatty acids impair
+ mitochondrail energy production.]
+
+
+ A. Golay, et al., "Effect of lipid oxidation on the regulation of glucose utilization in obese patients,"
+ Acta Diabetologica 32(1), 44-48, 1995. [Free fatty acids strongly and quickly depress the ability to oxidize
+ or store glucose.]
+
+
+ A. Gomes, et al., "Anti-hyperglycemic effect of black tea (Camellia sinensis) in rat," J. of
+ Ethnopharmacology 45(3), 223-226, 1995. It "was found to possess both preventive and curative effects on
+ experimentally produced diabetes in rats."
+
+
+ Y. Hattori, et al., "Phorbol esters elicit Ca++-dependent delayed contractions in diabetic rat aorta," Eur.
+ J. Pharmacol. 279(1), 51-58, 1995. [Diabetic tissue is more responsive to activation of protein kinase C by
+ phorbol esters.]
+
+
+ B. A. Houssay and C. Martinez, "Experimental diabetes and diet," Science 105, 548-549, 1947. [Mortality was
+ zero on the high coconut oil diet, 100% on the high lard diet. It was 90% on the low protein diet, and 33%
+ on the high protein diet. With a combination of coconut oil and lard, 20%.]
+
+
+ B. A. Houssay, et al., "Accion de la administracion prolongada de glucosa sobre la diabetes de la rata,"
+ Rev. Soc. argent. de biol. 23, 288-293, 1947.
+
+
+ S. Ikemoto, et al., "High fat diet-induced hyperglycemia: Prevention by low level expression of a glucose
+ transporter (GLUT4) minigene in transgenic mice," Proc. Nat. Acad. Sci. USA 92(8), 3096-3099, 1995. "...mice
+ fed a high-fat (safflower oil) diet develop defective glycemic control, hyperglycemia, and obesity."
+
+
+ M. Inaba, et al., "Influence of high glucose on 1,25-dihydroxyvitamin D-3-induced effect on human
+ osteoblast-like MG-63 cells," J. Bone Miner. Res. 10(7), 1050-1056, 1995.
+
+
+ J. S. Jensen, et al., "Microalbuminuria reflects a generalized transvascular albumin leakiness in clinically
+ healthy subjects," Clin. Sci. 88(6), 629-633, 1995.
+
+
+ G. Jorneskog, et al., "Skin capillary circulation severely impaired in toes of patients with IDDM, with and
+ without late diabetic complications," Diabetologia 38(4), 474-480, 1995.
+
+
+ A. M. Kahn and T. Song, "Insulin inhibits dog vascular smooth muscle contraction and lowers Ca++[i] by
+ inhibiting Ca++ influx," J. of Nutrition 125(6 Suppl.), S1732-S1737, 1995.
+
+
+ F. Kuhlencordt, et al., "Examination of the skeleton in diabetic patients up to age 45," Deutsche med.
+ Wchnschr. 91, 1913-1917, 1966. "Some patients have a generalized osteoporosis-like process, and some have
+ localized bone lesions...."
+
+
+ M. Kusunoki, et al., "Amelioration of high fat feeding-induced insulin resistance in skeletal muscle with
+ the antiglucocorticoid RU486," Diabetes 44(6), 718-720, 1995. "These results suggest that glucocorticoids
+ play, in a tissue-specific manner, a role in the maintenance and/or production of insulin resistance
+ produced by high-fat feeding."
+
+
+ A. Lazarow, "Protection against alloxan diabetes," Anat. Rec. 97, 353, 1947.
+
+
+ A. Lazarow, "Protective effect of glutathione and cysteine against alloxan diabetes in the rat," Proc. Soc.
+ Exp. Biol. & Med. 61, 441-447, 1946. [While certain doses of cysteine, glutathione, and thioglycolic
+ acid completely prevented alloxan diabetes, it was interesting that all of the rats receiving ascorbic acid
+ became diabetic. To me, this argues for the free radical cause of diabetes, rather than just the sulfhydryl
+ oxidation. Lazarow suggested that succinic dehydrogenase, and various other sulfhydryl enzymes, including
+ those involved in fatty acid oxidation, might be involved.]
+
+
+ R. B. Lipton and J. A. Fivecoate, "High risk of IDDM in African-American and Hispanic children in Chicago,
+ 1985-1990," Diabetes Care 18(4), 476-482, 1995. "The relatively early age at onset may point to an
+ environmental factor associated with this high incidence of the disease."
+
+
+ G. S. Meneilly, et al., "Insulin-mediated increase in blood flow is impaired in the elderly," J. Clin.
+ Endocrinol. Metab. 80(6), 1899-1903, 1995. "Normal aging is characterized by resistance to insulin-mediated
+ glucose uptake."
+
+
+ J. Ma, et al., "Associations of serum and dietary magnesium with cardiovascular disease, hypertension,
+ diabetes, insulin, and carotid arterial wall thickness: The ARIC study," J. Clin. Epidemiol. 48(7), 927-940,
+ 1995. [Carotid wall thickness increased in women as serum Mg level decreased.]
+
+
+ Y. Matsumoto, et al., "Creatine kinase kinetics in diabetic cardiomyopathy," Amer. J. Physiol.-Endocrinol.
+ Met. 31(5), E1070-E1076, 1995.
+
+
+ F. Mercure and G. Vanderkraak, "Inhibition of gonadotropin-stimulated ovarian steroid production by
+ polyunsaturated fatty acids in teleost fish," Lipids 30(6), 547-554, 1995. "The inhibitory actions by PUFAs
+ were not restricted to long-chain PUFAs, as linoleic and linolenic acids had similar actions in the
+ goldfish. The inhibitory action of EPA on testosterone production was reversible upon removal of the PUFA
+ from medium." "[Stimulated] ...testosterone production ... was attenuated by PUFAs...."
+
+
+
+ H. Mulder, et al., "Non-parallelism of islet amyloid polypeptide (amylin) and insulin gene expression in rat
+ islets following dexamethasone treatment," Diabetologia 38(4), 395-402, 1995.
+
+
+ S. Nagasaka, et al., "Effect of glycemic control on calcium and phosphorus handling and parathyroid hormone
+ level in patients with non-insulin-dependent diabetes mellitus," Endocr. J. 42(3), 377-383, 1995.
+ "...hyperglycemia causes excess urinary calcium and phosphorus excretion in patients with NIDDM. In response
+ to urinary calcium loss, PTH secretion is mildly stimulated. Bone formation seems to be suppressed in the
+ hyperglycemic state in spite of increased PTH secretion." [These are the changes I would expect to see in
+ hypothyroid people with high cortisol.]
+
+
+ B. Oztas and M. Kucuk, "Influence of acute arterial hypertension on blood-brain barrier permeability in
+ streptozocin-induced diabetic rats," Neuroscience Letters 188(1), 53-56, 1995.
+
+
+
+ S. Phillips, et al., "Neuropathic arthropathy of the spine in diabetes," Diabetes Care 18(6), 876-869, 1995.
+
+
+ J. F. Pouliot and R. Beliveau, "Palmitoylation of the glucose transporter in blood-brain barrier
+ capillaries," Bioch. et Bioph. Acta--Biomembranes 1234(2), 191-196, 1995. "Palmitoylation may be involved in
+ the regulation of glucose transport activity in hyperglycemia."
+
+
+ R. Ramakrishnan and A. Namasivayam, "Norepinephrine and epinephrine levels in the brain of alloxan diabetic
+ rats," Neuroscience Letters 186(2-3), 200-202, 1995. [Epinephrine increased in striatum, hippocampus and
+ hypothalamus, Norepinephrine increased in hypothalamus and decreased in pons and medulla.]
+
+
+ J. G. Regensteiner, et al., "Effects of non-insulin-dependent diabetes on oxygen consumption during
+ treadmill exercise," Med. Sci. Sports Exerc. 27(6), 874-881, 1995. "The reduced rate of increase in oxygen
+ consumption during increasing submaximal work loads in NIDDM suggests that limitations in oxygen delivery
+ may impair exercise performance in otherwise healthy persons with diabetes."
+
+
+ A. A. Shaltout, et al., "High incidence of childhood-onset IDDM in Kuwait," Diabetes Care 18(7), 923-927,
+ 1995. The incidence of IDDM in children is high in the region and has apparently increased nearly fourfold
+ in the last decade. This is especially significant, since diabetes that appears in childhood is especially
+ important for the theory of genetic causation. This study should give the gene people real trouble. They
+ might have to call in the "gene for bed-wetting" people to help with their case.
+
+
+
+ M. A. Smith, et al., "Radical AGEing in Alzheimer's disease," Trends in Neurosciences 18(4), 172-176, 1995.
+
+
+ A. Tchernof, et al., "Relation of steroid hormones to glucose tolerance and plasma insulin levels in men:
+ Importance of visceral adipose tissue," Diabetes Care 28(3), 292-299, 1995.
+
+
+ A. Tchernof, et al., "Reduced testosterone and adrenal C-19 steroid levels in obese men," Metabolism--Clin.
+ and Exp. 44(4), 513-519, 1995. "...reduced concentrations of testosterone and adrenal C-19 steroid
+ precursors are associated with increased body fatness rather than with excess visceral fat accumulation."
+ [These results] "...emphasize the importance of adrenal steroids as correlates of body composition in men."
+
+
+
+ B. G. Trumper, et al., "Circadian variation of insulin requirement in insulin dependent diabetes
+ mellitus--The relationship between circadian change in insulin demand and diurnal patterns of growth
+ hormone, cortisol and glucagon during euglycemia," Hormone and Metabolic Research 27(3), 141-147, 1995. "The
+ results of the study showed that the early morning rise in the insulin demand is related to the increased
+ early morning cortisol secretion and to the nocturnal peaks of growth hormone concentration."
+
+
+ M. Udvardy, et al., "Altered lysis resistance of platelet-rich clots in patients with insulin-dependent
+ diabetes mellitus," Thromb. Res. 79(1), 57-63, 1995. Suppression of clot-dissolving "...was remarkably
+ stronger in IDDM, along with the highest PAI-1 activity concentration ratio of the platelet lysates,
+ compared to plasmatic levels."
+
+
+ P. Vague, et al., "Hypofibrinolysis and the insulin resistance syndrome," Int. J. Obes. 19(Suppl. 1),
+ S11-S15, 1995. Hypofibrinolysis is observed among obese subjects and it has been shown that an excess of
+ plasminogen activator inhibitor 1 (PAI 1) the main regulator of the fibrinolytic system, is closely
+ associated to other components of the insulin resistance syndrome, namely, excessive body weight, high waist
+ to hip ratio, elevated blood pressure, hyperinsulinemia and hypertriglyceridemia."
+
+
+
+ E. O. Vianna and J. Garcialeme, "Allergen-induced airway inflammation in rats: Role of insulin," American J.
+ of Respiratory and Critical Care Med. 151(3), 809-814, 1995. "Clinical asthma appears to be less severe when
+ diabetes mellitus is superimposed."
+
+
+ A. Warley, et al., "Capillary surface area is reduced and tissue thickness from capillaries to myocytes is
+ increased in the left ventricle of streptozotocin-diabetic rats," Diabetologia 38(4), 413-421, 1995.
+
+
+ G. C. Weir, "Which comes first in non-insulin-dependent diabetes mellitus: Insulin resistance or beta-cell
+ failure? Both come first," JAMA 273(23), 1878-1879, 1995.
+
+
+
+ N. R. Williams, et al., "Plasma, granulocyte and mononuclear cell copper and zinc in patients with diabetes
+ mellitus," Analyst 120(3), 887-890, 1995. "...the copper and zinc status of these diabetic patients was
+ reduced, providing further evidence of a role for these antioxidant" trace elements in this disease.
+
+
+ T. Yamakawa, et al., "Augmented production of tumor necrosis factor-alpha in obese mice," Clinical
+ Immunology and Immunopathology 75(1), 51-56, 1995. "...the TNF-alpha derived from adipose tissues might be
+ involved in the induction of peripheral insulin resistance..."
+
+
+ T. Yamashita, et al., "Increased transendothelial permeation of albumin by high glucose concentration,"
+ Metabolism 44(6), 739-744, 1995.
+
+
+ M. B. Zemel, "Insulin resistance vs. hyperinsulinemia in hypertension: Insulin regulation of Ca++ transport
+ and Ca++-regulation of insulin sensitivity," Journal of Nutrition 125(6 Suppl.), S1738-S1743, 1995.
+
+
+ B. M. Zenere, et al., "Noninvasive detection of functional alterations of the arterial wall in IDDM patients
+ with and without microalbuminuria," Diabetes Care 18(7), 975-982, 1995. [There is a reduced vasodilatory
+ capacity in diabetes, and especially in patients who are leaking albumin.]
+
+
+ D. B. Zilvermit, et al., "Oxidation of glucose labelled with radioactive carbon by normal and
+ alloxandiabetic rats," J. Biol. Chem. 176, 389-400, 1948. [Diabetic rats had the same rate of glucose
+ oxidation as normal rats, in this experiment. This is an artificial form of diabetes that doesn't
+ immediately involve an excess of unsaturated fatty acids, as occurs during stress, estrogen excess,
+ hypothyroidism, or diets high in polyunsaturated fats which can cause a more "natural" kind of diabetes. The
+ artificial alloxandiabetes forces the animal to oxidize an excess of fatty acids, and eventually should lead
+ to the same kind of mitochondrial damage seen in natural diabetes.]
+
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
+
diff --git a/raypeat-articles/processed/eclampsia.html b/raypeat-articles/processed/eclampsia.html
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+
+
+
+ Eclampsia in the Real Organism: A Paradigm of General Distress Applicable in Infants, Adults, Etc.
+
+
+
+
+ Eclampsia in the Real Organism: A Paradigm of General Distress Applicable in Infants, Adults, Etc.
+
+
+
+ To prevent the appropriation and abuse of our language by academic and professional cliques, I like to
+ recall my grandparents' speech. When my grandmother spoke of eclampsia, the word was still normal
+ English, that reflected the Greek root meaning, "shining out," referring to the visual effects that are
+ often prodromal to seizures. The word was most often used in relation to pregnancy, but it could also be
+ applied to similar seizures in young children. The word is the sort that might have been coined by a
+ person who had experienced the condition, but the experience of seeing hallucinatory lights is seldom
+ mentioned in the professional discussion of "eclampsia and preeclampsia."
+
+
+ Metaphoric thinking--using comparisons, models, or examples--is our natural way of gaining new
+ understanding. Ordinary language, and culture, grow when insightful comparisons are generally adopted,
+ extending the meaning of old categories. Although the free growth of insight and understanding might be
+ the basic law of language and culture, we have no institutions that are amenable to that principle of
+ free development of understanding. Institutions devoted to power and control are naturally hostile to
+ the free development of ideas.
+
+
+ Among physicians, toxemia (meaning poisons in the blood) has been used synonymously with preeclampsia,
+ to refer to the syndrome in pregnant women of high blood pressure, albumin in the urine, and edema,
+ sometimes ending in convulsions. Eclampsia is reserved for the convulsions themselves, and is restricted
+ to the convulsions which follow preeclampsia, when there is "no other reason" for the seizure such as
+ "epilepsy" or cerebral hemorrhage. Sometimes it is momentarily convenient to use medical terms, but we
+ should never forget the quantity of outrageous ignorance that is attached to so many technical words
+ when they suggest the identity of unlike things, and when they partition and isolate things which have
+ meaning only as part of a process. Misleading terminology has certainly played an important role in
+ retarding the understanding of the problems of pregnancy.
+
+
+ In 1974, when I decided to write Nutrition for Women, I was motivated by the awful treatment I saw women
+ receiving, especially during pregnancy, from physicians and dietitians. Despite the research of people
+ like the Shutes and the Biskinds, there were still "educated" and influential people who said that the
+ mother's diet had no influence on the baby. (That strange attitude affects many aspects of behavior and
+ opinion.)
+
+
+ How can people believe that the mother's diet has no effect on the baby's health? Textbooks used to talk
+ about the "insulated" fetus, which would get sufficient nutrients from the mother's body even if she
+ were starving. To "prove" the doctrine, it was pointed out that the fetus gets enough iron to make blood
+ even when the mother is anemic. In the last few years, the recognition that smoking, drinking, and using
+ other drugs can harm the baby has helped to break down the doctrine of "insulation," but there is still
+ not a medical culture in which the effects of diet on the physiology of pregnancy are appreciated. This
+ is because of a mistaken idea about the nature of the organism and its development. "Genes make the
+ organism," according to this doctrine, and if there are congenital defects in the baby, the genes are
+ responsible. A simple sort of causality flows from the genes to the finished organism, according to that
+ idea. It was taught that if "the genes" are really bad, the defective baby can make the mother
+ sick, and she contributed to the baby's bad genes. The idea isn't completely illogical, but
+ it isn't based on reality, and it is demonstrably false. (Race, age and parity have no effect on
+ incidence of cerebral palsy; low birth weight and complications of pregnancy are
+ associated with it: J. F. Eastman, "Obstetrical background of 753 cases of cerebral
+ palsy," Obstet. Gynecol. Surv. 17, 459-497, 1962.)
+
+
+ Although Sigmund Freud sensibly argued in 1897 that it was more reasonable to think that an infant's
+ cerebral palsy was caused by the same factors that caused the mother's sickness, than to think that the
+ baby's cerebral palsy caused maternal sickness and premature labor, more than 50 years
+ later people were still taking seriously the idea that cerebral palsy might cause maternal
+ complications and prematurity. (A.M. Lilienfield and E. Parkhurst, "A study of the
+ association of factors of pregnancy and parturition with the development of cerebral palsy," Am. J.
+ Hyg. 53, 262-282, 1951.)
+
+
+ Medical textbooks and articles still commonly list the conditions that are associated with
+ eclampsia: Very young and very old mothers, a first pregnancy or a great number of
+ previous pregnancies, diabetes, twins, obesity, excessive weight gain, and kidney disease. Some authors,
+ observing the high incidence of eclampsia in the deep South, among Blacks and on American Indian
+ reservations, have suggested that it is a genetic disease because it "runs in families." If poverty and
+ malnutrition are also seen to "run in families," some of these authors have argued that the bad genes
+ which cause birth defects also cause eclampsia and poverty. (L. C. Chesley, et al., "The familial factor
+ in toxemia of pregnancy," Obstet. Gynec. 32, 303-311, 1968, reported that women whose mothers suffered
+ eclampsia during their gestation were likely to have eclampsia themselves. Some "researchers" have
+ concluded that eclampsia is good, because many of the babies die, eliminating the "genes" for eclampsia
+ and poverty.)* Any sensible farmer knows that pregnant animals must have good food if
+ they are to successfully bear healthy young, but of course those farmers don't have a sophisticated
+ knowledge of genetics.
+
+
+ The inclusion of obesity and "excessive weight gain" among the conditions associated with eclampsia has
+ distracted most physicians from the fact that malnutrition is the basic cause of eclampsia. The
+ pathologist who, knowing nothing about a woman's diet, writes in his autopsy report that the subject is
+ "a well nourished" pregnant woman, reflects a medical culture which chooses to reduce "nutritional
+ adequacy" to a matter of gross body weight. The attempt to restrict weight gain in pregnancy has
+ expanded the problem of eclampsia beyond its association with poverty, into the more affluent classes.
+
+
+ Freud wasn't the first physician who grasped the idea that the baby's health depends on the mother's,
+ and that her health depends on good nutrition. Between 1834 and 1843, John C. W. Lever, M.D., discovered
+ that 9 out of 10 eclamptic women had protein in their urine. He described an eclamptic woman who bore a
+ premature, low-weight baby, as having "...been living in a state of most abject penury for two or three
+ months, subsisting for days on a single meal of bread and tea. Her face and body were covered with
+ cachectic sores." ("Cases of puerperal convulsions," Guy's Hospital Reports, Volume 1, series 2, 495-517, 1843.) S. S. Rosenstein observed that eclampsia was preceded by changes in the serum (Traite Pratique des Maladies des Reins, Paris, 1874). L. A. A. Charpentier specifically documented
+ low serum albumin as a cause of eclampsia (A Practical Treatise on Obstetrics, Volume 2,
+ William Wood & Co., 1887). Robert Ross, M.D., documented the role of malnutrition as the cause of
+ proteinuria and eclampsia (Southern Medical Journal 28, 120, 1935).
+
+
+
+ In outline, we can visualize a chain of causality beginning with a diet deficient in protein, impairing
+ liver function, producing inability to store glycogen, to inactivate estrogen and insulin, and to
+ activate thyroid. Low protein and high estrogen cause increased tendency of the blood to clot. High
+ estrogen destroys the liver's ability to produce albumin (G. Belasco and G. Braverman, Control of
+ Messenger RNA Stability, Academic Press, 1994). Low thyroid causes sodium to be lost. The loss
+ of sodium albuminate causes tissue edema, while the blood volume is decreased. Decreased blood volume
+ and hemoconcentration (red cells form a larger fraction of the blood) impair the circulation. Blood
+ pressure increases. Blood sugar becomes unstable, cortisol rises, increasing the likelihood of premature
+ labor. High estrogen, hypoglycemia, viscous blood, increased tendency of the blood to clot cause
+ seizures. Women who die from eclampsia often have extensive intravascular clotting, and sometimes the
+ brain and liver show evidence of earlier damage, probably from clots that have been cleared. (Sometimes
+ prolonged clotting consumes fibrinogen, causing inability to clot, and a tendency to hemorrhage.) M.
+ M. Singh, "Carbohydrate metabolism in pre-eclampsia," Br. J. Obstet. Gynaecol. 83, 124-131. 1976.
+ Sodium decrease, R. L. Searcy, Diagnostic Biochemistry, McGraw-Hill, 1969. Viscosity, L. C. Chesley,
+ 'Hypertensive Disorders in Pregnancy, Appleton-Century-Crofts, 1978. Clotting, T. Chatterjee, et
+ al., "Studies on plasma fibrinogen level in preeclampsia and eclampsia, Experientia 34, 562-3,
+ 1978; D. M. Haynes, "Medical Complications During Pregnancy, McGraw-Hill Co.
+ Blakiston Div., 1969. Progesterone decrease, G. V. Smith, et al., "Estrogen and progestin metabolism
+ in pregnant women, with especial reference to pre-eclamptic toxemia and the effect of hormone
+ administration," Am. J. Obstet. Gynecol. 39, 405, 1940; R. L. Searcy, Diagnostic Biochemistry,
+ McGraw-Hill, 1969.
+
+
+ But the simple chain of causality has many lines of feedback, exacerbating the problem, and the
+ nutritional problem is usually worse than a simple protein deficiency. B vitamin deficiencies alone are
+ enough to cause the liver's underactivity, and to cause estrogen dominance, and a simple vitamin A
+ deficiency causes an inability to use protein efficiently or to make progesterone, and in itself mimics
+ some of the effects of estrogen.
+
+
+ Anything that causes a thyroid deficiency will make the problem worse. Thyroid therapy alone has had
+ spectacular success in treating and preventing eclampsia. (H. O. Nicholson, 1904, cited in Dieckman's
+ Toxemias of Pregnancy, 1952; 1929, Barczi, of Budapest; Broda Barnes, who prescribed thyroid as
+ needed, delivered more than 2,000 babies and never had a case of pre-eclampsia, though statistically 100
+ would have been expected.)
+
+
+ The clotting which sometimes kills women, can, if it is not so extensive, cause spotty brain damage,
+ similar to that seen in "multiple sclerosis," or it can occur in the liver, or other organ, or in the
+ placenta, or in the fetus, especially in its brain and liver. Some cases of supposed "post-partum
+ psychosis" have been the result of multiple strokes. When large clots occur in the liver or placenta,
+ the fibrinogen which has been providing the fibrin for disseminated intravascular coagulation can appear
+ to be consumed faster than it is produced by the liver. I think its disappearance may sometimes be the
+ result of the liver's diminished blood supply, rather than the "consumption" which is the way this
+ situation is usually explained. It is at this point that hemorrhages, rather than clots, become the
+ problem. The undernourished liver can produce seizures in a variety of ways--clots, hemorrhages,
+ hypoglycemia, and brain edema, for example, so eclampsia needn't be so carefully discriminated from "the
+ other causes of seizures."
+
+
+ Because I had migraines as a child, I was interested in their cause. Eating certain foods, or skipping
+ meals, seemed to be involved, but I noticed that women often had migraines premenstrually. Epilepsy too,
+ I learned, often occurred premenstrually.
+
+
+ In my experience of migraine, nausea and pain followed the visual signs, which consisted of a variable
+ progression of blind spots and lights. When I eventually learned that I could stop the progression of
+ symptoms by quickly eating a quart of ice cream, I saw that my insight could be applied to other
+ situations in which similar visual events played a role, especially "eclampsia" and "epilepsy." For
+ example, a woman who was 6 months pregnant called me around 10 o'clock one morning, to say that she had
+ gone blind, and was alone in her country house. She said she had just eaten breakfast around 9 AM, and
+ wasn't hungry, but I knew that the 6 month fetus has a great need for glucose, so I urged her to eat
+ some fruit. She called me 15 minutes later to report that she had eaten a banana, and her vision had
+ returned.
+
+
+ Early in pregnancy, "morning sickness" is a common problem, and it is seldom thought to have anything to
+ do with eclampsia, because of the traditional medical idea that the fetus "causes" eclampsia, and in the
+ first couple of months of pregnancy the conceptus is very small. But salty carbohydrate (soda crackers,
+ typically) is the standard remedy for morning sickness. Some women have "morning sickness"
+ premenstrually, and it (like the nausea of migraine) is eased by salt and carbohydrate. X-ray studies
+ have demonstrated that there are spasms of the small intestine (near the bile duct) associated with
+ estrogen-induced nausea.
+
+
+ Hypoglycemia is just one of the problems that develops when the liver malfunctions, but it is so
+ important that orange juice or Coca Cola or ice cream can provide tremendous relief from symptoms.
+ Sodium (orange juice and Pepsi provide some) helps to absorb the sugar, and--more basically--is
+ essential for helping to restore the blood volume. Pepsi has been recommened by the World Health
+ Organization for the rehydration of babies with diarrhea, in whom hypovolemia (thickening of the blood
+ from loss of water) is also a problem.
+
+
+ The problem of refeeding starving people has many features in common with the problem of correcting the
+ liver malfunction and hormone imbalances which follow prolonged malnutrition of a milder sort. The use
+ of the highest quality protein (egg yolk or potato juice, or at least milk or meat) is important, but
+ the supplementation of thyroid containing T 3 is often necessary. Intravenous albumin, hypertonic
+ solutions of glucose and sodium, and magnesium in an effective form should be helpful (magnesium sulfate
+ injected intramuscularly is the traditional treatment for eclampsia, since it is quickly effective in
+ stopping convulsions). While the sodium helps to restore blood volume and to regulate glucose, under
+ some circumstances (high aldosterone) it helps to retain magnesium; aldosterone is not
+ necessarily high during eclampsia.. Triiodothyronine directly promotes cellular absorption of magnesium.
+ Hypertonic glucose with minerals is known to decrease the destruction of protein during stress: M. Jeevanandam, et al., Metabolism 40, 1199-1206, 1991.
+
+
+ Katherina Dalton observed that her patients who suffered from PMS (and were benefitted by progesterone
+ treatment) were likely to develop "toxemia" when they became pregnant, and to have problems at the time
+ of menopause. In these women, it is common for "menstruation" to continue on the normal cycle during the
+ first several months of pregnancy. This cyclic bleeding seems to represent times of an increased ratio
+ of estrogen to progesterone, and during such periods of cyclic bleeding the risk of miscarriage is high.
+ Researchers found that a single injection of progesterone could sometimes eliminate the signs of toxemia
+ for the remainder of the pregnancy. Katherina Dalton, who continued to give her patients progesterone
+ throughout pregnancy, later learned that the babies treated in this way were remarkably healthy and
+ bright, while the average baby delivered after a "toxemic" pregnancy has an IQ of only 85.
+
+
+ Marian Diamond's work with rats clearly showed that increased exposure to estrogen during pregnancy
+ reduced the size of the cerebral cortex and the animals' ability to learn, while progesterone increased
+ the brain size and intelligence. Zamenhof's studies suggested that these hormones probably have their
+ effects largely through their actions on glucose, though they also affect the availability of oxygen in
+ the same way, and have a variety of direct effects on brain cells that would operate toward the same
+ end.
+
+
+ If Katherina Dalton's patients' IQs averaged 130, instead of the expected 85, the potential social
+ effects of proper health care during pregnancy are enormous.
+
+
+ But there is evidence that healthy gestation affects more than just the IQ. Strength of character,
+ ability to reason abstractly, and the absence of physical defects, for example, are strongly associated
+ with weight at birth.
+
+
+ Government studies and Social Security statistics suggest the size of the problem. The National
+ Institute of Neurological Diseases and Stroke found that birth weight was directly related to IQ at age
+ four, and that up to half of all children who were underweight at birth have an IQ under 70.(Chase.)
+ According to standard definitions, about 8% of babies in the U.S. have low birth weight.
+
+
+ Among people receiving Social Security income because of disability that existed at the age of 18, 75%
+ were disabled before birth. In 94% of these cases, the abnormality was neurological. (HEW.)
+
+
+ A study of 8 to 10-year-old children found that abstract verbal reasoning and perceptual/motor
+ integration are more closely related to birth weight than they are to IQ. (Wiener.)
+
+
+ National nutritional data show that in the U.S. the development of at least a million babies a
+ year is "substantially compromised" by prenatal malnutrition. Miscarriages, which are also
+ causally related to poor nutrition, occur at a rate of a few hundred thousand per year. (Williams.)
+
+
+ When a muscle is fatigued, it swells, taking up sodium and water, and it is likely to become sore.
+ Energy depletion causes any cell to take up water and sodium, and to lose potassium. An abnormal excess
+ of potassium in the blood, especially when sodium is low, affects nerve, muscle, and secretory
+ cells; a high level of potassium can stop the heart, for example. Cellular energy can
+ be depleted by a combination of work, insufficient food or oxygen, or a deficiency of the hormones
+ needed for energy production. When the swelling happens suddenly, the movement of water and sodium from
+ the blood plasma into cells decreases the volume of blood, while the quantity of red cells remains the
+ same, making the blood more viscous.
+
+
+ During the night, as adrenalin, cortisol, and other stress hormones rise, our blood becomes more viscous
+ and clots more easily. In rats, it has been found that the concentration of serum proteins increases
+ significantly during the night, presumably because water is moving out of the circulatory system. Even
+ moderate stress causes some loss of water from the blood.
+
+
+ If a person is malnourished, a moderate stress can overcome the body's regulatory capacity. If tissue
+ damage is extreme, or blood loss is great, even a healthy person experiences hypovolemia and shock.
+
+
+ C.A. Crenshaw, who was a member of the trauma team at Parkland Hospital in Dallas that worked on Kennedy
+ and Oswald, had been involved in research with G. T. Shires on traumatic shock. In his words, "we made
+ medical history by discovering that death from hemorrhagic shock (blood loss) can be due primarily to
+ the body's adjunctive depletion of internal salt water into the cells." (Shires' work involved isotopes
+ of sodium to show that sodium seems to be taken up by cells during shock.)
+
+
+ According to Crenshaw, "Oswald did not die from damaged internal organs. He died from the chemical
+ imbalances of hemorrhagic shock. From the time he was shot...until the moment fluids
+ were introduced into the body..." [19 minutes] "there was very little blood circulating
+ in Oswald's body. As a result, he was not getting oxygen, and waste built up in his cells. Then, when
+ the fluids were started, the collection of waste from the cells was dumped into the bloodstream,
+ suddenly increasing the acid level, and delivering these impurities to his heart. When the contaminated
+ blood reached the heart, it went into arrest...." The "waste" he refers to includes
+ potassium and lactic acid. Crenshaw advocates the use of Ringer's lactate to replace some of the lost
+ fluid. Since the blood already contains a large amount of lactate because the body is unable to consume
+ it, this doesn't seem reasonable. I think a hypertonic version of Locke's solution, containing glucose
+ and sodium bicarbonate as well as sodium chloride, would be better, though I think the potassium should
+ be omitted too, and extra magnesium would seem desirable. Triiodothyronine, I suspect, would help
+ tremendously to deal with the problems of shock, causing potassium, magnesium, and phosphate to move
+ back into cells, and sodium to move out, helping to restore blood volume and reduce the wasteful
+ conversion of glucose to lactic acid..
+
+
+ Albumin has been used therapeutically in preeclampsia (Kelman), to restore blood volume. Synthetic
+ polymers with similar osmotic properties are sometimes used in shock, and might also be useful in
+ eclampsia, but simply eating extra protein quickly restores blood albumin. For example, in a group of
+ women who were in their seventh month of pregnancy, the normal women's serum osmotic pressure was 247
+ mm. of water, that of the women with nonconvulsive toxemia was 215 mm., and in the women with eclampsia,
+ the albumin and osmotic pressure were lowest, with a pressure of 175 mm. In the eighth month, the
+ toxemic women who ate 260 grams of protein daily had a 7% increase in osmotic pressure, and a group who
+ ate 20 grams had a decline of 9%.(Strauss) In a group of preeclamptics, plasma volume was 39% below that
+ of normal pregnant women.
+
+
+
+ If the physiology of shock has some relevance for eclampsia, so does the physiology of heart failure,
+ since Meerson has shown that it is a consequence of uncompensated stress. The failing heart shifts from
+ mainly glucose oxidation to the inefficient use of fatty acids, which are mobilized during stress, and
+ with its decreased energy supply, it is unable to beat efficiently, since it remains in a partly
+ contracted state. Estrogen (which is increased in men who have had heart attacks) is another factor
+ which decreases the heart's stroke volume, and estrogen is closely associated with the physiology of the
+ free unsaturated fatty acids. The partly contracted state of the heart is effectively a continuation of
+ the partly contracted state of the blood vessels that causes the hypertension, and reduced tissue
+ perfusion seen in shock and eclampsia. Since shock can be seen as a generalized inflammatory state, and
+ since aspirin has been helpful in protecting against heart disease, it's reasonable that aspirin has
+ been tried as a treatment in pre-eclampsia. It seems to protect the fetus against intrauterine growth
+ retardation, an effect that I think relates to aspirin's ability to protect in several ways against
+ excesses of uunsaturated fatty acids and of estrogen. But, since aspirin can interfere with blood
+ clotting, its use around the time of childbirth can be risky, and it is best to correct the problem
+ early enough that aspirin isn't needed.
+
+
+
+ Besides protein deficiency and other nutritional deficiencies, excess estrogen and low thyroid can also
+ limit the liver's ability to produce albumin. Hypovolemia reduces liver function, and (like hepatic
+ infarcts) will reduce its ability to maintain albumin production..
+
+
+ The studies which have found that hospitalized patients with the lowest albumin are the least likely to
+ survive suggest that the hypovolemia resulting from hepatic inefficiency is a problem of general
+ importance, and that it probably relates to the multiple organ failure which is an extremely common form
+ of death among hospitalized patients. A diet low in sodium and protein probably kills many more people
+ than has been documented. If old age is commonly a hypovolemic condition, then the common salt
+ restriction for old-age hypertension is just as irrational as is salt-restriction in pregnancy or in
+ shock. Thyroid (T 3), glucose, sodium, magnesium and protein should be considered in any state in which
+ weakened homeostatic control of the composition of plasma is evident.
+
+
+
+ *Note: Although Konrad Lorenz (who later received the Nobel Prize) was the architect of
+ the Nazi's policy of "racial hygiene" (extermination of those with unwanted physical, cultural, or
+ political traits which were supposedly determined by "genes") he took his ideas from the leading U.S.
+ geneticists, whose works were published in the main genetics journals. Following the Nazis' defeat, some
+ of these journals were renamed, and the materials on eugenics were often removed from libraries, so that
+ a new historical resume could be presented by the profession.
+
+
+ ADDITIONAL REFERENCES
+
+
+ G. Wiener, et al., "Correlates of low birth weight: Psychological status at eight to ten years of age,"
+ Pediatr. Res. 2, 110-118, 1968.
+
+
+ A. Chase, "The great pellagra cover-up," Psychol. Today, pp. 83-86, Feb., 1975.
+
+ Prevention Handbook, Natl. Assoc. for Retarded Citizens, 1974.
+
+ US HEW, The Women and Their Pregnancies, W.B. Saunders Co., 1972.
+
+
+ M. Winick and P. Rosso, "The effect of severe early malnutrition on cellular growth of human brain,"
+ Pediatr. Res. 3, 181-184, 1969.
+
+
+ Roger Williams, Nutrition Against Disease, Pitman Publ., 1971.
+
+ H.M. Schmeck, Jr., "Brain harm in US laid to food lack," N.Y. times, Nov. 2, 1975.
+
+ R. Hurley, Poverty and Mental Retardation: A Causal Relationship, Random House, 1970.
+
+ D. Shanklin and J. Hodin, Maternal Nutrition and Child Health, C. C. Thomas, 1978.
+
+
+ H.H. Reese, H. A. Paskind, and E. L. Sevringhaus, 1936 Year Book of Neurology, Psychiatry and
+ Endocrinology, Year Book Publishers, Chicago, 1937.
+
+
+
+ M. B. Strauss, "Observations on the etiology of the toxemias of pregnancy: The relationship of
+ nutritional deficiency, hypoproteinemia, and elevated venous pressure to water retention in pregnancy,"
+ Am. J. Med. Sci. 190, 811-824, 1935.
+
+
+ "Albumin concentration can be used for mild preeclampsia," Obstet. Gynecol. News, October 1, 1974.
+
+ L. Kelman, et al., "Effects of dietary protein restriction on albumin synthesis, albumin catabolism, and
+ the plasma aminogram," Am. J. Clin. Nutr. 25, 1174-1178, 1972.
+
+
+
+ T. H. Brewer, "Role of malnutrition, hepatic dysfunction, and gastrointestinal bacteria in the
+ pathogenesis of acute toxemia of pregnancy," Am. J. Obstet. Gynecol. 84, 1253-1256, 1962.
+
+
+ "Plasma volume 'a clue' to hypertension risks," Obstet. Gynecol. Observer, August/September, 1975.
+
+ C. A. Crenshaw, MD, J. Hansen and J. G. Shaw, JFK: Conspiracy of Silence, Signet, 1992.
+
+
+ T. Backstrom, "Epileptic seizures in women related to plasma estrogen and progesterone during the
+ menstrual cycle," Acta Neurol. Scand. 54, 321-347, 1976.
+
+
+
+ C. Muller, et al., "Reversible bilateral cerebral changes on magnetic resonance imaging during
+ eclampsia," Deutsche Medizinische Wochenschrift 121(39), 1184-1188, 1996. (Brain edema was
+ demonstrated.)
+
+
+
+ Uzan S; Merviel P; Beaufils M; Breart G; Salat-Baroux J. [Aspirin during pregnancy. Indications and
+ modalities of prescription after the publication of the later trials]. Presse Medicale, 1996 Jan 6-13,
+ 25(1):31-6. Aspirin, an inhibitor of cyclo-oxygenase, is prescribed in a number of conditions related to
+ abnormal production of prostaglandins including gravidic hypertension. Results of the most recent trials
+ demonstrate that in patients with a past history of pre-eclampsia or intra-uterine growth retardation, a
+ pathological Doppler examination of the uterus, a pathological angiotensin test or an antiphospholipid
+ syndrome, prescription of aspirin at the dose of 100 mg/day can prevent recurrence or development of
+ pre-eclampsia or intra-uterine growth retardation. Treatment should begin as soon as possible during
+ pregnancy, certainly before development of clinical manifestations. After history taking and
+ identification of possible contraindications, bleeding time (Ivy method) is recorded before and after
+ prescription and should be lower than 8 minutes. In case bleeding time exceeds 10 minutes 10 to 15 days
+ after initiating aspirin, doses may be reduced to 50 mg per day or even 50 mg every two or three days to
+ reach the target level. Treatment should generally be continued up to 36 weeks gestation.
+
+
+
+ Randall, C L; Anton, R F; Becker, H C; Hale, R L; Ekblad, U. Aspirin dose-dependently reduces
+ alcohol-induced birth defects and prostaglandin E levels in mice. Teratology, v.44, n.5, (1991):
+ 521-530. The purpose of the present study was threefold. The first purpose was to determine if aspirin
+ (ASA) decreases alcohol-induced birth defects in mice in a dose-dependent fashion. The second purpose
+ was to see if the antagonism of alcohol-induced birth defects afforded by ASA pretreatment was related
+ to dose-dependent decreases in prostaglandin E (PGE) levels in uterine/embryo tissue. The third purpose
+ was to determine if ASA pretreatment altered maternal blood alcohol level.” In experiments 1 and 2,
+ pregnant C57BL/6J mice were administered ASA (0, 18.75, 37.5, 75, 150, or 300 mg/kg) on gestation day
+ 10. One hour following the subcutaneous injection of ASA, mice received alcohol (5.8 g/kg) or an
+ isocaloric sucrose solution intragastrically. In experiment 1 the incidence of birth defects was
+ assessed in fetuses delivered by caesarean section on gestation day 19. In experiment 2 uterine/embryo
+ tissue samples were collected on gestation day 10 1 hr following alcohol intubation for subsequent PGE
+ analysis. In experiment 3 blood samples were taken at five time points following alcohol intubation from
+ separate groups of alcohol-treated pregnant mice pretreated with 150 mg/kg ASA or vehicle The results
+ from the three experiments indicated that ASA dose-dependently reduced the frequency of alcohol-induced
+ birth defects in fetuses examined at gestation day 19, ASA decreased the levels of PGE in gestation day
+ 10 uterine/embryo tissue in a similar dose-dependentfashion, and ASA pretreatment did not significantly
+ influence maternalblood alcohol levels. These results provide additional support for the hypothesis that
+ PGs may play an important role in mediating the teratogenic actions of alcohol.
+
+
+
+
+
+ An aspirin a day to prevent prematurity. Sibai BM. Clin Perinatol, 1992 Jun, 19:2, 305-17. Intrauterine
+ fetal growth retardation and preeclampsia remain a substantial cause of preterm birth world wide. There
+ is evidence to suggest that a functional imbalance between vascular prostacyclin and platelet-derived
+ thromboxane A2 production plays a central role in the pathogenesis of these disorders. Low-dose aspirin
+ appears to reverse the above functional balance resulting in increased prostacyclin to thromboxane
+ ratio. The efficacy and safety of low-dose aspirin in preventing preeclampsia and fetal growth
+ retardation were tested in several randomized and uncontrolled trials. The data in the literature
+ suggest that low-dose aspirin is effective in reducing preterm birth due to the above complications in
+ selected high-risk pregnant women.
+
+
+
+ Rosental, D G; Machiavelli, G A; Chernavsky, A C; Speziale, N S; Burdman, J A. Indomethacin inhibits the
+ effects of estrogen in the anterior pituitary gland of the rat. Journal of Endocrinology, v.121, n.3,
+ (1989): 513-520. Two inhibitors of prostaglandin synthesis, indomethacin and aspirin, blocked the
+ increase of oestrogen-binding sites in the nuclear subcellular fraction, an increase which occurs after
+ the administration of oestradiol.
+
+
+ Zanagnolo, V; Dharmarajan, A M; Endo, K; Wallach, E E. Effects of acetylsalicylic acid (aspirin) and
+ naproxen sodium (naproxen) on ovulation, prostaglandin, and progesterone production in the rabbit.
+ Fertility and Sterility, v.65, n.5, (1996): 1036-1043.
+
+
+
+
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+
+ Fats and degeneration
+
+
+ Fats and degeneration
+
+
+
+
+
+
+
+
+ 50 years ago, in the first phase of marketing the polyunsaturated fatty acids (PUFA), linoleic acid
+ was "heart protective," and the saturated fats raised cholesterol and caused heart disease.
+
+
+ In the second phase, the other "essential fatty acid," linolenic acid, was said to be even better
+ than linoleic acid.
+
+
+ In the third phase, the longer chain omega -3 (omega minus three, or n minus three) fatty acids, DHA
+ and EPA, are said to be even better than linolenic acid.
+
+
+ Along the way, the highly unsaturated arachidonic acid, which we and other animals make out of the
+ linoleic acid in foods, was coming to be identified with the "harmful animal fats." But we just didn't
+ hear much about how the amount of arachidonic acid in the tissues depended on the amount of linoleic
+ acid in the diet.
+
+
+
+ U.S. marketing dominates the world economy, including of course the communication media, so we
+ shouldn't expect to hear much about the role of PUFA in causing cancer, diabetes, obesity, aging,
+ thrombosis, arthritis and immunodeficiency, or to hear about the benefits of the saturated fats.
+
+
+
+ The saturated fats include the "tropical fats," because they are synthesized in very warm organisms,
+ and are very stable at those temperatures. Their stability offers some protection against the unstable
+ PUFA.
+
+
+
+ Several of the degenerative conditions produced by the "essential fatty acids" can be reversed by
+ use of saturated fats, varying in length from the short chains of coconut oil to the very long chains of
+ waxes.
+
+
+
+
+
+
+
+ When a person uses a drug, there is generally an awareness that the benefit has to be weighed against the
+ side effects. But if something is treated as a "nutrient," especially an "essential nutrient," there is an
+ implication that it won't produce undesirable side effects.
+
+
+ Over the last thirty years I have asked several prominent oil researchers what the evidence is that there is
+ such a thing as an "essential fatty acid." One professor cited a single publication about a solitary sick
+ person who recovered from some sickness after being given some unsaturated fat. (If he had known of any
+ better evidence, wouldn't he have mentioned it?) The others (if they answered at all) cited "Burr and Burr,
+ 1929." The surprising thing about that answer is that these people can consider any nutritional research
+ from 1929 to be definitive. It's very much like quoting a 1929 opinion of a physicist regarding the
+ procedure for making a hydrogen bomb. What was known about nutrition in 1929? Most of the B vitamins weren't
+ even suspected, and it had been only two or three years since "vitamin B" had been subdivided into two
+ factors, the "antineuritic factor," B1, and the "growth factor," B2. Burr had no way
+ of really understanding what deficiencies or toxicities were present in his experimental diet.
+
+
+
+ A few years after the first experiments, Burr put one of his "essential fatty acid deficient" rats under a
+ bell jar to measure its metabolic rate, and found that the deficient animals were metabolizing 50% faster
+ than rats that were given linoleic and linolenic acids as part of their diet. That was an important
+ observation, but Burr didn't understand its implications. Later, many experiments showed that the
+ polyunsaturated fats slowed metabolism by profoundly interfering with the function of the thyroid hormone
+ and the cellular respiratory apparatus. Without the toxic fats, respiratory energy metabolism was very
+ intense, and a diet that was nutritionally sufficient for a sluggish animal wouldn't necessarily be adequate
+ for the vigorous animals.
+
+
+ Several publications between 1936 and 1944 made it very clear that Burr's basic animal diet was deficient in
+ various nutrients, especially vitamin B6.
+ The disease that appeared in Burr's animals could be cured by fat free B-vitamin preparations, or by
+ purified vitamin B6 when it became available.
+
+ A zinc deficiency produces similar symptoms,
+
+
+ and at the time Burr did his experiments, there was no information on the effects of fats on mineral
+ absorption. If a diet is barely adequate in the essential minerals, increasing the metabolic rate, or
+ decreasing intestinal absorption of minerals, will produce mineral deficiencies and metabolic problems.
+
+
+ Although "Burr's disease" clearly turned out to be a B-vitamin deficiency, probably combined with a mineral
+ deficiency, it continues to be cited as the basis justifying the multibillion dollar industry that has grown
+ up around the "essential" oils.
+
+
+ Two years before Burr's experiment, German researchers found that a fat-free diet prevented almost all
+ spontaneous cancers in rats. Later work showed that the polyunsaturated fats both initiate and promote
+ cancer. With that knowledge, the people who kept claiming that "linoleic, linolenic, and maybe arachidonic
+ acid are the essential fatty acids," should have devoted some effort to finding out how much of that
+ "essential nutrient" was enough, so that people could minimize their consumption of the carcinogenic stuff.
+
+
+ Between the first and second world wars, cod liver oil was recommended as a vitamin supplement, at first as
+ a source of vitamin A, and later as a source of vitamins A and D. But in the late 1940s, experimenters used
+ it as the main fat in dogs' diet, and found that they all died from cancer, while the dogs on a standard
+ diet had only a 5% cancer mortality. That sort of information, and the availability of synthetic vitamins,
+ led to the decreased use of cod liver oil.
+
+
+ But around that time, the seed oil industry was in crisis because the use of those oils in paints and
+ plastics was being displaced by new compounds made from petroleum. The industry needed new markets, and
+ discovered ways to convince the public that seed oils were better than animal fats. They were called the
+ "heart protective oils," though human studies soon showed the same results that the animal studies had,
+ namely, that they were toxic to the heart and increased the incidence of cancer.
+
+
+
+ The "lipid hypothesis" of heart disease argued that cholesterol in the blood caused atherosclerosis, and
+ that the polyunsaturated oils lowered the amount of cholesterol in the blood. Leaving behind the concept of
+ nutritional essentiality, this allowed the industry (and their academic supporters, such as Frederick Stare
+ at Harvard) to begin promoting the oils as having drug-like therapeutic properties. Larger amounts of
+ polyunsaturated fat were supposed to be more protective by lowering the cholesterol, and were to be
+ substituted for the saturated fats, which supposedly raised cholesterol and increased heart disease,
+ producing atherosclerotic plaques in the blood vessels and increasing the formation of blood clots.
+
+
+ Since all ordinary foods contain significant amounts of the polyunsaturated fats, there was no reason to
+ think that, even if they were essential nutrients, people were likely to become deficient in them. So the
+ idea of treating the seed oils as drug-like substances, to be taken in large amounts, appealed to the food
+ oil industry.
+
+
+ Prostaglandins, which are produced in the body by oxidizing the polyunsaturated fatty acids, provided an
+ opportunity for the drug industry to get involved in a new market, and
+ the prostaglandins offered a new way of arguing for the nutritional essentiality of linoleic and related
+ acids: A whole system of "hormones" is made from these molecules. Since some of the
+ prostaglandins suppress immunity, cause inflammation and promote cancer growth, some people have divided
+ them into the "good prostaglandins" and the "bad prostaglandins."
+
+
+ PGI2, or prostacyclin, is considered to be a good prostaglandin, because it causes vasodilatation, and so
+ drug companies have made their own synthetic equivalents: Epoprostenol, iloprost, taprostene, ciprostene,
+ UT-15, beraprost, and cicaprost. Some of these are being investigated for possible use in killing cancer.
+
+
+
+ But many very useful drugs that already existed, including cortisol and aspirin, were found to achieve some
+ of their most important effects by inhibiting the formation of the prostaglandins. It was the body's load of
+ polyunsaturated fats which made it very susceptible to inflammation, stress, trauma, infection, radiation,
+ hormone imbalance, and other fundamental problems, and drugs like aspirin and cortisone, which limit the
+ activation of the stored "essential fatty acids," gain their remarkable range of beneficial effects partly
+ by the restraint they impose on those stored toxins.
+
+
+ Increasingly, the liberation of arachidonic acid from tissues during stress is seen as a central factor in
+ all forms of stress, either acute (as in burns or exercise) or chronic (as in diabetes or aging). And, as
+ the fat stores become more toxic, it seems that they more readily liberate the free fatty acids. (For
+ example, see Iritani, et al., 1984)
+
+
+ During this same period, a few experimenters were finding that animals which were fed a diet lacking the
+ "essential" fatty acids had some remarkable properties: They consumed oxygen and calories
+ at a very high rate, their mitochondria were unusually tough and stable, their tissues could be transplanted
+ into other animals without provoking immunological rejection, and they were very hard to kill by trauma and
+ a wide variety of toxins that easily provoke lethal shock in animals on the usual diet. As the Germans had
+ seen in 1927, they had a low susceptibility to cancer, and new studies were showing that they weren't
+ susceptible to various fibrotic conditions, including alcoholic liver cirrhosis.
+
+
+ In 1967 a major nutrition publication, Present Knowledge in Nutrition,
+
+ published Hartroft and Porta's observation that the "age pigment," lipofuscin, was formed in proportion to
+ the amount of polyunsaturated fat and oxidants in the diet. The new interest in organ transplantation led to
+ the discovery that the polyunsaturated fats prolonged graft survival, by suppressing the immune system.
+ Immunosuppression was considered to have a role in the carcinogenicity of the "essential" fatty acids.
+
+
+ Around the same time, there were studies that showed that unsaturated fats retarded brain development and
+ produced obesity.
+
+
+ Substances very much like the prostaglandins, called isoprostanes and neuroprostanes, are formed
+ spontaneously from highly unsaturated fatty acids, and are useful as indicators of the rate of lipid
+ peroxidation in the body. Most of the products of lipid peroxidation are toxic, as a result of their
+ reactions with proteins, DNA, and the mitochondria. The age-related glycation products that are usually
+ blamed on sugar, are largely the result of peroxidation of the polyunsaturated fatty acids.
+
+
+ Through the 1970s, this sort of information about the harmful effects of the PUFA was being slowly
+ assimilated by the culture, though many dietitians still spoke of "the essential fatty acids, vitamin F." By
+ 1980, it looked as though responsible researchers would see the promotion of cancer, heart disease,
+ mitochondrial damage, hypothyroidism and immunosuppression caused by the polyunsaturated fats as their most
+ important feature, and would see that there had never been a basis for believing that they were essential
+ nutrients.
+
+
+ But then, without acknowledging that there had been a problem with the doctrine of essentiality, fat
+ researchers just started changing the subject, shifting the public discourse to safer, more profitable
+ topics. The fats that had been called essential, but that had so many toxic effects, were no longer
+ emphasized, and the failed idea of "essentiality" was shifted to different categories of polyunsaturated
+ fats.
+
+
+ The addition of the long chain highly unsaturated fats to baby food formulas was recently approved, on the
+ basis of their supposed "essentiality for brain development." One of the newer arguments for the
+ essentiality of the PUFA is that "they are needed for making cell membranes." But human cells can grow and
+ divide in artificial culture solutions which contain none of the polyunsaturated fats, and no one has
+ claimed that they are growing "without membranes."
+
+
+
+ The long chain fats found in fish and some algae don't interfere with animal enzymes as strongly as the seed
+ oils do, and so by comparison, they aren't so harmful. They are also so unstable that relatively little of
+ them is stored in the tissues. (And when they are used as food additives, it's necessary to use antioxidants
+ to keep them from becoming smelly and acutely toxic.)
+
+
+ When meat is grilled at a high temperature, the normally spaced double bonds in PUFA migrate towards each
+ other, becoming more stable, so that linoleic acid is turned into "conjugated linoleic acid." This analog of
+ the "essential" linoleic acid competes against the linoleic acid in tissues, and protects against cancer,
+ atherosclerosis, inflammation and other effects of the normal PUFA. Presumably, anything which interferes
+ with the essential fatty acids is protective, when the organism contains dangerous amounts of PUFA. Even the
+ trans-isomers of the unsaturated fatty acids (found in butterfat, and convertible into conjugated linoleic
+ acid) can be protective against cancer.
+
+
+ In the 1980s the oil promoters were becoming more sophisticated, and were publishing many experiments in
+ which the fish oils were compared with corn oil, or safflower, or soy oil, and in many of those experiments,
+ the animals' health was better when they didn't eat the very toxic seed oils, that contained the "essential
+ fatty acids," linoleic and linoleic acids.
+
+
+ Besides comparing the fish oils to the stronger toxins, another trick is to take advantage of the same
+ immunosuppressive property that had seemed troublesome, and to emphasize their ability to temporarily
+ alleviate some autoimmune or allergic diseases. X-rays were once used that way, to treat arthritis and
+ ringworm, for example.
+
+
+
+ And, knowing that cancer cells have the ability to consume large amounts of fatty acids, they would test
+ these fats in tissue culture dishes, and demonstrate that they were poisonous, cytotoxic, to the fast
+ growing cancer cells. Although they caused cancer in animals, if they could be shown to kill cancer cells in
+ a dish, they could be sold as anticancer drugs/nutrients, with the special mystique of being "essential
+ fatty acids." Strangely, their ability to kill cancer cells under some circumstances and to suppress some
+ immunological reactions is being promoted in close association with the doctrine that these fats are
+ nutritionally essential.
+
+
+ Arachidonic acid is made from linoleic acid, and so those two oils were considered as roughly equivalent in
+ their ability to meet our nutritional needs, but a large part of current research is devoted to showing the
+ details of how fish oils protect against arachidonic acid. The "balance" between the omega -3 and the omega
+ -6 fatty acids is increasingly being presented as a defense against the toxic omega -6 fats. But the
+ accumulation of unsaturated fats with aging makes any defense increasingly difficult, and the extreme
+ instability of the highly unsaturated omega -3 fats creates additional problems.
+
+
+ PUFA and x-rays have many biological effects in common. They are immunosuppressive, but they produce their
+ own inflammatory reactions, starting with increased permeability of capillaries, disturbed coagulation and
+ proteolysis, and producing fibrosis and tumefaction or tissue atrophy. This isn't just a coincidence, since
+ ionizing radiation attacks the highly unstable polyunsaturated molecules, simply accelerating processes that
+ ordinarily happen more slowly as a result of stress and aging.
+
+
+ Prolonged stress eventually tends to be a self-sustaining process, impairing the efficient respiratory
+ production of energy, converting muscle tissue to amino acids, suppressing the thyroid, and activating
+ further mobilization of fatty acids. Fatty acids are mobilized from within the structure of cells by
+ phospholipases, and from fat tissues by other lipases.
+
+
+ The highly unsaturated fatty acids, as well as the ordinary "essential fatty acids," act directly to
+ increase capillary permeability, even without conversion into prostaglandins, and they interfere in many
+ ways with the clotting and clot removal systems. The effects of PUFA taken in a meal probably disturb the
+ clotting system more than the same quantity of saturated fat, contrary to many of the older publications.
+ The PUFA are widely believed to prevent clotting, but when cod liver oil is given to "EFA deficient"
+ animals, it activates the formation of clots (Hornstra, et al., 1989). An opposite effect is seen when a
+ long chain fatty acid synergizes with aspirin, to restrain clotting (Molina, et al., 2003).
+
+
+ Fibrosis is a generalized consequence of the abnormal capillary permeability produced by things that disrupt
+ the clotting system. Estrogen, with its known contribution to the formation of blood clots and edema and
+ fibrosis and tumors, achieves part of its effect by maintaining a chronically high level of free fatty
+ acids, preferentially liberating arachidonic acid, rather than saturated fatty acids.
+
+
+
+ Butter, beef fat, and lamb fat are the only mostly saturated fats produced on a large scale in the U.S., and
+ the cheapness/profitability of the seed oils made it easy to displace them. But, in the face of the immense
+ amount of propagandistic "health" claims that have been made against the saturated fats, it's instructive to
+ look at some of their actual effects, especially on the clotting system, and the related fibrotic reactions.
+
+
+ The saturated fatty acids are very unreactive chemically. Coconut oil, despite containing about 1% of the
+ unstable PUFA, can be left in a bucket at room temperature for a year or more without showing any evidence
+ of deterioration, suggesting that the predominance of saturated fat acts as an antioxidant for the
+ unsaturated molecules. In the body, the saturated fats seem to act the same way, preventing or even
+ reversing many of the conditions caused by oxidation of fats.
+
+
+ The stress-induced liberation of arachidonic acid causes blood vessels to leak, and this allows fibrin to
+ escape from the blood stream, into the basement membrane and beyond into the extracellular matrix, where it
+ produces fibrosis. (Cancer, autoimmune diseases, and heart disease involve the same inflammatory,
+ thrombotic, fibrotic processes as the nominal fibroses.) Scleroderma, liver cirrhosis, fibrosis of the
+ lungs, heart, and other organs, and all the diseases in which fibrous tissue becomes dense and progressively
+ contracts, involve similar processes, and the treatments which are successful are those that stop the
+ inflammation produced by the oxidation of the polyunsaturated fatty acids.
+
+
+ Retroperitoneal fibrosis is now known to be produced by estrogen, and is treated by antiestrogenic and
+ antiserotonergic drugs, but as early as 1940 Alejandro Lipschutz demonstrated that chronic exposure to very
+ low doses of estrogen produced fibromas in essentially every part of the body. Earlier, Loeb had studied the
+ action of large doses of estrogen, which produced fibrosis of the uterus, as if it had accelerated aging.
+ Following Lipschutz' work, in which he demonstrated the "antifibromatogenic" actions of pregnenolone and
+ progesterone, several Argentine researchers showed that progesterone prevented and cured abdominal adhesions
+ and other fibrotic conditions, including retroperitoneal fibrosis.
+
+
+ Since estrogen produces both leakiness of the capillaries and excessive formation of fibrin, its effects
+ will be seen first in the organs where it concentrates, but eventually anywhere capillaries leak fibrin.
+ Estrogen activates the phospholipase which liberates arachidonic acid, and progesterone inhibits that
+ phospholipase.
+
+
+
+ As the fat tissues become more burdened with arachidonic acid, they release it more easily in response to
+ moderately lipolytic stress signals. This could explain the increased levels of free fatty acids and lipid
+ peroxidation that occur with aging. In animals that are "deficient" in the polyunsaturated fatty acids,
+ adrenalin doesn't have the lipolytic effect that it does in animals on the standard diet. With aging, there
+ is not only a tendency to have chronically higher free fatty acids in the blood, but for those fatty acids
+ to be more unsaturated. The phospholipids of mitochondria and microsomes become more unsaturated with aging
+ (Laganiere and Yu, 1993, Lee, et al., 1999). In the human retina there is a similar accumulation of PUFA
+ with aging (Nourooz-Zadeh and Pereira, 1999), which implies that the aged retina will be more easily damaged
+ by light.
+
+
+ Several studies suggest that a high degree of unsaturation in the fats is fundamentally related to the aging
+ process, since long lived species have a lower degree of unsaturation in their fats. Caloric restriction
+ decreases the age-related accumulation of the fatty acids with 4 and 5 double bonds.
+
+
+ Although publicity has emphasized the anti-inflammatory effects of fish oil, experiments show that it is
+ extremely effective in producing alcohol-related liver cirrhosis. Breakdown products of polyunsaturated fats
+ (isoprostanes and 4-HNE) are found in the blood of people with alcoholic liver disease (Aleynik, et al.,
+ 1998). In the absence of polyunsaturated fats, alcohol doesn't produce cirrhosis. Saturated fats allow the
+ fibrosis to regress:
+
+
+ "A diet enriched in saturated fatty acids effectively reverses alcohol-induced necrosis,
+ inflammation, and fibrosis despite continued alcohol consumption. The therapeutic effects of saturated
+ fatty acids may be explained, at least in part, by reduced endotoxemia and lipid peroxidation...."
+ (Nanji, et al., 1995, 2001)
+
+
+ In these studies, the animals were switched from fish oil to either palm oil or medium chain triglycerides
+ (a major fraction of coconut oil). In other studies, Knittel, et al. (1995), show that fibrinogen, in "a
+ clotting-like process," is involved in the development of liver fibrosis, and that this appears to provide a
+ basis for the growth of additional extracellular matrix.
+
+
+
+ Brown, et al. (1989), discussed this developmental process (leaky capillaries, fibrosis) in relation to
+ wound healing, lung disease, and tumor growth.
+
+
+ The relatively few studies of fish oil and linoleic acid that compare them with palmitic acid or coconut oil
+ have produced some very important results. For example, pigs exposed to endotoxin developed severe lung
+ problems (resembling "shock lung") when they had been on a diet with either fish oil or Intralipid (which is
+ mostly linoleic acid, used for intravenous feeding in hospitals), but not after palmitic acid (Wolfe, et
+ al., 2002).
+
+
+ Eating low-fat seafood (sole, whitefish, turbot, scallops, oysters, lobster, shrimp, squid, etc.) once in a
+ while can provide useful trace minerals, without much risk. However, fish from some parts of the ocean
+ contain industrial contaminants in the fat, and large fish such as tuna, swordfish, Chilean sea bass and
+ halibut contain toxic amounts of mercury in the muscles. Chilean sea bass (Patagonian toothfish) is very
+ high in fat, too.
+
+
+ About ten years ago I met a young man with a degenerative brain disease, and was interested in the fact that
+ he (working on a fishing boat) had been eating almost a pound of salmon per day for several years. There is
+ now enough information regarding the neurotoxic effects of fish oil to justify avoidance of the fatty fish.
+
+
+ Some of the current advertising is promoting fish oil to prevent cancer, so it's important to remember that
+ there are many studies showing that it increases cancer.
+
+
+ The developmental and physiological significance of the type of fatty acid in the diet has been established
+ for a long time, but cultural stereotypes and commercial interests are threatened by it, so it can't be
+ discussed publicly.
+
+
+ REFERENCES
+
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+
+
+ Ann N Y Acad Sci. 1976;275:28-46. Metabolic influences in experimental thrombosis.
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+
+
+
+ Nutr Cancer. 2001;41(1-2):91-7.
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+ premalignant lesions in rat mammary gland. Banni S, Angioni E, Murru E, Carta G, Melis MP,
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+
+
+ Obstet Gynecol. 1987 Sep;70(3 Pt 2):502-4. The treatment of retroperitoneal fibromatosis with
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+ variety of medications have been used to treat patients with recurrent tumors, but the response to these
+ agents has not been uniform. The patient presented was successfully treated with medroxyprogesterone acetate
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+ radiation therapy.
+
+
+ Medicina (B Aires). 1978 Mar-Apr;38(2):215-6. [Fibromatosis, relaxin and progesterone] [in
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+
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+ gland in vitro: formation of an lodolactone.
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+
+
+ Am Rev Respir Dis 1989 Oct;140(4):1104-7.
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+
+
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+
+ Biochem Mol Biol Int 1993 Jan;29(1):175-83.
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+ PC, Newsholme EA. "Vitamin E (10 microM) increased human lymphocyte proliferation by 35%. However, vitamin E
+ did not prevent the inhibitory effects of fatty acids upon lymphocyte proliferation. It is concluded that
+ inhibition of lymphocyte proliferation by fatty acids is not caused by their conversion to peroxidised
+ products."
+
+
+
+ Clin Sci (Lond). 1992 Jun;82(6):695-700.
+ Polyunsaturated fatty acids suppress human peripheral blood lymphocyte proliferation and interleukin-2
+ production. Calder PC, Newsholme EA.
+
+
+ J Neurochem 1980 Oct;35(4):1004-7.
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+
+
+ Int J Cancer 2001 Mar 15;91(6):894-9. Tumor invasiveness and liver metastasis of colon cancer cells
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+
+
+
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+
+
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+
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+
+
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+
+
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+
+
+
+ J Physiol. 1998 Mar 1;507 ( Pt 2):541-7. Arachidonic acid increases cerebral microvascular
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+
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+
+
+ Am J Physiol. 1992 May;262(5 Pt 1):E637-43. ATP depletion stimulates calcium-dependent protein breakdown in
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+
+
+
+ Cancer Res 1998 Aug 1;58(15):3312-9. Dietary omega-3 polyunsaturated fatty acids promote colon
+ carcinoma metastasis in rat liver. Griffini P, Fehres O, Klieverik L, Vogels IM, Tigchelaar W,
+ Smorenburg SM, Van Noorden CJ.
+
+
+
+ J Indian Med Assoc 1997 Mar;95(3):67-9, 83.
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+ males.
+
+ Gupta R, Prakash H
+
+
+ Transplantation 1995 Sep 27;60(6):570-7. The effect of dietary polyunsaturated fatty acids (PUFA) on
+ acute rejection and cardiac allograft blood flow in rats. Haw MP, Linnebjerg H, Chavali SR,
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+ possible adjunctive treatment in organ transplantation should be considered."
+
+
+ Dtsch Med Wochenschr. 2003 Jun 20;128(25-26):1395-8. [Rare cause of chronic abdominal pain:
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+ mesenteritis is a rare cause of chronic abdominal pain with variable symptoms. Its aetiology is unknown. In
+ case of bowel ischemia a surgical approach is preferred, milder forms may be treated with immunosuppressive
+ agents as well as oral progesterone. Progesterone has exhibited positive effects on fatty tissue with
+ successful treatment in desmoid tumors and retroperitoneal fibrosis. Here in we could demonstrate its safe
+ and efficient use in a patient with retractile mesenteritis."
+
+
+
+ Mech Ageing Dev 2001 Apr 15;122(4):427-43. Effect of the degree of fatty acid unsaturation of rat
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+ long-lived animals have lower fatty acid double bond content in their mitochondrial membranes than
+ short-lived ones. In order to ascertain whether this trait protects mitochondria by decreasing lipid and
+ protein oxidation and oxygen radical generation, the double bond content of rat heart mitochondrial
+ membranes was manipulated by chronic feeding with semi-purified AIN-93G diets rich in highly unsaturated
+ (UNSAT) or saturated (SAT) oils. UNSAT rat heart mitochondria had significantly higher double bond content
+ and lipid peroxidation than SAT mitochondria. They also showed increased levels of the markers of protein
+ oxidative damage malondialdehyde-lysine, protein carbonyls, and N(e)-(carboxymethyl)lysine adducts." "These
+ results demonstrate that increasing the degree of fatty acid unsaturation of heart mitochondria increases
+ oxidative damage to their lipids and proteins, and can also increase their rates of mitochondrial oxygen
+ radical generation in situations in which the degree of reduction of Complex III is higher than normal.
+ These observations strengthen the notion that the relatively low double bond content of the membranes of
+ long-lived animals could have evolved to protect them from oxidative damage."
+
+
+ Biochem J. 1994 May 15;300 ( Pt 1):251-5. Regulation of fibrinolysis by non-esterified fatty
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+ specificity showed that a minimal chain length of 16 carbon atoms and the presence of at least one
+ double bond, preferably in a cis configuration, were required for inhibition of the fibrinolytic
+ activity of plasmin."
+
+
+
+ Science. 1976 Feb 27;191(4229):861-2. Nicotinic acid reduction of plasma volume loss after thermal
+ trauma. Hilton JG, Wells CH. Intravenous administration of nicotinic acid to the anesthetized
+ dog prior to thermal trauma reduced plasma loss at 10 minutes after burn from 7 milliliters per kilogram to
+ less than 2 millimeters per kilogram. During the next 50 minutes plasma loss was the same in treated and
+ untreated animals. An additional dose of nicotinic acid 30 minutes after burn prevented this further loss.
+
+
+
+ Z Gesamte Inn Med. 1976 Oct 15;31(20):838-43. [Age-dependence of catecholamine effects in man. IV.
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+
+
+ Neurochem Res. 2000 Feb;25(2):269-76. Cortical impact injury in rats promotes a rapid and sustained
+ increase in polyunsaturated free fatty acids and diacylglycerols. Homayoun P, Parkins NE,
+ Soblosky J, Carey ME, Rodriguez de Turco EB, Bazan NG. "At day one, free 22:6 and 22:6-DAGs
+ showed the greatest increase (590% and 230%, respectively). These results suggest that TBI elicits the
+ hydrolysis of phospholipids enriched in excitable membranes, targeting early on 20:4-phospholipids (by 30
+ min post- trauma) and followed 24 hours later by
+ preferential hydrolysis of DHA-phospholipids. These lipid metabolic changes may contribute to the
+ initiation and maturation of neuronal and fiber track degeneration observed following cortical impact
+ injury."
+
+
+ Thromb Res. 1989 Jan 1;53(1):45-53. Normalization by dietary cod-liver oil of reduced thrombogenesis
+ in essential fatty acid deficient rats.
+ Hornstra G, Haddeman E, Don JA.
+
+
+ Radiographics. 2003 Nov-Dec;23(6):1561-7. CT Findings in Sclerosing Mesenteritis (Panniculitis):
+ Spectrum of Disease. Horton KM, Lawler LP, Fishman EK.
+
+
+ Nutr Cancer. 1985;7(4):199-209. Isomeric fatty acids and tumorigenesis: a commentary on recent
+ work. Hunter JE, Ip C, Hollenbach EJ. "Neither epidemiological nor experimental studies
+ published to date have demonstrated any valid association between trans fatty acid ingestion and
+ tumorigenesis. A recent study showed that under controlled conditions, a fat with a high content of trans
+ fatty acids did not promote the development of mammary tumors induced in rats by
+ 7,12-dimethylbenz[a]anthracene to any greater extent than did a comparable fat with a high content of cis
+ fatty acids. In addition, in this
+ study a high trans fat was less tumor promoting than was a blend of fats that simulated the dietary fat
+ composition of the United States and had a lower level of trans fatty acids."
+
+
+
+ Medicina (B Aires). 1978 Mar-Apr;38(2):215. [Progesterone and retroperitoneal fibrosis] [in
+ Spanish] Introzzi A.[Letter]
+
+
+ Cancer Res. 1985 May;45(5):1997-2001. Requirement of essential fatty acid for mammary tumorigenesis
+ in the rat. Ip C, Carter CA, Ip MM. "Mammary tumorigenesis was very sensitive to
+ linoleate intake and increased proportionately in the range of 0.5 to 4.4% of dietary
+ linoleate."
+
+
+ Biochim Biophys Acta. 1984 Nov 6;802(1):17-23.
+ Activation of bovine platelets induced by long-chain unsaturated fatty acids at just below their lytic
+ concentrations, and its mechanism. Kitagawa S, Endo J, Kametani F.
+
+
+
+ Clin Exp Metastasis 2000;18(5):371-7. Promotion of colon cancer metastases in rat liver by fish oil
+ diet is not due to reduced stroma formation.
+ Klieveri L, Fehres O, Griffini P, Van Noorden CJ, Frederiks WM.
+ "Recently, it was demonstrated that dietary omega-3 polyunsaturated fatty acids (PUFAs) induce 10-fold
+ more metastases in number and 1000-fold in volume in an animal model of colon cancer metastasis in rat
+ liver."
+
+
+ Folia Haematol Int Mag Klin Morphol Blutforsch. 1977;104(1):1-10. [Review: hemorrhagic diathesis
+ resulting from acute exposure to ionizing Radiation]
+ [Article in German] Krantz S, Lober M. The symptoms of the acute radiopathy are chiefly characterized by a
+ severe blood coagulation disorder. The main results and problems of research work on this haemorrhagic
+ diathesis are shortly reviewed.
+
+
+ Prostaglandins. 1978 Apr;15(4):557-64. Prostaglandin I2 as a potentiator of acute inflammation in
+ rats. Komoriya K, Ohmori H, Azuma A, Kurozumi S, Hashimoto Y, Nicolaou KC, Barnette WE, Magolda
+ RL.
+
+
+ Gerontology 1993;39(1):7-18. Modulation of membrane phospholipid fatty acid composition by age and
+ food restriction. Laganiere S, Yu BP. H.M. "Phospholipids from liver mitochondrial and
+ microsomal membrane preparations were analyzed to further assess the effects of age and lifelong calorie
+ restriction on membrane lipid composition." "The data revealed characteristic patterns of
+ age-related changes in ad libitum (AL) fed rats:
+
+ membrane levels of long-chain polyunsaturated fatty acids, 22:4 and 22:5, increased progressively, while
+ membrane linoleic acid (18:2) decreased steadily with age. Levels of 18:2 fell by approximately 40%, and
+ 22:5 content almost doubled making the peroxidizability index increase with age." "We
+ concluded that the membrane-stabilizing action of long-term calorie restriction relates to the selective
+ modification of membrane long-chain polyunsaturated fatty acids during aging."
+
+
+ Medicina (B Aires). 1978 Mar-Apr;38(2):123-32. [Effective treatment of several types of fibromatosis
+ with progesterone. Fibrous mediastinitis, desmoid tumors, paraneoplastic fibrosis] [in Spanish]
+ Lanari A, Molinas FC, Castro Rios M, Paz RA.
+
+
+
+ Medicina (B Aires). 1979 Nov-Dec;39(6):826-35. [Progesterone in fibromatosis and
+ atherosclerosis] [in Spanish] Lanari A.
+
+
+ Free Radic Biol Med 1999 Feb;26(3-4):260-5. Modulation of cardiac mitochondrial membrane fluidity by
+ age and calorie intake. Lee J, Yu BP, Herlihy JT. "The fatty acid composition of the
+ mitochondrial membranes of the two ad lib fed groups differed: the long-chain polyunsaturated 22:4 fatty
+ acid was higher in the older group, although linoleic acid (18:2) was lower. DR eliminated the
+ differences." "Considered together, these results suggest that DR maintains the
+ integrity of the cardiac mitochondrial membrane fluidity by minimizing membrane damage through
+ modulation of membrane fatty acid profile."
+
+
+ Lipids 2001 Jun;36(6):589-93.
+ Effect of dietary restriction on age-related increase of liver susceptibility to peroxidation in
+ rats. Leon TI, Lim BO, Yu BP, Lim Y, Jeon EJ, Park DK.
+
+
+ Acta Chir Scand. 1976;142(1):20-5. Induction of endogenous fibrinolysis inhibition in the dog.
+ Effect of intravascular coagulation and release of free fatty acids. Lindquist O, Bagge L,
+ Saldeen T. "In all groups subjected to infusion of thrombin an increase in plasma free fatty acids (FFA) was
+ observed. The role of this increase for the development
+ of fibrinolysis inhibition was tested by infusion of norepinephrine alone and in combination with
+ nicotinic acid. Norepinephrine caused an increase of FFA after 2 hours and in urokinase inhibitor
+ activity after 24-48 hours. Both of these were diminished by high doses of nicotinic acid,
+ indicating that the release of FFA rather than intravascular coagulation might be the principal mechanism
+ underlying the occurrence of fibrinolysis inhibition following trauma."
+
+
+
+ Proc Natl Acad Sci U S A 1990 Nov;87(22):8845-9. Incorporation of marine lipids into mitochondrial
+ membranes increases susceptibility to damage by calcium and reactive oxygen species: evidence for
+ enhanced activation of phospholipase A2 in mitochondria enriched with n-3 fatty acids.
+ Malis CD, Weber PC, Leaf A, Bonventre JV.
+
+
+ Prostaglandins Leukot Essent Fatty Acids 1994 Jul;51(1):33-40.
+ Suppression of human T-cell growth in vitro by cis-unsaturated fatty acids: relationship to free
+ radicals and lipid peroxidation. Madhavi N, Das UN, Prabha PS, Kumar GS, Koratkar R, Sagar PS.
+
+
+ Clin Exp Metastasis 1998 Jul;16(5):407-14.
+ Diminution of the development of experimental metastases produced by murine metastatic lines in
+ essential fatty acid-deficient host mice. Mannini A, Calorini L, Mugnai G, Ruggieri S.
+
+
+ Biochem Pharmacol. 1990 Mar 1;39(5):879-89. Histamine release from rat mast cells induced by
+ metabolic activation of polyunsaturated fatty acids into free radicals. Masini E, Palmerani B,
+ Gambassi F, Pistelli A, Giannella E, Occupati B, Ciuffi M, Sacchi TB, Mannaioni PF.
+
+
+ Journal of Lipid Research, Vol. 44, 271-279, February 2003. Arachidonic acid and prostacyclin
+ signaling promote adipose tissue development : a human health concern?
+ F. Massiera, P. Saint-Marc, J. Seydoux , T. Murata , T. Kobayashi , S. Narumiya , P. Guesnet, Ez-Zoubir
+ Amri, R. Negrel and G. Ailhaud1.
+
+
+ Infection. 1994 Mar-Apr;22(2):106-12. Influence of dietary (n-3)-polyunsaturated fatty acids on
+ leukotriene B4 and prostaglandin E2 synthesis and course of experimental tuberculosis in guinea
+ pigs. Mayatepek E, Paul K, Leichsenring M, Pfisterer M, Wagner D, Domann M, Sonntag HG, Bremer
+ HJ.
+
+
+
+ Biochim Biophys Acta 1994 Sep 15;1214(2):209-20. Reinvestigation of lipid peroxidation of linolenic
+ acid. Mlakar A, Spiteller G. "Thus, a great number of previously unknown lipid peroxidation
+ products was detected. It is assumed that these compounds also occur--at least as intermediates--in lipid
+ peroxidation processes in mammalian tissue."
+
+
+ Prostaglandins Leukot Essent Fatty Acids. 2003 May;68(5):305-10. Synergistic effect of D-003 and
+ aspirin on experimental thrombosis models. Molina V, Arruzazabala ML, Carbajal D, Mas R.
+
+
+ Chem Res Toxicol. 2001 Apr;14(4):431-7. Defining mechanisms of toxicity for linoleic acid
+ monoepoxides and diols in Sf-21 cells. Moran JH, Mon T, Hendrickson TL, Mitchell LA, Grant DF.
+
+
+
+ J Biochem (Tokyo). 1977 Aug;82(2):529-33. Effects of free fatty acids on fibrinolytic
+ activity. Muraoka T, Okuda H. A novel method for the estimation of fibrinolytic activity is
+ proposed. In this method, a fibrin clot suspension is used as a substrate (fibrin is known to be a
+ physiological substrate of plasmin). The fibrin clot suspension was prepared by homogenization of human
+ fibrin clots. With this method, we found that free fatty
+ acids inhibited the plasmin activity, and long-chain, unsaturated free fatty acids had a particularly
+ strong inhibitory action on plasmin. As regards the mechanism of the inhibitory action, free fatty acids
+ may not inhibit complex formation between plasmin and fibirin, but may make it impossible for plasmin to
+ act on fibrin due to deformation of the surface of the fibrin clot.
+
+
+ Alcohol Clin Exp Res. 1986 Jun;10(3):271-3. Dietary factors and alcoholic cirrhosis. Nanji
+ AA, French SW.
+
+
+ Gastroenterology. 1995 Aug;109(2):547-54. Dietary saturated fatty acids: a novel treatment for
+ alcoholic liver disease.
+
+
+ Nanji AA, Sadrzadeh SM, Yang EK, Fogt F, Meydani M, Dannenberg AJ.
+
+
+ J Pharmacol Exp Ther. 1996 Jun;277(3):1694-700. Medium chain triglycerides and vitamin E reduce the
+ severity of established experimental alcoholic liver disease. Nanji AA, Yang EK, Fogt F,
+ Sadrzadeh SM, Dannenberg AJ.
+
+
+ Hepatology. 1997 Dec;26(6):1538-45.
+ Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse
+ fibrosis in alcohol-induced liver disease in the rat. Nanji AA, Zakim D, Rahemtulla A, Daly T,
+ Miao L, Zhao S, Khwaja S, Tahan SR, Dannenberg AJ.
+
+
+
+ J Pharmacol Exp Ther. 2001 Nov;299(2):638-44.
+ Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued
+ ethanol administration. Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ.
+
+
+ Gastroenterology 1995 Apr;108(4):1124-35.
+ Accumulation and cellular localization of fibrinogen/fibrin during short-term and long-term rat liver
+ injury.
+ Neubauer K, Knittel T, Armbrust T, Ramadori G "Fibrinogen/fibrin deposition in damaged livers was
+ studied by immunohistology."
+
+ "Immunohistology showed striking amounts of fibrinogen and fibrin deposits in pericentral necrotic areas
+ (short-term damage) and within fibrotic septa (long-term damage)." "The results show fibrinogen/fibrin
+ deposition during short-term liver injury and liver fibrogenesis, which may suggest the involvement of a
+ "clotting-like process" in short-term liver damage and liver fibrosis. The data might indicate that
+ fibrin/fibronectin constitute a "provisional matrix," which affects the attraction and proliferation of
+ inflammatory and matrix-producing cells."
+
+
+ Ophthalmic Res. 1999;31(4):273-9. Age-related accumulation of free polyunsaturated fatty acids in
+ human retina. Nourooz-Zadeh J, Pereira P.
+
+
+ Chem Res Toxicol. 2002 Mar;15(3):367-72. Formation of cyclic deoxyguanosine adducts from omega-3 and
+ omega-6 polyunsaturated fatty acids under oxidative conditions. Pan J, Chung FL.
+
+
+ Radiobiologiia. 1985 Nov-Dec;25(6):763-7. [Mechanism of circulatory disorders in animals irradiated
+ at high doses] [in Russian] Pozharisskaia TD, Vasil'eva TP, Sokolova EN, Alekseeva II. Some
+ data are reported on pathoanatomical changes, a status of the microcirculatory channel and the coagulogram
+ of animals affected by high doses of ionizing radiation. The signs of disseminated intravascular
+ blood coagulation have been revealed.
+
+
+ J Biol Chem. 1998 May 29;273(22):13605-12. Formation of isoprostane-like compounds (neuroprostanes)
+ in vivo from docosahexaenoic acid. Roberts LJ 2nd, Montine TJ, Markesbery WR, Tapper AR, Hardy
+ P, Chemtob S, Dettbarn WD, Morrow JD.
+
+
+ Nutr Cancer 1995;24(1):33-45.
+ Effects of linoleic acid and gamma-linolenic acid on the growth and metastasis of a human breast cancer
+ cell line in nude mice and on its growth and invasive capacity in vitro. Rose DP, Connolly JM,
+ Liu XH
+
+
+ Arch Toxicol. 1997;71(9):563-74.
+ Impaired cellular immune response in rats exposed perinatally to Baltic Sea herring oil or
+ 2,3,7,8-TCDD.
+
+ Ross PS, de Swart RL, van der Vliet H, Willemsen L, de Klerk A, van Amerongen G, Groen J, Brouwer A,
+ Schipholt I, Morse DC, van Loveren H, Osterhaus AD, Vos JG.
+
+
+ Nutr Cancer 1998;30(2):137-43.
+ Effects of dietary n-3-to-n-6 polyunsaturated fatty acid ratio on mammary carcinogenesis in rats.
+ Sasaki T, Kobayashi Y, Shimizu J, Wada M, In'nami S, Kanke Y, Takita T. "An increase in the n-3/n-6
+ ratio did not suppress the incidence or reduce the latency of mammary tumor development.
+ The number and weight of mammary tumors per tumor-bearing rat tended to be large in the group with an
+ n-3/n-6 ratio of 7.84 compared with those in the other groups. As the n-3/n-6 ratios were elevated, the
+ total number and weight of tumors increased gradually."
+
+
+ J. Biol. Chem. 1940 132: 539-551. Essential fatty acids, vitamin B
+ 6
+ , and other factors in the cure of rat acrodynia. H. Schneider, H. Steenbock, and Blanche
+ R. Platz
+
+
+
+ Science. 1988 May 20;240(4855):1032-3. Essential fatty acid depletion of renal allografts and
+ prevention of rejection. Schreiner GF, Flye W, Brunt E, Korber K, Lefkowith JB.
+
+
+ Physiol Bohemoslov. 1990;39(2):125-34.
+ Proportion of individual fatty acids in the non-esterified (free) fatty acid (FFA) fraction in the serum
+ of laboratory rats of different ages. Smidova L, Base J, Mourek J, Cechova I.
+
+
+ Placenta. 2003 Nov;24(10):965-73. Augmented PLA(2)Activity in Pre-eclamptic Decidual Tissue-A Key
+ Player in the Pathophysiology of 'Acute Atherosis' in Pre-eclampsia? Staff AC, Ranheim T,
+ Halvorsen B.
+
+
+ Acta Neurochir Suppl (Wien) 1994;60:20-3. Mechanisms of glial swelling by arachidonic acid.
+ Staub F, Winkler A, Peters J, Kempski O, Baethmann A.
+
+
+ Arch Biochem Biophys. 1991 Aug 15;289(1):33-8. A possible mechanism of mitochondrial dysfunction
+ during cerebral ischemia: inhibition of mitochondrial respiration activity by arachidonic acid.
+
+ Takeuchi Y, Morii H, Tamura M, Hayaishi O, Watanabe Y.
+
+
+ J Drug Target. 2003 Jan;11(1):45-52.
+ Modulation of tumor-selective vascular blood flow and extravasation by the stable prostaglandin 12
+ analogue beraprost sodium. Tanaka S, Akaike T, Wu J, Fang J, Sawa T, Ogawa M, Beppu T, Maeda H.
+
+
+ Am J Clin Nutr. 2003 May;77(5):1125-32. Effect of individual dietary fatty acids on postprandial
+ activation of blood coagulation factor VII and fibrinolysis in healthy young men. Tholstrup T,
+ Miller GJ, Bysted A, Sandstrom B.
+
+
+ Biochem Soc Trans. 2003 Oct;31(Pt 5):1075-9. Regression of pre-established atherosclerosis in the
+ apoE-/- mouse by conjugated linoleic acid.
+
+ Toomey S, Roche H, Fitzgerald D, Belton O.
+
+
+ Int J Biochem Cell Biol. 2003 May;35(5):749-55. Increased muscle proteasome activities in rats fed a
+ polyunsaturated fatty acid supplemented diet. Vigouroux S, Farout L, Clavel S, Briand Y, Briand
+ M. "Changes in the proteasome system, a dominant actor in protein degradation in eukaryotic cells, have been
+ documented in a large number of physiological and pathological conditions." "With the polyunsaturated fatty
+ acid enriched diet, the chymotrypsin-like and peptidylglutamylpeptide hydrolase activities increased by 45%
+ in soleus and extensor digitorum longus (EDL), and by 90% in the gastrocnemius medialis (GM) muscle.
+ Trypsin-like activity of the proteasome increased by 250% in soleus, EDL and GM." "Proteasome activities and
+ level were less stimulated with a monounsaturated fatty acid supplemented diet." "Unsaturated fatty acids
+ are particularly prone to free radical attack. Thus, we suggest that alterations in muscle proteasome may
+ result from monounsaturated and polyunsaturated fatty acid-induced peroxidation, in order to eliminate
+ damaged proteins."
+
+
+ J Am Coll Nutr. 2000 Aug;19(4):478S-486S. Conjugated linoleic acid and bone biology.
+ Watkins BA, Seifert MF. "Recent investigations with growing rats given butter fat and
+ supplements of CLA demonstrated an increased rate of bone formation and reduced ex vivo bone PGE2
+ production, respectively."
+
+
+
+ Ups J Med Sci. 1979;84(3):195-201. Effect of nicotinic acid on the posttraumatic increase in free
+ fatty acids and fibrinolysis inhibition activity in the rat. Wegener T, Bagge L, Saldeen T.
+ Nicotinic acid effectively inhibited the posttraumatic increase in both free fatty acids (FFA) and
+ fibrinolysis inhibition activity (FIA) in the blood in rats, indicating that FFA might be involved in the
+ posttraumatic increase of FIA. The FIA in the liver was greater than that in other organs studied and was
+ increased in the posttraumatic phase. The possible role of the liver in the posttraumatic increase of FIA is
+ discussed.
+
+
+ Am J Physiol Regul Integr Comp Physiol. 2001 Mar;280(3):R908-12. CLA reduces antigen-induced
+ histamine and PGE(2) release from sensitized guinea pig tracheae. Whigham LD, Cook EB, Stahl
+ JL, Saban R, Bjorling DE, Pariza MW, Cook ME.
+
+
+ Toxicol Appl Pharmacol 1993 May;120(1):72-9.
+ Essential fatty acid deficiency in cultured human keratinocytes attenuates toxicity due to lipid
+ peroxidation.
+
+ Wey HE, Pyron L, Woolery M.
+
+
+ Nutrition. 2002 Jul-Aug;18(7-8):647-53. Dietary fat composition alters pulmonary function in
+ pigs. Wolfe RR, Martini WZ, Irtun O, Hawkins HK, Barrow RE. © Ray Peat Ph.D. 2009. All Rights
+ Reserved. www.RayPeat.com
+
+
+
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+
+
+
+
+
+
+
+
+ Fats, functions &
+ malfunctions
+
+
+
+
+ Saturated fatty acids
+ terminate the stress reactions, polyunsaturated fatty acids amplify them.
+
+
+ The most highly unsaturated
+ fats, including DHA, accumulate with aging, and their toxic fragments are increased in
+ Alzheimer's disease.
+
+
+ The most highly unsaturated
+ fats found in fish oil break down into chemicals that block the use of glucose and
+ oxygen.
+
+
+ The ratio of saturated fatty
+ acids to polyunsaturated fatty acids is decreased in cancer. Omega-3 fats promote
+ metastasis.
+
+
+
+ Around the beginning of the 20th
+ century, it was commonly believed that aging resulted from the accumulation of insoluble
+ metabolic by-products, sort of like the clinker ash in a coal furnace. Later, age pigment or
+ lipofuscin, was proposed to be such a material. It is a brown pigment that generally increases
+ with age, and its formation is increased by consumption of unsaturated fats, by vitamin E
+ deficiency, by stress, and by exposure to excess estrogen. Although the pigment can contribute
+ to the degenerative processes, aging involves much more than the accumulation of insoluble
+ debris; aging increases the tendency to form the debris, as well as vice versa.
+
+
+
+ There is a growing recognition that
+ a persistent increase of free fatty acids in the serum, which is seen in shock, heart failure,
+ and aging, indicates a bad prognosis, but there is no generally recognized explanation for the
+ fact that free fatty acids are harmful. I want to mention some evidence showing that it is the
+ accumulation of polyunsaturated fats in the body that makes them harmful.
+
+
+
+ The physical and functional
+ properties of saturated fatty acids and polyunsaturated fatty acids (PUFA) are as different from
+ each other as day is from night. The different fatty acids are directly involved, very often
+ with opposite effects, in cell division and growth, cell stability and dissolution, the
+ organization of cells, tissues, and organs, the regulation of pituitary hormones, adrenalin and
+ sympathetic nervous activation, histamine and serotonin synthesis, adrenal cortex hormones,
+ thyroid hormones, testosterone, estrogen, activators of the immune system and inflammation
+ (cytokines), autoimmune diseases, detoxification, obesity, diabetes, puberty,
+ epilepsy,
+
+
+
+ Parkinson's disease, other
+ degenerative nerve diseases and Alzheimer's disease, cancer, heart failure, atherosclerosis, and
+ strokes. In each of these situations, the PUFA have harmful effects.
+
+
+
+ Most people are surprised to hear
+ about the systematically harmful effects of the common dietary polyunsaturated fats and the
+ protective effects of saturated fats. That's because there is a pervasive mythology of fats in
+ our culture. Officials are proposing to tax saturated fats. Laws are being passed prescribing
+ the fats that can be served in restaurants, and people write letters to editors about them, and
+ great amounts of money are spent publicizing the importance of eating the right fats. Their
+ focus is on obesity, atherosclerosis, and heart disease. The details of the myth change a
+ little, as new fat products and industries appear.
+
+
+
+ As I understand the basic myth, the
+ difference between the "essential" polyunsaturated fats and the saturated fats has to do with
+ their shape---the unsaturated fatty acids bend or fold in a way that makes them more mobile than
+ saturated fats of the same length, and this causes the all-important "membranes" of cells to be
+ more fluid, and thus to have "better functions," though the myth isn't very clear on the issue
+ of fluidity and functionality. At that point, it passes responsibility to the more fundamental
+ biological myth, of the metabolically active cell membrane.
+
+
+
+ Practically everyone learns, in
+ grade school and from television, about the good and the bad oils, and cell membranes, but it
+ might seem likely that people who spend their lives investigating the role of fats in organisms
+ would have acquired a different, more complicated, view. But one of the most famous food fat
+ researchers, J.M. Bourre, has succinctly (and thoughtlessly) expressed his understanding of the
+ function of fatty substances in the body: "In fact the brain, after adipose tissue, is the organ
+ richest in lipids, whose only role is to participate in membrane structure." (J.M. Bourre,
+ 2004.) The fact that his editor let him publish the statement shows how the myth functions,
+ causing people to accept things because they are "common knowledge." The influence of the
+ medical and pharmaceutical industries is so pervasive that it becomes the context for most
+ biological research.
+
+
+
+ Luckily, many people are working
+ outside the myth, in specialized problems of physiology and cell biology, and their observations
+ are showing a reality much more complex and interesting than the mythology.
+
+
+
+ When we eat more protein or
+ carbohydrate than we need, the excess can be converted to fats, to be stored (as triglycerides),
+ but even on a maintenance diet we synthesize some fats that are essential parts of all of our
+ cells, including a great variety of phospholipids. People seldom talk about the importance of
+ fats in the nucleus of the cell, but every nucleus contains a variety of lipids--phospholipids,
+ sphingolipids, cholesterol, even triglycerides--similar to those that are found elsewhere in the
+ cell and in every part of the body, including the brain (Balint and Holczinger, 1978; Irvine,
+ 2002). Phospholipids are often considered to be "membrane lipids," but they have been
+ demonstrated in association with elements of the cell's skeleton, involved in cell division,
+ rather than in membranes (Shogomori, et al., 1993).
+
+
+
+ The cytoskeleton, a fibrous
+ framework of the cell that's responsible for maintaining the organized structure of the cell,
+ internal movement of organelles, coordination, locomotion, and cell division, is made up of
+ three main kinds of protein, and all of these are affected differently by different kinds of
+ fat.
+
+
+
+ Actions of lipids on the cell
+ skeleton can change cells' movements, migrations, and invasiveness. Unsaturated fats cause
+ clumping of some types of cell filament, condensation and polymerization of other types, in ways
+ that are associated with brain degenerative diseases and cancer. For example, DHA alters the
+ structure of the protein alpha-synuclein, causing it to take the form seen in Parkinson's
+ disease and other brain conditions. The synucleins regulate various structural proteins, and are
+ affected by stress, aging, and estrogen exposure, as well as by the polyunsaturated fats. One
+ type of synuclein is involved in the promotion of breast cancer. Saturated fatty acids have
+ exactly the opposite effects of PUFA on the synucleins, reversing the polymerization caused by
+ the PUFA (Sharon, et al., 2003).
+
+
+
+ When cancers are metastasizing,
+ their phospholipids contain less stearic acid than the less malignant tumors (Bougnoux, et al.,
+ 1992), patients with advanced cancer had less stearic acid in their red blood cells (Persad, et
+ al., 1990), and adding stearic acid to their food delayed the development of cancer in mice
+ (Bennett, 1984). The degree of saturation of the body's fatty acids corresponds to resistance to
+ several types of cancer that have been studied (Hawley and Gordon, 1976; Singh, et al.,
+ 1995).
+
+
+
+ The phospholipids are being
+ discussed in relation to drugs that can modify "signaling" by acting on phospholipid receptors,
+ using language that was developed in relation to hormones. A surface barrier membrane, with
+ receptors that send signals to the nucleus, is invoked by many of the recent discussions of
+ phospholipids. There's no question that the fats do affect regulatory processes, but the theory
+ and the language should correspond to the physiological and ecological realities. Vernadski's
+ metaphor, that an organism is a "whirlwind of atoms," is probably more appropriate than
+ "targeted signals and receptors" for understanding the physiology of fatty acids and
+ phospholipids. The rate of change and renewal of these structural fats is very high. In rats,
+ one study found a 30% decrease in the total phospholipid pool in the brain in the first 30
+ minutes after death (Adineh, et al., 2004). Another study in the brains of living rats
+ found that a particular class of brain lipids, ethanolamine plasmalogens, had a turnover time of
+ about 5 hours (Masuzawa, et al., 1984). (This type of lipid is an important component of the
+ lipoproteins secreted by the liver into the serum [Vance, 1990], and is also a major lipid in
+ the heart and brain.) Stresses such as the loss of sleep cause great distortions in
+ phospholipid metabolism throughout the body, especially in the brain and liver.
+
+
+
+ Actions of lipids on the cell
+ skeleton can change cells' movements, migrations, and invasiveness, even in short term
+ experiments. The effects of the "essential fatty acid" linoleic acid have been compared to the
+ drug colchicine, which is known to interfere with the cell skeleton and cell division. According
+ to Hoover, et al., (1981), it disturbed the structure of the cytoskeleton more than colchicine
+ does; it caused the cell filaments to clump together, while saturated fatty acids didn't have
+ such an effect.
+
+
+
+ The fatty molecules that participate
+ in the normal cell functions are made by cells even when they are grown in a fat-free solution
+ in a culture dish. They include saturated fatty acids such as palmitate and stearate, and
+ omega-9 unsaturated fats, such as oleic acid and omega-9 polyunsaturated fatty acids. The
+ saturated fatty acids found in the nucleus associated with the chromosomes are resistant to
+ change when the composition of the animal's diet changes (Awad and Spector, 1976), while the
+ unsaturated fats change according to the diet. These intracellular fats are essential for cell
+ division and the regulation of the genes, and for cell survival (Irvine, 2002). Although cells
+ make the saturated fats that participate in those basic functions, the high rate of metabolism
+ means that some of the lipids will quickly reflect in their structure the free fatty acids that
+ circulate in the blood. The fats in the blood reflect the individual's diet history, but
+ recently eaten fats can appear in the serum as free fatty acids, if the liver isn't able to
+ convert them into triglycerides.
+
+
+
+ The polyunsaturated fatty acids
+ differ from the saturated fats in many ways, besides their shape and their melting temperature,
+ and each type of fatty acid is unique in its combination of properties. The polyunsaturated
+ fatty acids, made by plants (in the case of fish oils, they are made by algae), are less stable
+ than the saturated fats, and the omega-3 and omega-6 fats derived from them, are very
+ susceptible to breaking down into toxins, especially in warm-blooded animals. Other differences
+ between saturated and polyunsaturated fats are in their effects on surfaces (as surfactant),
+ charges (dielectric effects), acidity, and their solubility in water relative to their
+ solubility in oil. The polyunsaturated fatty acids are many times more water soluble than
+ saturated fatty acids of the same length. This property probably explains why only palmitic acid
+ functions as a surfactant in the lungs, allowing the air sacs to stay open, while unsaturated
+ fats cause lung edema and respiratory failure.
+
+
+
+ The great difference in water/oil
+ solubility affects the strength of binding between a fatty acid and the lipophilic, oil-like,
+ parts of proteins. When a protein has a region with a high affinity for lipids that contain
+ double bonds, polyunsaturated fatty acids will displace saturated fats, and they can sometimes
+ displace hormones containing multiple double bonds, such as thyroxine and estrogen, from the
+ proteins that have a high specificity for those hormones. Transthyretin (also called prealbumin)
+ is important as a carrier of the thyroid hormone and vitamin A. The unsaturation of vitamin A
+ and of thyroxin allow them to bind firmly with transthyretin and certain other proteins, but the
+ unsaturated fatty acids are able to displace them, with an efficiency that increases with the
+ number of double bonds, from linoleic (with two double bonds) through DHA (with six double
+ bonds).
+
+
+
+ The large amount of albumin in the
+ blood is important in normal fatty acid binding and transport, but it is also an important part
+ of our detoxifying system, since it can carry absorbed toxins from the intestine, lungs, or skin
+ to the liver, for detoxification. Albumin facilitates the uptake of saturated fatty acids by
+ cells of various types (Paris, et al., 1978), and its ability to bind fatty acids can protect
+ cells to some extent from the unsaturated fatty acids (e.g., Rhoads, et al., 1983). The liver's
+ detoxification system processes some polyunsaturated fats for excretion, along with hormones and
+ environmental toxins.
+
+
+
+ The movement of proteins from the
+ plasma into cells has often been denied, but there is clear evidence that a variety of proteins,
+ including IgG, transferrin haptoglobin, and albumin can be found in a variety of cells, even in
+ the brain (Liu, et al., 1989). Cells are lipophilic, and absorb molecules in proportion to their
+ fattiness; this long ago led people to theorize that cells are coated with a fat
+ membrane.
+
+
+
+ The idea of a semipermeable
+ membrane, similar in function to the membrane inside an egg shell, was proposed about 150 years
+ ago, to explain the ability of living cells to concentrate certain chemicals, such as potassium
+ ions, while excluding others, such as sodium ions. This idea of a molecular sieve was shown to
+ be invalid when radioactive isotopes made it possible to observe that sodium ions diffuse freely
+ into cells, and it was replaced by the idea of a metabolically active membrane, containing
+ "pumps" that made up for the inability to exclude various things, and that allowed cells to
+ retain high concentrations of some dissolved substances that are free to diffuse out of the
+ cell. The general idea of the membrane as a barrier persisted as a sort of "common sense" idea,
+ that has made people ignore experiments that show that some large molecules, including some
+ proteins, can quickly and massively enter cells. Albumin and transthyretin are two proteins that
+ are sometimes found in large quantities inside cells, and their primary importance is that they
+ bind and transport biologically active oily molecules.
+
+
+
+ While the competition by PUFA for
+ protein binding sites blocks the effects of thyroid hormone and vitamin A, the action of PUFA on
+ the sex steroid binding protein (SBP, or SSBG, for sex steroid binding globulin) increases the
+ activity of estrogen. That's because the SSBG neutralizes estrogen by binding it, keeping it out
+ of cells; free PUFA keep it from binding estrogen (Reed, et al., 1986). People with low
+ SSBG/estrogen ratio have an increased risk of cancer. When the SSBG protein is free of estrogen,
+ it is able to enter cells, and in that estrogen-free state it probably serves a similar
+ protective function, capturing estrogen molecules that enter cells before they can act on other
+ proteins or chromosomes. Transthyretin, the main transporter of thyroid and vitamin A, and
+ albumin (which can also transport thyroid hormone) are both able to enter cells, while loaded
+ with thyroid hormone and vitamin A. Albumin becomes more lipophilic as it binds more lipid
+ molecules, so its tendency to enter cells increases in proportion to its fat burden. Albumin in
+ the urine is a problem associated with diabetes and kidney disease; albumin loaded with fatty
+ acids passes from the blood into the urine more easily than unloaded albumin, and it is the
+ fatty acids, not the albumin, which causes the kidney damage (Kamijo, et al., 2002). It's
+ possible that SSBG's opposite behavior, entering cells only when it carries no hormones, is the
+ result of becoming less lipophilic when it's loaded with estrogen.
+
+
+
+ Since most people believe that cells
+ are enclosed within a barrier membrane, a new industry has appeared to sell special products to
+ "target" or "deliver" proteins into cells across the barrier. Combining anything with fat makes
+ it more likely to enter cells. Stress (which increases free fatty acids and lowers cell energy)
+ makes cells more permeable, admitting a broader range of substances, including those that are
+ less lipophilic.
+
+
+
+ Linoleic acid and arachidonic acid,
+ which are said to "make the lipid membrane more permeable," in fact make the whole cell more
+ permeable, by binding to the structural proteins throughout the cell, increasing their affinity
+ for water, causing generalized swelling, as well as mitochondrial swelling (leading to reduced
+ oxidative function or disintegration), allowing more calcium to enter the cell, activating
+ excitatory processes, stimulating a redox shift away from oxidation and toward inflammation,
+ leading to either (inappropriate) growth or death of the cell.
+
+
+ When we don't eat for many hours,
+ our glycogen stores decrease, and adrenaline secretion is increased, liberating more glucose as
+ long as glycogen is available, but also liberating fatty acids from the fatty tissues. When the
+ diet has chronically contained more polyunsaturated fats than can be oxidized immediately or
+ detoxified by the liver, the fat stores will contain a disproportionate amount of them, since
+ fat cells preferentially oxidize saturated fats for their own energy, and the greater water
+ solubility of the PUFA causes them to be preferentially released into the bloodstream during
+ stress.
+
+
+
+ In good health, especially in
+ children, the stress hormones are produced only in the amount needed, because of negative
+ feedback from the free saturated fatty acids, which inhibit the production of adrenalin and
+ adrenal steroids, and eating protein and carbohydrate will quickly end the stress. But when the
+ fat stores contain mainly PUFA, the free fatty acids in the serum will be mostly linoleic acid
+ and arachidonic acid, and smaller amounts of other unsaturated fatty acids. These PUFA stimulate
+ the stress hormones, ACTH, cortisol, adrenaline, glucagon, and prolactin, which increase
+ lipolysis, producing more fatty acids in a vicious circle. In the relative absence of PUFA, the
+ stress reaction is self limiting, but under the influence of PUFA, the stress response becomes
+ self-amplifying.
+
+
+
+ When stress is very intense, as in
+ trauma or sepsis, the reaction of liberating fatty acids can become dangerously
+ counter-productive, producing the state of shock. In shock, the liberation of free fatty acids
+ interferes with the use of glucose for energy and causes cells to take up water and calcium
+ (depleting blood volume and reducing circulation) and to leak ATP, enzymes, and other cell
+ contents (Boudreault and Grygorczyk, 2008; Wolfe, et al., 1983; Selzner, et al, 2004; van der
+ Wijk, 2003), in something like a systemic inflammatory state (Fabiano, et al., 2008) often
+ leading to death.
+
+
+
+ The remarkable resistance of
+ "essential fatty acid deficient" animals to shock (Cook, et al., 1981; Li et al., 1990; Autore,
+ et al., 1994) shows that the polyunsaturated fats are centrally involved in the maladaptive
+ reactions of shock. The cellular changes that occur in shock--calcium retention, leakiness,
+ reduced energy production--are seen in aging and the degenerative diseases; the stress hormones
+ and free fatty acids tend to be chronically higher in old age, and an outstanding feature of old
+ age is the reduced ability to tolerate stress and to recover from injuries.
+
+
+
+ Despite the instability of
+ polyunsaturated fatty acids, which tend to break down into toxic fragments, and despite their
+ tendency to be preferentially liberated from fat cells during stress, the proportion of them in
+ many tissues increases with age (Laganiere and Yu, 1993, 1987; Lee, et al., 1999; Smidova, et
+ al., 1990;Tamburini, et al., 2004; Nourooz-Zadeh J and Pereira, 1999 ). This progressive
+ increase with age can be seen already in early childhood (Guerra, et al., 2007). The reason for
+ this increase seems to be that the saturated fatty acids are preferentially oxidized by many
+ types of cell, (fat cells can slowly oxidize fat for their own energy maintenance). Albumin
+ preferentially delivers saturated fatty acids into actively metabolizing cells such at the heart
+ (Paris, 1978) for use as fuel. This preferential oxidation would explain Hans Selye's results,
+ in which canola oil in the diet caused the death of heart cells, but when the animals received
+ stearic acid in addition to the canola oil, their hearts showed no sign of damage.
+
+
+
+ Since healthy cells are very
+ lipophilic, saturated fatty acids would have a greater tendency to enter them than the more
+ water soluble polyunsaturated fats, especially those with 4, 5, or 6 double bonds, but as cells
+ become chronically stressed they more easily admit the unsaturated fats, which slow oxidative
+ metabolism and create free radical damage. The free radicals are an effect of stress and aging,
+ as well as a factor in its progression.
+
+
+
+ When stress signals activate enzymes
+ in fat cells to release free fatty acids from the stored triglycerides, the enzymes in the
+ cytoplasm act on the surface of the droplet of fat. This means that the fatty acids with the
+ greatest water solubility will be liberated from the fat to move into the blood stream, while
+ the more oil soluble fatty acids will remain in the droplet. The long chain of saturated carbon
+ atoms (8 in the case of oleic acid, 15 in palmitic acid, and 17 in stearic acid) in the "tail"
+ of oleic, palmitic, and stearic acid will be buried in the fat droplet, while the tail of the
+ n-3 fatty acids, with only 2 saturated carbons, will be the most exposed to the lipolytic
+ enzymes. This means that the n-3 fatty acids are the first to be liberated during stress, the
+ n-6 fatty acids next. Saturated and monounsaturated fatty acids are selectively retained by fat
+ cells (Speake, et al., 1997).
+
+
+
+ Women are known to have a greater
+ susceptibility than men to lipolysis, with higher levels of free fatty acids in the serum and
+ liver, because of the effects of estrogen and related hormones.
+
+
+
+ Women on average have more DHA
+ circulating in the serum than men (Giltay, et al., 2004; McNamara, et al., 2008; Childs, et al.,
+ 2008). This highly unsaturated fatty acid is the first to be liberated from the fat stores under
+ stress, and, biologically, the meaning of estrogen is to mimic stress. Estrogen and
+ polyunsaturated fatty acids have similar actions on cells, increasing their water content and
+ calcium uptake. Long before the Women's Health Initiative reported in 2002 that the use of
+ estrogen increased the risk of dementia, it was known that the incidence of Alzhemer's disease
+ was 2 or 3 times higher in women than in men. Men with Alzheimer's disease have higher levels of
+ estrogen than normal men (Geerlings, et al., 2006). The amount of DHA in the brain (and other
+ tissues) increases with aging, and its breakdown products, including neuroprostanes, are
+ associated with dementia. Higher levels of DHA and total PUFA are found in the plasma of
+ demented patients (Laurin, et al., 2003).
+
+
+
+ Another interesting association of
+ the highly unsaturated fats and estrogen in relation to brain function is that DHA increases the
+ entry of estrogen into the pregnant uterus, but inhibits the entry of progesterone (Benassayag,
+ et al., 1999), which is crucial for brain cell growth. When Dirix, et al., (2009) supplemented
+ pregnant women with PUFA, they found that fetal memory was impaired.
+
+
+
+ The crucial mitochondrial
+ respiratory enzyme, cytochrome c oxidase, declines with aging (Paradies, et al., 1997), as the
+ lipid cardiolipin declines, and the enzyme's activity can be restored to the level of young
+ animals by adding cardiolipin. The composition of cardiolipin changes with aging, "specifically
+ an increase in highly unsaturated fatty acids" (Lee, et al., 2006). Other lipids, such as a
+ phosphatidylcholine containing two myristic acid groups, can support the enzyme's activity
+ (Hoch, 1992). Even supplementing old animals with hydrogenated peanut oil restores mitochondrial
+ respiration to about 80% of normal (Bronnikov, et al., 2010).
+
+
+ Supplementing thyroid hormone
+ increases mitochondrial cardiolipin (Paradies and Ruggiero, 1988). Eliminating the
+ polyunsaturated fats from the diet increases mitochondrial respiration (Rafael, et al.,
+ 1984).
+
+
+
+ Excitotoxicity is the process in
+ which activation of a nerve cell beyond its capacity to produce energy injures or kills the
+ cell, by increasing intracellular calcium. Glutamic acid and aspartic acid are the normal
+ neurotransmitter excitatory amino acids. Estrogen increases the activity of the excitatory
+ transmitter glutamate (Weiland, 1992), and glutamate increases the release of free fatty acids
+ (Kolko, et al., 1996). DHA (more strongly even than arachidonic acid) inhibits the uptake of the
+ excitotoxic amino acid aspartate, and in some situations glutamate, prolonging their actions.
+ Thymocytes are much more easily killed by stress than nerve cells, and they are easy to study.
+ The PUFA kill them by increasing their intracellular calcium. The toxicity of DHA is greater
+ than that of EPA, whose toxicity is greater than alpha-linolenic acid, and linoleic acid was the
+ most potent (Prasad, et al., 2010). Excitotoxicity is probably an important factor in
+ Alzheimer's disease (Danysz and Parsons, 2003).
+
+
+
+ When the brain is injured, DHA and
+ arachidonic acid contribute to brain edema, weakening the blood-brain-barrier, increasing
+ protein breakdown, inflammation, and peroxidation, while a similar amount of stearic acid in the
+ same situation caused no harm (Yang, et al., 2007). In other situations, such as the important
+ intestinal barrier, EPA and DHA also greatly increased the permeability (Dombrowsky, et al.,
+ 2011).
+
+
+
+ The process by which excitotoxicity
+ kills a cell is probably a foreshortened version of the aging process.
+
+
+
+ Excitotoxins (including endotoxin)
+ increase the formation of neuroprostanes and isoprostanes (from n-3 and n-6 PUFA) (Milatovic, et
+ al., 2005), and acrolein and other fragments, which inhibit the use of glucose and oxygen.
+ DHA and EPA produce acrolein and HHE, which react with lysine groups in proteins, and modify
+ nucleic acids, changing the bases in DNA.
+
+
+
+ Increased intracellular calcium
+ activates lipolysis (by phospholipases), producing more free fatty acids, as well as excitation
+ and protein breakdown, and in the brain neurodegenerative diseases, calcium excess contributes
+ to the clumping of synuclein (Wojda, et al., 2008), an important regulator of the cytoskeletal
+ proteins. The reduced function of normal synuclein makes cells more susceptible to
+ excitotoxicity (Leng and Chuang, 2006).
+
+
+
+ If the cells adapt to the increased
+ calcium, rather than dying, their sensitivity is reduced. This is probably involved in the
+ "defensive inhibition" seen in many types of cell. In the brain, DHA and arachidonic acid
+ "brought the cells to a new steady state of a moderately elevated [intracellular calcium] level,
+ where the cells became virtually insensitive to external stimuli. This new steady state can be
+ considered as a mechanism of self-protection" (Sergeeva, et al., 2005). In the heart, the PUFAs
+ decreased the sensitivity to stimulation (Coronel et al., 2007) and conduction velocity
+ (Tselentakis, et al., 2006; Dhein, et al., 2005). Both DHA and EPA inhibit calcium-ATPase (which
+ keeps intracellular calcium low to allow normal neurotransmission) in the cerebral cortex; this
+ suggests "a mechanism that explains the dampening effect of omega-3 fatty acids on neuronal
+ activity" (Kearns and Haag, 2002).
+
+
+
+ In normal aging, most processes are
+ slowed, including nerve conduction velocity, and conduction velocity in the heart (Dhein and
+ Hammerath, 2001). A similar "dampening" or desensitization is seen in sensory, endocrine, and
+ immune systems, as well as in energy metabolism. Calorie restriction, by decreasing the
+ age-related accumulation of PUFA (20:4, 22:4, and 22:5), can prevent the decrease of
+ sensitivity, for example in lymphoid cells (Laganier and Fernandes, 1991). The known effects of
+ the unsaturated fats on the organizational framework of the cell are consistent with the changes
+ that occur in aging.
+
+
+
+ One of the essential protective
+ functions that decline with aging is the liver's ability to detoxify chemicals, by combining
+ them with glucuronic acid, making them water soluble so that they can be excreted in the urine.
+ The liver (and also the intestine and stomach) efficiently process DHA by glucuronidation
+ (Little, et al., 2002). Oleic acid, one of the fats that we synthesize ourselves, increases
+ (about 8-fold) the activity of the glucuronidation process (Krcmery and Zakim, 1993; Okamura, et
+ al., 2006). However, this system is inhibited by the PUFA, arachidonic acid (Yamashita, et al.,
+ 1997), and also by linoleic acid (Tsoutsikos, et al., 2004), in one of the processes that
+ contribute to the accumulation of PUFA with aging.
+
+
+
+ Animals that naturally have a
+ relatively low level of the highly unsaturated fats in their tissues have the greatest
+ longevity. For example, the naked mole rate has a life expectancy of more than 28 years, about 9
+ times as long as other rodents of a similar size. Only about 2% to 6% of its phospholipids
+ contain DHA, while about 27% to 57% of the phospholipids of mice contain DHA Mitchell, et al.,
+ 2007).
+
+
+
+ The famously long-lived people of
+ Azerbaijan eat a diet containing a low ratio of unsaturated to saturated fats, emphasizing
+ fruits, vegetables, and dairy products (Grigorov, et al., 1991).
+
+
+ Some of the clearest evidence of the
+ protective effects of saturated fats has been published by A.A. Nanji's group, showing that they
+ can reverse the inflammation, necrosis, and fibrosis of alcoholic liver disease, even with
+ continued alcohol consumption, while fish oil and other unsaturated fats exacerbate the problem
+ (Nanji, et al., 2001). Glycine protects against fat accumulation in alcohol-induced liver injury
+ (Senthilkumar, et al., 2003), suggesting that dietary gelatin would complement the protective
+ effects of saturated fats.
+
+
+
+ The least stable n-3 fats which
+ accumulate with age and gradually reduce energy production also have their short term effects on
+ endurance. Endurance was much lower in rats fed a high n-3 fat diet, and the effect persisted
+ even after 6 weeks on a standard diet (Ayre and Hulbert, 1997). Analogous, but less extreme
+ effects are seen even in salmon, which showed increased oxidative stress on a high n-3 diet (DHA
+ or EPA), and lower mitochondrial cytochrome oxidase activity (Kjaer, et al., 2008).
+
+
+
+ Maintaining a high rate of oxidative
+ metabolism, without calorie restriction, retards the accumulation of PUFA, and a high metabolic
+ rate is associated with longevity. An adequate amount of sugar maintains both a high rate of
+ metabolism, and a high respiratory quotient, i.e., high production of carbon dioxide. Mole rats,
+ bats, and queen bees, with an unusually great longevity, are chronically exposed to high levels
+ of carbon dioxide. Carbon dioxide forms carbamino bonds with the amino groups of proteins,
+ inhibiting their reaction with the reactive "glycating" fragments of PUFA.
+
+
+
+ To minimize the accumulation of the
+ highly unsaturated fatty acids with aging, it's probably reasonable to reduce the amount of them
+ directly consumed in foods, such as fish, but since they are made in our own tissues from the
+ "essential fatty acids," linoleic and linolenic acids, it's more important to minimize the
+ consumption of those (from plants, pork, and poultry, for example).
+
+
+ In the resting state, muscles
+ consume mainly fats, so maintaining relatively large muscles is important for preventing the
+ accumulation of fats.
+
+
+
+
+
+
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+ these pathologies."
+
+
+
+ © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com
+
+
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+
+ The Great Fish Oil Experiment
+
+
+ The Great Fish Oil Experiment
+
+
+ Reading medical journals and following the mass media, it's easy to get the idea that fish oil is something any
+ sensible person should use. It's rare to see anything suggesting that it could be dangerous. During the recent
+ years in which the U.S. government has gone from warning against the consumption of too much of these omega-3
+ oils
+ ("to assure that the combined daily intake of two fatty acids that are components" "(i.e., eicosapentaenoic
+ acid (EPA) and docosahexaenoic acid (DHA)) would not exceed 3 grams per person per day (g/p/d)") to
+ sponsoring biased industry claims, there has been considerable accumulation of information about the dangers of
+ fish oils and omega-3 fatty acids. But there has been an even greater increase in the industry's promotional
+ activities. The US government and the mass media selectively promote research that is favorable to the fish oil
+ industry. The editorial boards of oil research journals often include industry representatives, and their
+ editorial decisions favor research conclusions that promote the industry, in the way that editorial decisions in
+ previous decades favored articles that denied the dangers of radiation and reported that estrogen cures almost
+ everything. Marcia Angell, former editor of the NEJM, has observed that the "significant results" reported in
+ published studies can be properly interpreted only by knowing how many studies reporting opposite results were
+ rejected by the editors. One way to evaluate published studies is to see whether they tell you everything you
+ would need to know to replicate the experiment, and whether the information they provide is adequate for drawing
+ the conclusions they draw, for example whether they compared the experimental subjects to proper control
+ subjects. With just a few minimal critical principles of this sort, most "scientific" publications on nutrition,
+ endocrinology, cancer and other degenerative diseases are seen to be unscientific. In nutritional experiments
+ with fish oil, controls must receive similar amounts of vitamins A, D, E, and K, and should include fat free or
+ "EFA" deficient diets for comparison. In declaring EPA and DHA to be safe, the FDA neglected to evaluate their
+ antithyroid, immunosuppressive, lipid peroxidative (Song et al., 2000), light sensitizing, and antimitochondrial
+ effects, their depression of glucose oxidation (Delarue et al., 2003), and their contribution to metastatic
+ cancer (Klieveri, et al., 2000), lipofuscinosis and liver damage, among other problems.
+
+
+
+ "Houston-based Omega Protein Inc.'s bottom line may get a little fatter. The publicly traded company, which
+ produces an Omega-3 fatty acid product called OmegaPure, has signed an agreement to provide its fish oil in
+ school lunches in 38 school districts in South Texas beginning this month. The 500-person company, which has
+ ties to former President George Bush's Zapata Corp., will distribute the product through an agreement with
+ Mercedes-based H&H Foods. Although the dollar amount of the contract between Omega Protein and H&H Foods
+ hinges on future sales, the company is poised to cash in as school administrators and parents refocus their
+ attention on the nutritional content of student diets. Omega Protein President and CEO Joseph von Rosenberg says
+ the company's recent investment of $16.5 million for a fish oil refinery in Reedville, Va., scheduled for
+ completion in May, and an increased awareness of the benefits of Omega-3 in human food, positions Omega to
+ capitalize on predicted demand." Jenna Colley Houston Business Journal
+
+
+
+
+
+ Andrew Weil was on the radio recently recommending DHA (usually found in fish oil*) to treat depression, and I
+ think that means that a lot of people are buying it and eating it. A few years ago the government declared that
+ it was "generally regarded as safe" and approved its use in baby formula, and a few months ago Texas school
+ districts contracted with Omega Protein (which grew out of the Bush family's Zapata Corporation) to provide
+ menhaden fish oil for school lunches. Between the 1950s and the 1970s, people were assured that eating
+ polyunsaturated seed oils would protect them against heart disease. There's no evidence that the bad outcome of
+ that campaign decreased the gullibility of the public. They are happily joining in the latest public health
+ experiment.
+
+
+ *Weil recommends eating "oily fish"--"wild Alaskan salmon, mackerel, sardines, or herring"--. "If you do
+ take supplements, fish oil is a better source of DHA than algae"
+
+ When a group of people in government and industry decide on a policy, they can use carrots (good jobs,
+ grants, and prestige) and sticks (loss of jobs and grants, organized slander, and worse) to make their
+ guidelines clear, and most people will choose to follow those cues, even if they know that the policy is
+ wrong. Historically, policy makers have told the public that "radiation is good for you," "estrogen will
+ make you fertile (or safely infertile) and feminine and strong and intelligent," "starchy foods will prevent
+ diabetes and obesity," "using diuretics and avoiding salt will make pregnancy safer," and that the
+ polyunsaturated fatty acids are "nutritionally essential, and will prevent heart disease."
+
+ The original "essential fatty acids" were linoleic, linolenic, and arachidonic
+ acids. Now that the toxic effects of those are coming to be recognized, new "essential fatty acids," the
+ omega-3 fatty acids, including those with long chains, found in fish oils, are said to make babies more
+ intelligent, to be necessary for good vision, and to prevent cancer, heart disease, obesity, arthritis,
+ depression, epilepsy, psychosis, dementia, ulcers, eczema and dry skin. With just a normal amount of vitamin
+ E in the diet, cod liver oil is certain to be highly oxidized in the tissues of a mammal that eats a lot of
+ it, and an experiment with dogs showed that it could increase their cancer mortality from the normal 5% to
+ 100%. Although fish oils rapidly destroy vitamin E in the body, some of them, especially the liver oils, can
+ provide useful vitamins, A and D. In studies comparing fish oil diets with standard diets, these nutrients,
+ as well as any toxins besides fatty acids (Huang, et al., 1997; Miyazaki, et al., 1998) in either type of
+ oil, should be taken into account, but they seldom are.
+
+
+ Despite the nutritional value of those vitamins, fish oils are generally much more immunosuppressive than
+ the seed oils, and the early effects of fish oil on the "immune system" include the suppression of
+ prostaglandin synthesis, because the more highly unsaturated long chain fats interfere with the conversion
+ of linoleic acid into arachidonic acid and prostaglandins. The prostaglandins are so problematic that their
+ suppression is helpful, whether the inhibition is caused by aspirin or vitamin E, or by fish oil.
+
+
+
+ Some of the important antiinflammatory effects of fish oil result from the oxidized oils, rather than the
+ unchanged oils (Sethi, 2002; Chaudhary, et al., 2004). These oils are so unstable that they begin to
+ spontaneously oxidize even before they reach the bloodstream.
+
+
+ In experiments that last just a few weeks or months, there may not be time for cancers to develop, and on
+ that time scale, the immunosuppressive and antiinflammatory effects of oxidized fish oil might seem
+ beneficial. For a few decades, x-ray treatments were used to relieve inflammatory conditions, and most of
+ the doctors who promoted the treatment were able to retire before their patients began suffering the fatal
+ effects of atrophy, fibrosis, and cancer. (But a few people are still advocating x-ray therapy for
+ inflammatory diseases, e.g., Hildebrandt, et al., 2003.) The fish oil fad is now just as old as the x-ray
+ fad was at its peak of popularity, and if its antiinflammatory actions involve the same mechanisms as the
+ antiinflammatory immunosuppressive x-ray treatments, then we can expect to see another epidemic of fibrotic
+ conditions and cancer in about 15 to 20 years. Around 1970 researchers reported that animals given fish oil
+ in their food lived longer than animals on the standard diet. Alex Comfort, who was familiar with the
+ research showing that simple reduction of food intake increased longevity, observed that the animals were
+ very reluctant to eat the food containing smelly fish oil, and were eating so little food that their
+ longevity could be accounted for by their reduced caloric intake. Even when "fresh" deodorized fish oil is
+ added to the diet, its spontaneous oxidation before it reaches the animal's tissues reduces its caloric
+ value. Without antioxidants, fish oil is massively degraded within 48 hours, and even with a huge amount of
+ antioxidant there is still considerable degradation (Gonzalez, 1988; Klein, et al., 1990). Fish oil has been
+ used for hundreds of years as varnish or for fuel in lamps, and the fatty fish have been used as fertilizer
+ and animal feed, and later the hydrogenated solid form of the oil, which is more stable, has been used in
+ Europe as a food substitute for people. When whale hunting was reduced around 1950, fish oil was substituted
+ for whale oil in margarine production. Like the seed oils, such as linseed oil, the fish oils were mostly
+ replaced by petroleum derivatives in the paint industry after the 1960s.
+
+
+ Although by 1980 many animal diseases were known to be caused by eating oily fish, and the unsaturated oils
+ were known to accelerate the formation of the "age pigment," lipofuscin, many "beneficial effects" of
+ dietary fish oil started appearing in research journals around that time, and the mass media, responding to
+ the industry's public relations campaign, began ignoring studies that showed harmful effects from eating
+ fish oil.
+
+
+ When reviewers in professional journals begin to ignore valid research whose conclusions are harmful to the
+ fish oil industry, we can see that the policy guidelines set by the industry and its agents in government
+ have become clear. Around the end of the century, we begin to see a strange literary device appearing, in
+ which research reports on the toxic effects of omega-3 oils are prefaced by remarks to the effect that "we
+ all know how great these oils are for good health." I think I detect groveling and shuffling of the feet by
+ authors who want to get their work published. If you are willing to say that your work probably doesn't mean
+ what it seems to mean, maybe they will publish it.
+
+
+
+ For more than 50 years, the great majority of the medical publications on estrogen were part of the drug
+ industry's campaign to fraudulently gain billions of dollars, and anyone who cared to analyze them could see
+ that the authors and editors were part of a cult, rather than seekers of useful knowledge. Likewise, the
+ doctrine of the harmlessness of x-rays and radioactive fallout was kept alive for several decades by
+ demonizing all who challenged it. It now looks as though we are in danger of entering another period of
+ medical-industrial-governmental cultism, this time to promote the universal use of polyunsaturated fats as
+ both drugs and foods. In 2004, a study of 29,133 men reported that the use of omega-3 oil or consumption of
+ fish didn't decrease depression or suicide, and in 2001, a study of 42,612 men and women reported that after
+ more than 9 years the use of cod liver oil showed no protective effect against coronary heart disease
+ (Hakkarainen, et al., 2004; Egeland, et al., 2001).
+
+
+ The most popular way of arguing that fish oil will prevent heart disease is to show that it lowers blood
+ lipids, continuing the old approach of the American Heart Association's "heart protective diet."
+ Unfortunately for that argument, it's now known that the triglycerides in the blood are decreased because of
+ the fish oil's toxic effects on the liver (Hagve and Christophersen, 1988; Ritskes-Hoitinga, et al., 1998).
+ In experiments with rats, EPA and DHA lowered blood lipids only when given to rats that had been fed, in
+ which case the fats were incorporated into tissues, and suppressed mitochondrial respiration (Osmundsen, et
+ al., 1998).
+
+
+
+ The belief that eating cholesterol causes heart disease was based mainly on old experiments with rabbits,
+ and subsequent experiments have made it clear that it is oxidized cholesterol that
+ damages the arteries (Stapran, et al., 1997). Since both fish oil and oxidized cholesterol damage rabbits'
+ arteries, and since the lipid peroxides associated with fish oil attack a great variety of biological
+ materials, including the LDL lipoproteins carrying cholesterol, the implications of the
+ rabbit experiments now seem very different.
+
+
+ Another way of arguing for the use of fish oil or other omega-3 fats is to show a correlation between
+ disease and a decreased amount of EPA, DHA, or arachidonic acid in the tissues, and to say "these oils are
+ deficient, the disease is caused by a deficiency of essential fatty acids." Those oils are extremely
+ susceptible to oxidation, so they tend to spontaneously disappear in response to tissue injury, cellular
+ excitation, the increased energy demands of stress, exposure to toxins or ionizing radiation, or even
+ exposure to light. That spontaneous oxidation is what made them useful as varnish or paint medium. But it is
+ what makes them sensitize the tissues to injury. Their "deficiency" in the tissues frequently corresponds to
+ the intensity of oxidative stress and lipid peroxidation; it is usually their presence, rather than their
+ deficiency, that created the disposition for the disease.
+
+
+ One of the earliest harmful effects of polyunsaturated fatty acids, PUFA, to be observed was their
+ acceleration of the formation of lipofuscin or ceroid, the "age pigment," during oxidative stress or vitamin
+ E deficiency. Associated with the formation of lipofuscin, the PUFA were discovered to cause degeneration of
+ the gonads and brain, and the fact that vitamin E could prevent some of their toxic effects led to the idea
+ that vitamin E was essentially an antioxidant. Unfortunately, the protective effect of vitamin E against the
+ PUFA is only partial (Allard, et al., 1997).
+
+
+ The degenerative diseases are all associated with disturbances involving fat metabolism and lipid
+ peroxidation. Alzheimer's disease, alcoholic and nonalcoholic liver disease, retinal degeneration, epilepsy,
+ AIDS, diabetes, and a variety of circulatory problems involve breakdown products of the PUFA. The products
+ of PUFA decomposition include acrolein, malondialdehyde, hydroxynonenal, crotonaldehyde, ethane, pentane,
+ and the neuroprostanes, which are prostaglandin-like molecules formed from DHA by free radical lipid
+ peroxidation products, especially in the brain and at a higher level in Alzheimer's disease.
+
+
+ The reactions of three types of cell--vascular endothelium, nerve cells, and thymus cells--to the PUFA will
+ illustrate some of the important processes involved in their toxicity.
+
+
+ When the body doesn't have enough glucose, free fatty acids are released from the tissues, and their
+ oxidation blocks the oxidation of glucose even when it becomes available from the breakdown of protein
+ caused by cortisol, which is released during glucose deprivation. Cells of the thymus are sensitive to
+ glucose deprivation, and even in the presence of glucose, cortisol prevents them from using glucose, causing
+ them to take up fatty acids. The thymic cells die easily when exposed either to excess cortisol, or
+ deficient glucose. The polyunsaturated fatty acids linoleate, arachidonate, and
+ eicosapentaenoic, are especially toxic to thymic cells by preventing their inactivation of cortisol,
+ increasing its action. (Klein, et al., 1987, 1989, 1990). Lymphocytes from people with AIDS and leukemia are
+ less able to metabolize cortisol. An extract of serum from AIDS patients caused lymphocytes exposed to
+ cortisol to die 7 times faster than cells from healthy people. AIDS patients have high levels of both
+ cortisol and free polyunsaturated fatty acids (Christeff, et al., 1988). The cytotoxicity caused by EPA and
+ its metabolites (15 mg. of EPA per liter killed over 90% of a certain type of macrophage) isn't inhibited by
+ vitamin E (Fyfe and Abbey, 2000). Immunological activation tends to kill T cells that contain PUFA (Switzer,
+ et al., 2003).
+
+
+ When animals are fed fish oil and then exposed to bacteria, their immunosuppressed thymic (T) cells cause
+ them to succumb to the infection more easily than animals fed coconut oil or a fat free diet. Natural killer
+ cells, which eliminate cancer cells and virus infected cells, are decreased after eating fish oil, and T
+ suppressor cells are often increased. More subtle interference with immunity is produced by the actions of
+ PUFA on the "immune synapse," a contact between cells that permits the transmission of immunological
+ information. The immunosuppressive effect of fish oil is recognized as a useful aid in preventing the
+ rejection of transplanted organs, but some studies are showing that survival a year after transplantation
+ isn't improved.
+
+
+
+ Polyunsaturated fatty acids, especially those that can be turned into prostaglandins, are widely involved in
+ causing inflammation and vascular leakiness. EPA and DHA don't form ordinary prostaglandins, though the
+ isoprostanes and neuroprostanes they produce during lipid peroxidation behave in many ways like the more
+ common prostaglandins, and their enzymically formed eicosanoids have some functions similar to those of the
+ common prostaglandins. The brain contains a very high concentration of these unstable fatty acids, and they
+ are released in synapses by ordinary excitatory process.
+
+
+ Chan, et al., 1983, found that polyunsaturated fats caused brain swelling and increased blood vessel
+ permeability. In 1988, Chan's group found that DHA and other polyunsaturated fatty acids added to cultured
+ cells from the cerebral cortex produced free radicals and stimulated production of malondialdehyde and
+ lactate, and inhibited the uptake of glutamic acid, which suggests that they would contribute to prolonged
+ excitation of the nerves (Yu, et al., 1986). In brain slices, the polyunsaturated fatty acids caused the
+ production of free radicals and swelling of the tissue, and the saturated fatty acids didn't (Chan and
+ Fishman, 1980). The PUFA inhibited the respiration of mitochondria in brain cells (Hillered and Chan, 1988),
+ and at a higher concentration, caused them to swell (Hillered and Chan, 1989), but saturated fatty acids
+ didn't produce edema. Free radical activity was shown to cause the liberation of free fatty acids from the
+ cellular structure (Chan, et al., 1982, 1984). The activation of lipases by free radicals and lipid
+ peroxides, with the loss of potassium from the cells, suggests that excitation can become a self-stimulating
+ process, leading to cellular destruction.
+
+
+ DHA itself, rather than its decomposition products, facilitates excitatory (glutamate) nerve transmission
+ (Nishikawa, et al., 1994), and that excitatory action causes the release of arachidonic acid (Pellerin and
+ Wolfe, 1991).
+
+
+ Considering just one of the products of fish oil peroxidation, acrolein, and a few of its effects in cells,
+ we can get an idea of the types of damage that could result from increasing the amount of omega-3 fats in
+ our tissues. The "barrier" between the brain and blood stream is one of the most effective vascular barriers
+ in the body, but it is very permeable to oils, and lipid peroxidation disrupts it, damaging the ATPase that
+ regulates sodium and potassium (Stanimirovic, et al., 1995). Apparently, anything that depletes the cell's
+ energy, lowering ATP, allows an excess of calcium to enter cells, contributing to their death (Ray, et al.,
+ 1994). Increasing intracellular calcium activates phospholipases, releasing more polyunsaturated fats
+ (Sweetman, et al., 1995) The acrolein which is released during lipid peroxidation inhibits mitochondrial
+ function by poisoning the crucial respiratory enzyme, cytochrome oxidase, resulting in a decreased ability
+ to produce energy (Picklo and Montine, 2001). (In the retina, the PUFA contribute to light-induced damage of
+ the energy producing ability of the cells [King, 2004], by damaging the same crucial enzyme.) Besides
+ inhibiting the ability of nerve cells to produce energy from the oxidation of glucose, acrolein inhibits the
+ ability of cells to regulate the excitatory amino acid glutamate (Lovell, et al., 2000), contributing to the
+ excitatory process. High levels of acrolein (and other products of PUFA degradation) are found in the brain
+ in Alzheimer's disease (Lovell, et al., 2001).
+
+
+ The "prion" diseases, CJD and TSE/BSE (mad cow disease) have many features in common with Alzheimer's
+ disease, and several studies have shown that the "prion" protein produces its damage by activating the
+ lipases that release polyunsaturated fatty acids and produce lipid peroxides (Bate, et al., 2004, Stewart,
+ et al., 2001). Acrolein reacts with DNA, causing "genetic" damage, and also reacts with the lysine in
+ proteins, for example contributing to the toxicity of oxidized low density lipoproteins (LDL), the proteins
+ that carry cholesterol and that became famous because of their involvement in the development of
+ atherosclerosis that was supposedly caused by eating saturated fats.
+
+
+ My newsletter on mad cow disease discussed the evidence incriminating the use of fish meal in animal feed,
+ as a cause of the degenerative brain diseases, and earlier newsletters (glycemia, and glycation) discussed
+ the reasons for thinking that inappropriate glycation of lysine groups in proteins, as a result of a lack of
+ protective carbon dioxide/carbamino groups, produces the amyloid (or "prion") proteins that characterize the
+ dementias. Acrolein, produced from the decomposing "fish oils" in the brain, is probably the most reactive
+ product of lipid peroxidation in the brain, and so would be likely to cause the glycation of lysine in the
+ plaque-forming proteins. These toxic effects of acrolein in the brain are analogous to the multitude of
+ toxic effects of the omega-3 fatty acids and their breakdown products in all of the other organs and tissues
+ of the body. Cancer cells are unusual in their degree of resistance to the lethal actions of the lipid
+ peroxides, but the inflammatory effects of the highly unsaturated fatty acids are now widely recognized to
+ be essentially involved in the process of cancerization (my newsletters on cancer and leakiness discuss some
+ of the ways the fats are involved in tumor development). The fats that we synthesize from sugar, or coconut
+ oil, or oleic acid, the omega-9 series, are protective against the inflammatory PUFA, in some cases more
+ effective even than vitamin E.
+
+
+
+ In Woody Allen's 1973 movie, Sleeper, the protagonist woke up after being frozen
+ for 200 years, to find that saturated fats were health foods. At the time the movie was made, that had
+ already been established (e.g., Hartroft and Porta, 1968 edition of
+ Present Knowledge in Nutrition, who showed that adequate saturated fat in the diet helped to
+ protect against the formation of lipofuscin). PS: Royal Society for the Protection of Birds says 2004 has
+ been the most catastrophic breeding season on record for seabirds along UK coasts. It says industrial
+ fishing to supply fish meal and oil is barely sustainable and imperils the whole marine food web. "The UK
+ has suffered serious seabird disasters this year already. In Shetland and Orkney, entire colonies of birds
+ failed to produce any young because of severe food shortages. "On top of that, hundreds of seabirds have
+ been washing ashore having perished at sea. Again, lack of food is thought to be one of the reasons." The
+ report, Assessment Of The Sustainability Of Industrial Fisheries Producing Fish Meal And Fish Oil, was
+ compiled for the RSPB by Poseidon Aquatic Resource Management Ltd and the University of Newcastle-upon-Tyne.
+
REFERENCES
+
+ Neuroreport. 2002 Oct 28;13(15):1933-8. Cyclo-oxygenase inhibitors protect against prion-induced
+ neurotoxicity in vitro. Bate C, Rutherford S, Gravenor M, Reid S, Williams A. Neuroreport. 2004
+ Mar 1;15(3):509-13.
+ The role of platelet activating factor in prion and amyloid-beta neurotoxicity. Bate C, Salmona
+ M, Williams A. J Biol Chem. 2004 Aug 27;279(35):36405-11. Phospholipase A2 inhibitors or
+ platelet-activating factor antagonists prevent prion replication.
+ Bate C, Reid S, Williams A. J Neurochem 1980 Oct;35(4):1004-7.
+ Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling. Chan PH, Fishman RA. Brain Res. 1982 Sep 23;248(1):151-7. Alterations of membrane integrity and
+ cellular constituents by arachidonic acid in neuroblastoma and glioma cells. Chan PH, Fishman
+ RA. J Neurochem. 1982 Feb;38(2):525-31. Phospholipid degradation and cellular edema induced by free
+ radicals in brain cortical slices.
+
+ Chan PH, Yurko M, Fishman RA. Ann Neurol. 1983 Jun;13(6):625-32. Induction of brain edema following
+ intracerebral injection of arachidonic acid. Chan PH, Fishman RA, Caronna J, Schmidley JW,
+ Prioleau G, Lee J. J Neurosci Res. 1984;12(4):595-605. Release of polyunsaturated fatty acids from
+ phospholipids and alteration of brain membrane integrity by oxygen-derived free radicals. Chan
+ PH, Fishman RA, Schmidley JW, Chen SF. J Neurochem 1988 Apr;50(4):1185-93.
+ Induction of intracellular superoxide radical formation by arachidonic acid and by polyunsaturated fatty
+ acids in primary astrocytic cultures.
+
+ Chan PH, Chen SF, Yu AC. Clin Exp Immunol. 2002 Oct;130(1):12-8.
+ Dietary n-3 PUFA affect TcR-mediated activation of purified murine T cells and accessory cell function
+ in co-cultures. Chapkin RS, Arrington JL, Apanasovich TV, Carroll RJ, McMurray DN. J Biol Chem.
+ 2004 Jul 16;279(29):30402-9. Epub 2004 Apr 14. Nonenzymatic glycation at the N terminus of
+ pathogenic prion protein in transmissible spongiform encephalopathies.
+ Choi YG, Kim JI, Jeon YC, Park SJ, Choi EK, Rubenstein R, Kascsak RJ, Carp RI, Kim YS.
+ Transmissible spongiform encephalopathies (TSEs) are transmissible neurodegenerative diseases characterized
+ by the accumulation of an abnormally folded prion protein, termed PrPSc, and the development of pathological
+ features of astrogliosis, vacuolation, neuronal cell loss, and in some cases amyloid plaques. Although
+ considerable structural characterization of prion protein has been reported, neither the method of
+ conversion of cellular prion protein, PrPC, into the pathogenic isoform nor the post-translational
+ modification processes involved is known. We report that in animal and human TSEs, one or more
+ lysines at residues 23, 24, and 27 of PrPSc are covalently modified with advanced glycosylation end
+ products (AGEs), which may be carboxymethyl-lysine (CML), one of the structural varieties of
+ AGEs. The arginine residue at position 37 may also be modified with AGE, but not the arginine residue at
+ position 25. This result suggests that nonenzymatic glycation is one of the post-translational modifications
+ of PrP(Sc). Furthermore, immunostaining studies indicate that, at least in clinically affected hamsters,
+ astrocytes are the first site of this glycation process. Eur J Cancer Clin Oncol 1988
+ Jul;24(7):1179-83.
+ Abnormal free fatty acids and cortisol concentrations in the serum of AIDS patients.
+
+ Christeff N, Michon C, Goertz G, Hassid J, Matheron S, Girard PM, Coulaud JP, Nunez EA Lipids. 1996
+ Aug;31(8):829-37. Effect of dietary n-9 eicosatrienoic acid on the fatty acid composition of plasma
+ lipid fractions and tissue phospholipids. Cleland LG, Neumann MA, Gibson RA, Hamazaki T,
+ Akimoto K, James MJ. J Nutr. 1996 Jun;126(6):1534-40. Dietary (n-9) eicosatrienoic acid from a
+ cultured fungus inhibits leukotriene B4 synthesis in rats and the effect is modified by dietary linoleic
+ acid. Cleland LG, Gibson RA, Neumann MA, Hamazaki T, Akimoto K, James MJ. Br J Nutr. 2003
+ Oct;90(4):777-86. Fish-oil supplementation reduces stimulation of plasma glucose fluxes during
+ exercise in untrained males.
+ Delarue J, Labarthe F, Cohen R. Int J Circumpolar Health. 2001 Apr;60(2):143-9. Cod liver oil
+ consumption, smoking, and coronary heart disease mortality: three counties, Norway.
+ Egeland GM, Meyer HE, Selmer R, Tverdal A, Vollset SE. Prostaglandins Leukot Essent Fatty Acids. 2000
+ Mar;62(3):201-7. Effects of n-3 fatty acids on growth and survival of J774 macrophages.
+
+ Fyfe DJ, Abbey M. Eur J Clin Nutr. 2003 Jun;57(6):793-800. Increased lipid peroxidation during
+ long-term intervention with high doses of n-3 fatty acids (PUFAs) following an acute myocardial
+ infarction. Grundt H, Nilsen DW, Mansoor MA, Nordoy A. Scand J Clin Lab Invest. 1988
+ Dec;48(8):813-6. Mechanisms for the serum lipid-lowering effect of n-3 fatty acids.
+
+
+ Hagve TA, Christophersen BO. Am J Psychiatry. 2004 Mar;161(3):567-9.
+ Is low dietary intake of omega-3 fatty acids associated with depression?
+
+ Hakkarainen R, Partonen T, Haukka J, Virtamo J, Albanes D, Lonnqvist J. J Neurosci Res 1988 Aug;20(4):451-6.
+ Role of arachidonic acid and other free fatty acids in mitochondrial dysfunction in brain
+ ischemia.
+ Hillered L, Chan PH. J Neurosci Res 1989 Oct;24(2):247-50. Brain mitochondrial swelling induced by
+ arachidonic acid and other long chain free fatty acids.
+ Hillered L, Chan PH. Endocrinology. 2003 Sep;144(9):3958-68. Diabetogenic impact of long-chain
+ omega-3 fatty acids on pancreatic beta-cell function and the regulation of endogenous glucose
+ production. Holness MJ, Greenwood GK, Smith ND, Sugden MC. Lipids. 1997
+ Jul;32(7):745-51.
+ Unusual effects of some vegetable oils on the survival time of stroke-prone spontaneously hypertensive
+ rats. Huang MZ, Watanabe S, Kobayashi T, Nagatsu A, Sakakibara J, Okuyama H. Transplant Proc.
+ 2001 Aug;33(5):2854-5.
+ Evaluation of the effect of fish oil on cell kinetics: implications for clinical
+ immunosuppression.
+ Istfan NW, Khauli RB. Boston University School of Medicine, Massachusetts, USA. Cancer Res. 1989 Apr
+ 15;49(8):1931-6.
+ Effects of fish oil and corn oil diets on prostaglandin-dependent and myelopoiesis-associated immune
+ suppressor mechanisms of mice bearing metastatic Lewis lung carcinoma tumors. Young MR, Young
+ ME. Department of Research Services, Edward J. Hines, Jr. "The fish oil diet increased the frequency of
+ myeloid progenitor cells in normal mice and in mice bearing small or large tumors. Concurrently,
+ the fish oil diet stimulated the appearance of bone marrow-derived suppressor cells. When
+ administered after the establishment of palpable primary tumors, a fish oil diet also increased the
+ formation of pulmonary lung nodules." "These data show that a fish oil diet can minimize the immune
+ suppression in tumor bearers when suppression is mediated by PGE2-producing suppressor cells, but can also
+ induce myelopoietic stimulation leading to the appearance of bone marrow-derived suppressor cells
+ and increased tumor metastasis."
+ J Exp Med 1993 Dec 1;178(6):2261-5. Effect of dietary supplementation with n-9
+ eicosatrienoic acid on leukotriene B4 synthesis in rats: a novel approach to inhibition of eicosanoid
+ synthesis. James MJ, Gibson RA, Neumann MA, Cleland LG Transplantation. 1989 Jul;48(1):98-102.
+ Enhancement of immunosuppression by substitution of fish oil for olive oil as a vehicle for
+ cyclosporine.
+ Kelley VE, Kirkman RL, Bastos M, Barrett LV, Strom TB. Photochem Photobiol. 2004 May;79(5):470-5. Mitochondria-derived reactive oxygen species mediate blue light-induced death of retinal pigment epithelial
+ cells. King A, Gottlieb E, Brooks DG, Murphy MP, Dunaief JL. Metabolism. 1989
+ Mar;38(3):278-81.
+ The effect of fatty acids on the vulnerability of lymphocytes to cortisol. Klein A, Bruser B,
+ Malkin A. Tumour Biol. 1989;10(3):149-52. Albumin and the unique pattern of inhibitors of cortisol
+ catabolism by lymphocytes in serum of cancer patients. Klein A, Bruser B, Malkin A. J
+ Endocrinol. 1987 Feb;112(2):259-64.
+ Effect of a non-viral fraction of acquired immunodeficiency syndrome plasma on the vulnerability of
+ lymphocytes to cortisol. Klein A, Bruser B, Robinson JB, Pinkerton PH, Malkin A. Biochem Cell
+ Biol. 1990 Apr;68(4):810-3. Cortisol catabolism by lymphocytes of patients with chronic lymphocytic
+ leukemia. Klein A, Lishner M, Bruser B, Curtis JE, Amato DJ, Malkin A. Clin Exp Metastasis
+ 2000;18(5):371-7.
+ Promotion of colon cancer metastases in rat liver by fish oil diet is not due to reduced stroma
+ formation.
+
+ Klieveri L, Fehres O, Griffini P, Van Noorden CJ, Frederiks WM. Free Radic Biol Med. 2000 Oct
+ 15;29(8):714-20. Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in
+ primary neuronal cultures. Lovell MA, Xie C, Markesbery WR. Clin Exp Metastasis 1998
+ Jul;16(5):407-14.
+ Diminution of the development of experimental metastases produced by murine metastatic lines in
+ essential fatty acid-deficient host mice. Mannini A, Calorini L, Mugnai G, Ruggieri S. Lipids.
+ 1998 Jul;33(7):655-61.
+ Free fatty acid fractions from some vegetable oils exhibit reduced survival time-shortening activity in
+ stroke-prone spontaneously hypertensive rats.
+
+
+ Miyazaki M, Huang MZ, Takemura N, Watanabe S, Okuyama H. J Physiol. 1994 Feb 15;475(1):83-93. Facilitatory effect of docosahexaenoic acid on N-methyl-D-aspartate response in pyramidal neurones of rat
+ cerebral cortex. Nishikawa M, Kimura S, Akaike N. Antioxid Redox Signal. 1999 Fall;1(3):255-84.
+ 4-Hydroxynonenal as a biological signal: molecular basis and pathophysiological
+ implications. Parola M, Bellomo G, Robino G, Barrera G, Dianzani MU. Neurochem Res. 1991
+ Sep;16(9):983-9. Release of arachidonic acid by NMDA-receptor activation in the rat
+ hippocampus. Pellerin L, Wolfe LS. Biochim Biophys Acta. 2001 Feb 14;1535(2):145-52. Acrolein inhibits respiration in isolated brain mitochondria.
+
+ Picklo MJ, Montine TJ. Neurochem Res. 1994 Jan;19(1):57-63. Inhibition of bioenergetics alters
+ intracellular calcium, membrane composition, and fluidity in a neuronal cell line. Ray P, Ray
+ R, Broomfield CA, Berman JD. Neurobiol Aging. 2005 Apr;26(4):465-74. Immunochemical crossreactivity
+ of antibodies specific for "advanced glycation endproducts" with "advanced lipoxidation
+ endproducts". Richter T, Munch G, Luth HJ, Arendt T, Kientsch-Engel R, Stahl P, Fengler D,
+ Kuhla B. Food Chem Toxicol. 1998 Aug;36(8):663-72. The association of increasing dietary
+ concentrations of fish oil with hepatotoxic effects and a higher degree of aorta atherosclerosis in the
+ ad lib.-fed rabbit. Ritskes-Hoitinga J, Verschuren PM, Meijer GW, Wiersma A, van de Kooij AJ,
+ Timmer WG, Blonk CG, Weststrate JA. Atherosclerosis. 2001 Mar;155(1):9-18. Enhanced level of n-3
+ fatty acid in membrane phospholipids induces lipid peroxidation in rats fed dietary docosahexaenoic acid
+ oil. Song JH, Miyazawa T. Neurochem Res. 1995 Dec;20(12):1417-27. Free radical-induced
+ endothelial membrane dysfunction at the site of blood-brain barrier: relationship between lipid
+ peroxidation, Na,K-ATPase activity, and 51Cr release.
+ Stanimirovic DB, Wong J, Ball R, Durkin JP. Atherosclerosis, November 1997, vol. 135, no. 1, pp.
+ 1-7(7) Oxidized Cholesterol in the Diet Accelerates the Development of Atherosclerosis in LDL
+ Receptor and Apolipoprotein EDeficient Mice
+ .
+
+ Staprans, I; Pan, X-M; Rapp, JH; Grunfeld, C; Feingold, KR. J Neurosci Res. 2001 Sep 15;65(6):565-72.
+ Involvement of the 5-lipoxygenase pathway in the neurotoxicity of the prion peptide PrP106-126.
+ Stewart LR, White AR, Jobling MF, Needham BE, Maher F, Thyer J, Beyreuther K, Masters CL, Collins SJ, Cappai
+ R. J Nutr. 2003 Feb;133(2):496-503. (n-3) Polyunsaturated fatty acids promote activation-induced
+ cell death in murine T lymphocytes. Switzer KC, McMurray DN, Morris JS, Chapkin RS. Arch
+ Biochem Biophys. 1995 Oct 20;323(1):97-107. Effect of linoleic acid hydroperoxide on endothelial
+ cell calcium homeostasis and phospholipid hydrolysis. Sweetman LL, Zhang NY, Peterson H,
+ Gopalakrishna R, Sevanian A. Biosci Biotechnol Biochem. 1997 Dec;61(12):2085-8. Oxidative stability
+ of docosahexaenoic acid-containing oils in the form of phospholipids, triacylglycerols, and ethyl
+ esters. Song JH, Inoue Y, Miyazawa T. J Nutr. 2000 Dec;130(12):3028-33. Polyunsaturated
+ (n-3) fatty acids susceptible to peroxidation are increased in plasma and tissue lipids of rats fed
+ docosahexaenoic acid-containing oils. Song JH, Fujimoto K, Miyazawa T. Atherosclerosis. 2001
+ Mar;155(1):9-18. Enhanced level of n-3 fatty acid in membrane phospholipids induces lipid
+ peroxidation in rats fed dietary docosahexaenoic acid oil. Song JH, Miyazawa T. Clin Exp
+ Allergy. 2004 Feb;34(2):194-200. Maternal breast milk long-chain n-3 fatty acids are associated with
+ increased risk of atopy in breastfed infants. Stoney RM, Woods RK, Hosking CS, Hill DJ,
+ Abramson MJ, Thien FC. Free Radic Res. 2001 Apr;34(4):427-35. Docosahexaenoic acid
+ supplementation-increased oxidative damage in bone marrow DNA in aged rats and its relation to
+ antioxidant vitamins. Umegaki K, Hashimoto M, Yamasaki H, Fujii Y, Yoshimura M, Sugisawa A,
+ Shinozuka K. J Neurochem 1986 Oct;47(4):1181-9. Effects of arachidonic acid on glutamate and
+ gamma-aminobutyric acid uptake in primary cultures of rat cerebral cortical astrocytes and
+ neurons. Yu AC, Chan PH, Fishman RA.
+
+
+ © Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Gelatin, stress, longevity
+
+
+ Gelatin, stress, longevity
+
+
+
+
+
+
+
+ The main bulk of an animal's body consists of water, protein, fat and bones. Fat tissue and bone are
+ metabolically more quiescent than the protein-water systems. During stress or starvation, or even
+ hibernation, animals lose lean mass faster than fat.
+
+
+ The amino acids that constitute protein have many hormone-like functions in their free state. When
+ our glucose (glycogen) stores have been depleted, we convert our own tissue into free amino acids, some
+ of which are used to produce new glucose. The amino acids cysteine and tryptophan, released in large
+ quantities during stress, have antimetabolic (thyroid-suppressing) and, eventually, toxic effects.
+ Hypothyroidism itself increases the catabolic turnover of protein, even though general metabolism is
+ slowed.
+
+
+ Other amino acids act as nerve-modifiers ("transmitters"), causing, for example, excitation or
+ inhibition.
+
+
+ Some of these amino acids, such as glycine, have a very broad range of cell-protective
+ actions.
+
+
+
+ Their physical properties, rather than their use for production of energy or other metabolic
+ function, are responsible for their important cytoprotective actions.
+
+
+ Gelatin (the cooked form of collagen) makes up about 50% of the protein in an animal, but a much
+ smaller percentage in the more active tissues, such as brain, muscle, and liver. 35% of the amino acids
+ in gelatin are glycine, 11% alanine, and 21% proline and hydroxyproline.
+
+
+ In the industrialized societies, the consumption of gelatin has decreased, relative to the foods
+ that contain an inappropriately high proportion of the antimetabolic amino acids, especially tryptophan
+ and cysteine.
+
+
+ The degenerative and inflammatory diseases can often be corrected by the use of gelatin-rich foods.
+
+
+
+
+
+
+
+ I usually think about something for a long time before I get around to integrating it into my life,
+ sometimes because old habits have to be changed, but usually because our social organization is set up to do
+ things in conventional ways. Our foods reflect our social organization, enforced by laws and rules. When I
+ first went to Mexico to study, many traditional foods were still available even in the city--fried pig skin,
+ served crisp or boiled with a sauce, blood tacos, cartilaginous parts of various animals, chicken-foot soup,
+ crustaceans, insects, etc. Later, when I studied biochemistry, I realized that each part of an organism has
+ a characteristic chemistry and special nutritional value. I knew of Weston Price's research on traditional
+ diets, and his argument that the degenerative "diseases of civilization" were produced by the simplified
+ diets that are characteristic of the highly industrialized societies.
+
+
+ As I began to study endocrinology, I realized that there were some radical misconceptions behind the ideas
+ of "scientific nutrition." I. P. Pavlov, who had studied nutritional physiology because it constituted the
+ animal's closest interactions with its environment, was motivated by a desire to understand life in its
+ totality, including consciousness. But western nutritionists were nearly all committed to an ideology that
+ forced them to think in terms of "essential factors for growth," leading to ideas such as "minimum daily
+ requirement" for each nutrient. Bodily bulk (especially body length) was the criterion, not the experienced
+ quality of life. And there has been no scarcity of evidence showing that rapid bodily growth has its
+ drawbacks (e.g., Miller, et al., 2002, "Big mice die young").
+
+
+ One of the brightest of the genetically oriented nutritionists, Roger Williams, used the idea of genetic
+ individuality to explain that the popular idea of a species-wide standard diet couldn't be applied to
+ exceptional individuals, and that disease was often the result of the mismatch between special nutritional
+ requirements and a "standard" diet. Linus Pauling's concept of orthomolecular medicine was a restatement of
+ Williams' principle for the general scientific community.
+
+
+ But still, the emphasis was on the match between a specific chemical and the genetic
+ constitution of the organism. Pavlov's idea of the "trophic" actions of nerves was
+ discarded, and the rest of his work was relegated to a crudely caricatured branch of psychology. His
+ therapeutic recommendation of beef broth for many ailments was ignored as having nothing to do with the
+ caricatured "Pavlovism."
+
+
+ If nerves are intimately involved in the processes of nutrition and development, the effects of nutrients on
+ the nerves and their development should have a central place in nutritional research. Our appetites reflect
+ our biochemical needs, and our "unconditional reflexes" are likely to be wiser than the theories that are
+ based simply on the amount of weight a young animal gains on a particular diet.
+
+
+ When I began teaching endocrinology, some of my students didn't want to hear about anything except "lock and
+ key" endocrinology, in which "a hormone" signals certain cells that have a suitable receptor for that
+ hormone. But the studies of Hans Selye and Albert Szent-Gyorgyi made it clear that Pavlov's global, holistic
+ approach to the organism in its environment was the soundest scientific basis for physiology, including
+ endocrinology. A cell's response to a hormone depended on the state of the cell. Nutrients and metabolites
+ and hormones and neurotransmitters all modify the cell's sensitivity to its surroundings. The assumptions of
+ "molecular biology," as generally understood, are fundamentally mistaken.
+
+
+ The idea of fixed requirements for specific nutrients, and especially the idea that rapid physical growth
+ was the way to determine the essentiality of a substance, led to a monstrous distortion of the official
+ dietary recommendations. Business, industry, government, and the health professions collaborated in the
+ propagation of an ideology about nutrition that misrepresented the nature of the living organism.
+
+
+
+ Most studies of the nutritional requirements for protein have been done for the agricultural industries, and
+ so have been designed to find the cheapest way to get the maximum growth in the shortest time. The industry
+ isn't interested in the longevity, intelligence, or happiness of their pigs, chickens, and lambs. The
+ industry has used chemical growth stimulants in combination with the foods that support rapid growth at
+ least expense. Antibiotics and arsenic and polyunsaturated fatty acids have become part of our national food
+ supply because they produce rapid weight gain in young animals.
+
+
+ The amino acids in proteins have been defined as "essential" on the basis of their contribution to growth,
+ ignoring their role in producing long life, good brain development, and good health. The amino acid and
+ protein requirements during aging have hardly been studied, except in rats, whose short life-span makes such
+ studies fairly easy. The few studies that have been done indicate that the requirements for tryptophan and
+ cysteine become very low in adulthood.
+
+
+ Although Clive McKay's studies of life extension through caloric restriction were done in the 1930s, only a
+ few studies have been done to find out which nutrients' restriction contributes most to extending the life
+ span. Restricting toxic heavy metals, without restricting calories, produces about the same life-extending
+ effect as caloric restriction.
+ Restricting only tryptophan, or only cysteine, produces a greater extension of the life span than
+ achieved in most of the studies of caloric restriction.
+ How great would be the life-span extension if both tryptophan and cysteine were restricted at the same time?
+
+
+
+ Both tryptophan and cysteine inhibit thyroid function and mitochondrial energy production, and have other
+ effects that decrease the ability to withstand stress. Tryptophan is the precursor to serotonin, which
+ causes inflammation, immunodepression, and generally the same changes seen in aging. Histidine is another
+ amino acid precursor to a mediator of inflammation, histamine;
+ would the restriction of histidine in the diet have a longevity promoting effect, too?
+
+
+ It happens that gelatin is a protein which contains no tryptophan, and only small amounts of cysteine,
+ methionine, and histidine. Using gelatin as a major dietary protein is an easy way to restrict the amino
+ acids that are associated with many of the problems of aging.
+
+
+ The main amino acids in gelatin are glycine and proline;
+ alanine is also present in significant quantity. Glycine and proline are responsible for the unusual fibrous
+ property of collagen.
+
+
+ An animal's body, apart from fat and water, is mostly protein, and about half of the protein in the body is
+ collagen (which is the native, uncooked form of gelatin). Its name is derived from its traditional use as
+ glue. It is responsible for the structural toughness of mature animal bodies.
+
+
+
+ When cells are stressed, they form extra collagen, but they can also dissolve it, to allow for tissue
+ remodeling and growth. Invasive cancers over-produce this kind of enzyme, destroying the extracellular
+ matrix which is needed for normal cellular differentiation and function. When collagen is broken down, it
+ releases factors that promote wound healing and suppress tumor invasiveness. (Pasco, et al., 2003) Glycine
+ itself is one of the factors promoting wound healing and tumor inhibition.
+
+
+ It has a wide range of antitumor actions, including the inhibition of new blood vessel formation
+ (angiogenesis), and it has shown protective activity in liver cancer and melanoma. Since glycine is
+ non-toxic (if the kidneys are working, since any amino acid will contribute to the production of ammonia),
+ this kind of chemotherapy can be pleasant.
+
+
+ When we eat animal proteins in the traditional ways (for example, eating fish head soup, as well as the
+ muscles, or "head-cheese" as well as pork chops, and chicken-foot soup as well as drumsticks), we assimilate
+ a large amount of glycine and gelatin. This whole-animal balance of amino acids supports all sorts of
+ biological process, including a balanced growth of children's tissues and organs.
+
+
+ When only the muscle meats are eaten, the amino acid balance entering our blood stream is the same as that
+ produced by extreme stress, when cortisol excess causes our muscles to be broken down to provide energy and
+ material for repair. The formation of serotonin is increased by the excess tryptophan in muscle, and
+ serotonin stimulates the formation of more cortisol, while the tryptophan itself, along with the excess
+ muscle-derived cysteine, suppresses the thyroid function.
+
+
+ A generous supply of glycine/gelatin, against a balanced background of amino acids, has a great variety of
+ antistress actions. Glycine is recognized as an "inhibitory" neurotransmitter, and promotes natural sleep.
+ Used as a supplement, it has helped to promote recovery from strokes and seizures, and to improve learning
+ and memory. But in every type of cell, it apparently has the same kind of quieting, protective antistress
+ action. The range of injuries produced by an excess of tryptophan and serotonin seems to be prevented or
+ corrected by a generous supply of glycine. Fibrosis, free radical damage, inflammation, cell death from ATP
+ depletion or calcium overload, mitochondrial damage, diabetes, etc., can be prevented or alleviated by
+ glycine.
+
+
+ Some types of cell damage are prevented almost as well by alanine and proline as by glycine, so the use of
+ gelatin, rather than glycine, is preferable, especially when the gelatin is associated with its normal
+ biochemicals. For example, skin is a rich source of steroid hormones, and cartilage contains "Mead acid,"
+ which is itself antiinflammatory.
+
+
+
+ The other well-studied inhibitory neurotransmitter is GABA, so it's significant that GABA (gamma amino
+ butyric acid) is a close analog of glycine (alpha amino acetic acid). A synthetic molecule structurally
+ similar to those natural inhibitory "transmitters," beta amino propanoic acid, has some of the protective
+ effects of glycine and GABA. The other molecules in the series, at least up to epsilon amino caproic acid,
+ have some of the same antiinvasive, antiinflammatory, anti-angiogenic, properties. Alanine and proline, with
+ cell-protecting actions, have the same basic composition, carbon (CH2 or CH) atoms separating acid and amino
+ groups. Even the amino acids in which the lipophilic carbon atoms extend out in a branched side-chain,
+ valine, leucine, and isoleucine, have some of the antiseizure (inhibitory) action (Skeie, et al., 1992,
+ 1994) of GABA and glycine. Tests done with one, or a few, of the relatively lipophilic (aliphatic) amino
+ acids prevent seizures, while the "balanced" mixtures of amino acids permit seizures;
+ unfortunately, results of this sort haven't led researchers to question the idea of "balance" that developed
+ within the setting of agricultural research.
+
+
+ The similarity between the structures and actions of glycine and GABA suggest that their "receptors" are
+ similar, if not identical. For years, it has been known that progesterone and pregnenolone act on the GABA
+ receptor, to reinforce the protective, inhibitory effects of GABA. Estrogen has the opposite effect,
+ inhibiting GABA's action. Since GABA opposes estrogen and inhibits the growth of breast cancer, it wouldn't
+ be surprising if glycine, alanine, etc., did the same.
+
+
+ Recent research shows that progesterone and its metabolites also act on the "glycine receptor," increasing
+ inhibition, and that the "phytoestrogen," genistein, antagonizes the inhibitory effect of glycine.
+
+
+ The inhibitory systems are opposed by excitatory systems, especially by the excitatory amino acid system,
+ activated by glutamic and aspartic acid. Progesterone and estrogen act on that system, too, decreasing and
+ increasing excitation, respectively.
+
+
+
+ I have previously discussed the arguments for viewing progesterone as a "cardinal adsorbent" (as in Ling and
+ Fu, 1987, 1988, Ling, et al., 1984, a steroid alters glycine's influence on the cell's electrical behavior)
+ which increases the lipophilic, fat-loving property of the cytoplasm, and estrogen as having the opposite
+ action, increasing the water-loving hydrophilic quality of the cytoplasm. If we think of the proteins known
+ as the GABA and glycine receptors as having some regions in which the basic amine of lysine associates with
+ the acidic group of aspartic or glutamic acid, then the action of glycine, or other amino acids would be to
+ introduce additional lipophilic carbon atoms into those regions (with the amino acids' polar ends pairing
+ with their opposites on the protein), where the cardinal adsorbents exert their influence.
+
+
+ Generally, biologists seem puzzled by such facts, because they don't fit into the "lock and key" model of
+ molecular biology. But I think they make the organism easier to understand, since these constellations of
+ facts illustrate simple and general physical principles. They suggest the idea that estrogen and
+ progesterone and glycine, GABA, etc., will be active in any functioning cell, at a suitable concentration.
+ It was this kind of thinking in terms of general physical principles that led Szent-Gyorgyi to investigate
+ the effects of estrogen and progesterone on heart physiology. The old characterization of estrogen and
+ progesterone as "sex" and "pregnancy" hormones acting on a few tissues through specific receptors never had
+ a good basis in evidence, but the accumulated evidence has now made those ideas impossible for an informed
+ person to accept. (Progesterone increases the heart's pumping efficiency, and estrogen is antagonistic, and
+ can produce cardiac arrhythmia.)
+
+
+ In the context of the excitatory actions of estrogen, and the inhibitory action of glycine, it would be
+ reasonable to think of glycine as one of the antiestrogenic substances. Another type of amino acid, taurine,
+ is structurally similar to glycine (and to beta amino propanoic acid, and to GABA), and it can be thought of
+ as antiestrogenic in this context. The specific kinds of excitation produced by estrogen that relate to
+ reproduction occur against a background of very generalized cellular excitation, that includes increased
+ sensitivity of sensory nerves, increased activity of motor nerves, changes in the EEG, and, if the estrogen
+ effect is very high, epilepsy, tetany, or psychosis.
+
+
+ Glycine's inhibitory effects appear to oppose estrogen's actions generally, in sensory and motor nerves, in
+ regulating angiogenesis, and in modulating the cytokines and "chemokines" that are involved in so many
+ inflammatory and degenerative diseases, especially tumor necrosis factor (TNF), nitric oxide (NO), and
+ prostaglandins. Exposure to estrogen early in life can affect the health in adulthood, and so can an early
+ deficiency of glycine. The degenerative diseases can begin in the earliest years of life, but because aging,
+ like growth, is a developmental process, it's never too late to start the corrective process.
+
+
+
+ One of estrogen's "excitatory" effects is to cause lipolysis, the release of fatty acids from storage
+ fat;
+ it directs the conversion of glucose into fat in the liver, so that the free fatty acids in the circulation
+ remain chronically high under its influence. The free fatty acids inhibit the oxidation of glucose for
+ energy, creating insulin resistance, the condition that normally increases with aging, and that can lead to
+ hyperglycemia and "diabetes."
+
+
+ Gelatin and glycine have recently been reported to facilitate the action of insulin in lowering blood sugar
+ and alleviating diabetes. Gelatin has been used successfully to treat diabetes for over 100 years (A.
+ Guerard, Ann Hygiene 36, 5, 1871; H. Brat, Deut. Med. Wochenschrift 28 (No. 2), 21, 1902). Glycine inhibits
+ lipolysis (another antiexcitatory, "antiestrogenic" effect), and this in itself will make insulin more
+ effective, and help to prevent hyperglycemia. (A gelatin-rich diet can also lower the serum triglycerides.)
+ Since persistent lipolysis and insulin resistance, along with a generalized inflammatory state, are involved
+ in a great variety of diseases, especially in the degenerative diseases, it's reasonable to consider using
+ glycine/gelatin for almost any chronic problem. (Chicken foot soup has been used in several cultures for a
+ variety of ailments; chicken foot powder has been advocated as a stimulant for spinal cord
+ regeneration--Harry Robertson's method was stopped by the FDA).
+
+
+ Although Hans Selye observed as early as the 1930s that stress causes internal bleeding (in lungs, adrenals,
+ thymus, intestine, salivary and tear glands, etc.), the medical establishment, which has the opportunity to
+ see it after surgery, burns or other trauma, and following strokes and head injuries, prefers to explain it
+ by "stomach hyperacidity," as if it were limited to the stomach and duodenum. And the spontaneous bruising,
+ and easy bruising, that is experienced by millions of women, especially with the premenstrual syndrome, and
+ nose bleeds, and scleral bleeding, purpura senilis, urinary bleeding, bleeding gums, and many other kinds of
+ "spontaneous" or stress related bleeding, are treated by main-line medicine as if they had no particular
+ physiological significance.
+
+
+
+ Stress is an energy problem, that leads to the series of hormonal and metabolic reactions that I have often
+ written about--lipolysis, glycolysis, increased serotonin, cortisol, estrogen, prolactin, leaky capillaries,
+ protein catabolism, etc. The capillaries are among the first tissues to be damaged by stress.
+
+
+ Although Selye showed that estrogen treatment mimics shock and stress, and that progesterone prevents the
+ stress reaction, the effects of these hormones on the circulatory system have never been treated
+ systematically. Katherina Dalton observed that progesterone treatment prevented the spontaneous bruising of
+ the premenstrual syndrome; Soderwall observed that estrogen caused enlargement of the
+ adrenals, sometimes with hemorrhage and necrosis; old female animals often have bleeding in
+ the adrenals (Dhom, et al., 1981). Strangely, estrogen's induction of uterine bleeding has been
+ compartmentalized, as if the endometrial blood vessels didn't follow the same rules as vessels elsewhere in
+ the body. Both estrogen and cortisol are known to cause clotting disorders and to increase capillary
+ fragility, but these steroids have been elevated to the realm of billion dollar drug products, beyond the
+ reach of ordinary physiological thinking. Other stress-released substances that are entangled in the drug
+ market (tryptophan, serotonin, nitric oxide, and unsaturated fats, for example) are similarly exempt from
+ consideration as factors in circulatory, neoplastic, and degenerative diseases.
+
+
+ At the time Selye was observing stress-induced bleeding, standard medicine was putting gelatin to
+ use--orally, subcutaneously, and intravenously--to control bleeding. Since ancient times, it had been used
+ to stop bleeding by applying it to wounds, and this had finally been incorporated into medical practice.
+
+
+
+ The 1936 Cyclopedia of Medicine (G.M. Piersol, editor, volume 6) mentions the use of gelatin solution to
+ quickly control nosebleeds, excessive menstrual bleeding, bleeding ulcers (using three doses of 18 grams as
+ a 10% solution during one day), and bleeding from hemorrhoids and the lower bowel, and hemorrhage from the
+ bladder. But since Selye's work relating the thrombohemorrhagic syndromes to stress wasn't known at that
+ time, gelatin was thought of as a useful drug, rather than as having potentially far-reaching physiological
+ effects, antagonizing some of the agents of stress-induced tissue damage.
+
+
+ Skin cells and nerve cells and many other cells are "electrically" stabilized by glycine, and this effect is
+ currently being described in terms of a "chloride current." A variety of mechanisms have been proposed for
+ the protective effects of some of the amino acids, based on their use as energy or for other metabolic
+ purpose, but there is evidence that glycine and alanine act protectively without being metabolized, simply
+ by their physical properties.
+
+
+ A small dose of glycine taken shortly after suffering a stroke was found to accelerate recovery, preventing
+ the spreading of injury through its inhibitory and antiinflammatory actions. Its nerve-stabilizing action,
+ increasing the amount of stimulation required to activate nerves, is protective in epilepsy, too. This
+ effect is important in the regulation of sleep, breathing, and heart rhythm.
+
+
+ Glycine's antispastic activity has been used to alleviate the muscle spasms of multiple sclerosis. It is
+ thought to moderate some of the symptoms of schizophrenia.
+
+
+ A recent publication shows that glycine alleviates colitis; but the use of gelatin, especially in the form
+ of a concentrated gelatinous beef broth, for colitis, dysentery, ulcers, celiac disease, and other diseases
+ of the digestive system, goes far back in medical history. Pavlov's observation of its effectiveness in
+ stimulating the secretion of digestive juices occurred because the stimulating value of broth was already
+ recognized.
+
+
+
+ Although I pointed out a long time ago the antithyroid effects of excessive cysteine and tryptophan from
+ eating only the muscle meats, and have been recommending gelatinous broth at bedtime to stop nocturnal
+ stress, it took me many years to begin to experiment with large amounts of gelatin in my diet. Focusing on
+ the various toxic effects of tryptophan and cysteine, I decided that using commercial gelatin, instead of
+ broth, would be helpful for the experiment. For years I hadn't slept through a whole night without waking,
+ and I was in the habit of having some juice or a little thyroid to help me go back to sleep. The first time
+ I had several grams of gelatin just before bedtime, I slept without interruption for about 9 hours. I
+ mentioned this effect to some friends, and later they told me that friends and relatives of theirs had
+ recovered from long-standing pain problems (arthritic and rheumatic and possibly neurological) in just a few
+ days after taking 10 or 15 grams of gelatin each day.
+
+
+ For a long time, gelatin's therapeutic effect in arthritis was assumed to result from its use in repairing
+ the cartilage or other connective tissues around joints, simply because those tissues contain so much
+ collagen. (Marketers suggest that eating cartilage or gelatin will build cartilage or other collagenous
+ tissue.) Some of the consumed gelatin does get incorporated into the joint cartilage, but that is a slow
+ process, and the relief of pain and inflammation is likely to be almost immediate, resembling the
+ antiinflammatory effect of cortisol or aspirin.
+
+
+ Inflammation produces fibrosis, because stress, hypoxia, and inadequate supply of glucose stimulate the
+ fibroblasts to produce increased amounts of collagen. In lungs, kidneys, liver, and other tissues, glycine
+ protects against fibrosis, the opposite of what the traditional view would suggest.
+
+
+ Since excess tryptophan is known to produce muscle pain, myositis, even muscular dystrophy, gelatin is an
+ appropriate food for helping to correct those problems, simply because of its lack of tryptophan. (Again,
+ the popular nutritional idea of amino acids as simply building blocks for tissues is exactly wrong--muscle
+ protein can exacerbate muscle disease.) All of the conditions involving excess prolactin, serotonin, and
+ cortisol (autism, postpartum and premenstrual problems, Cushing's disease, "diabetes," impotence, etc.)
+ should benefit from reduced consumption of tryptophan. But the specifically antiinflammatory amino acids in
+ gelatin also antagonize the excitatory effects of the tryptophan-serotonin-estrogen- prolactin system.
+
+
+
+ In some of the older studies, therapeutic results improved when the daily gelatin was increased. Since 30
+ grams of glycine was commonly used for treating muscular dystrophy and myasthenia gravis, a daily intake of
+ 100 grams of gelatin wouldn't seem unreasonable, and some people find that quantities in that range help to
+ decrease fatigue. For a growing child, though, such a large amount of refined gelatin would tend to displace
+ other important foods. The National Academy of Sciences recently reviewed the requirements for working
+ adults (male and female soldiers, in particular), and suggested that 100 grams of balanced protein was
+ needed for efficient work. For adults, a large part of that could be in the form of gelatin.
+
+
+ If a person eats a large serving of meat, it's probably helpful to have 5 or 10 grams of gelatin at
+ approximately the same time, so that the amino acids enter the blood stream in balance.
+
+
+ Asian grocery stores are likely to sell some of the traditional gelatin-rich foods, such as prepared pig
+ skin and ears and tails, and chicken feet.
+
+
+ Although the prepared powdered gelatin doesn't require any cooking, dissolving it in hot water makes it
+ digest a little more quickly. It can be incorporated into custards, mousses, ice cream, soups, sauces,
+ cheese cake, pies, etc., or mixed with fruit juices to make desserts or (with juice concentrate) candies.
+
+
+ Although pure glycine has its place as a useful and remarkably safe drug, it shouldn't be thought of as a
+ food, because manufactured products are always likely to contain peculiar contaminants.
+
+
+
+
+ REFERENCES
+
+
+ Am J Physiol. 1990 Jul;259(1 Pt 2):F80-7. Mechanisms of perfused kidney cytoprotection by alanine
+ and glycine. Baines AD, Shaikh N, Ho P.
+
+
+ Neurol. 1974; 24:392. Preliminary study of glycine administration in patients with
+ spasticity. Barbeau A.
+
+
+
+ Virchows Arch B Cell Pathol Incl Mol Pathol. 1981;36(2-3):195-206. Peliosis of the female adrenal
+ cortex of the aging rat. Dhom G, Hohbach C, Mausle E, Scherr O, Uebergerg H. Foci of apparent
+ peliosis are regularly observed in the mid-zone of the adrenal cortex in female rats older than 600 days.
+ The changes present range from ectasis of the sinusoids to extensive cystic change of the whole organ.
+ This lesion occurs almost exclusively in female animals and was seen in only one of 50 male animals
+ older than 600 days examined. Experimental stimulation or inhibition did not influence adrenal
+ peliosis. Electron microscopically, there was marked pericapillary edema with collapse of the capillaries,
+ and erythrocytes and thrombocytes were seen infiltrating the edema. Fibrin accumulated in the larger foci.
+ Degenerative alterations were not observed either in the epithelial cells of the cortex or in mesenchymal
+ cells. The pathogenesis is unknown, but the possible role of constant estrus in aging female rats
+ will be discussed.
+
+
+ Riv Neurol. 1976 Mar-Jun;46(3):254-61.
+ [Antagonism between focal epilepsy and taurine administered by cortical Perfusion] Durelli L,
+ Quattrocolo G, Buffa C, Valentini C, Mutani R. The therapeutic action of taurine cortical perfusion was
+ tested in cats affected with Premarin and cobalt cortical epileptogenic foci. In all animals taurine
+ provoked the disappearance of EEG epileptic abnormalities. In the case of Premarin focus the effect appeared
+ more quickly than in the cobalt one. This different time-course, according to previous reports on the
+ antiepileptic action of the parenteral administration of the amino acid, suggests the hypothesis of
+ a taurine direct inhibitory action against Premarin focus and, on the contrary, a mediated
+ action towards the cobalt's. The latter might be related to the metabolic production of some taurine
+ derivative.
+
+
+
+ Ann Neurol. 1998; 44:261-265. Beneficial effects of L-serine and glycine in the management of
+ seizures in 3-phosphoglycerate dehydrogenase deficiency. de Kooning JT, Duran M, Dorling L, et
+ al.
+
+
+ Arch Gen Psychiatry. 1999; 56:29-36.
+ Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia.
+ Heresco-Levy U, Javitt DC, Ermilov M, et al.
+
+
+ Free Radic Biol Med. 2001 Nov 15;31(10):1236-44. Dietary glycine inhibits activation of nuclear
+ factor kappa B and prevents liver injury in hemorrhagic shock in the rat. Mauriz JL, Matilla B,
+ Culebras JM, Gonzalez P, Gonzalez-Gallego J. "Feeding the rats glycine significantly reduced mortality, the
+ elevation of plasma
+
+ transaminase levels and hepatic necrosis. The increase in plasma TNFalpha and nitric oxide (NO) was
+ also blunted by glycine feeding."
+
+
+ Am Fam Phys 1979 May;19(5):77-86.
+ 'Not Cushing's syndrome'. Rincon J, Greenblatt RB, Schwartz RP Cushing's syndrome is
+ characterized by protein wasting secondary to hypergluconeogenesis, which produces thin skin, poor muscle
+ tone, osteoporosis and capillary fragility. These features distinguish patients with true
+ Cushing's syndrome from those who have some of the clinical findings often associated with the syndrome,
+ such as obesity, hypertension, striae and hirsutism. The dexamethasone suppression test helps identify
+ patients with pseudo-Cushing's syndrome.
+
+
+
+ Carcinogenesis. 1999; 20:2075-2081. Dietary glycine prevents the development of liver tumors caused
+ by the peroxisome proliferator WY-14, 643. Rose ML, Cattley RC, Dunn C, et al.
+
+
+ Carcinogenesis, Vol. 20, No. 5, 793-798, May 1999.
+ Dietary glycine inhibits the growth of B16 melanoma tumors in mice.
+
+
+
+ Carcinogenesis, Vol. 20, No. 11, 2075-2081, November 1999. Dietary glycine prevents the development
+ of liver tumors caused by the peroxisome proliferator WY-14,643. M.L.Rose, R.C.Cattley1,
+ C.Dunn, V.Wong, Xiang Li and R.G.Thurman. Simpson RK Jr, Gondo M, Robertson CS, Goodman JC. The
+ influence of glycine and related compounds on spinal cord injury-related spasticity.
+
+ Neurochem Res. 1995; 20:1203-1210.
+
+
+ Neurochem Res. 1995 Oct;20(10):1203-10.
+ The influence of glycine and related compounds on spinal cord injury-induced spasticity.
+ Simpson RK Jr, Gondo M, Robertson CS, Goodman JC.
+
+
+ Neurochem Res. 1996 Oct;21(10):1221-6. Reduction in the mechanonociceptive response by intrathecal
+ administration of glycine and related compounds.
+ Simpson RK Jr, Gondo M, Robertson CS, Goodman JC.
+
+
+ Neurol Res. 1998 Mar;20(2):161-8. Glycine receptor reduction within segmental gray matter in a rat
+ model in neuropathic pain. Simpson RK Jr, Huang W.
+
+
+
+ Neurol Res. 2000 Mar;22(2):160-4. Long-term intrathecal administration of glycine prevents
+ mechanical hyperalgesia in a rat model of neuropathic pain.
+ Huang W, Simpson RK.
+
+
+ Pharmacol Biochem Behav. 1992 Nov;43(3):669-71. Branched-chain amino acids increase the seizure
+ threshold to picrotoxin in rats. Skeie B, Petersen AJ, Manner T, Askanazi J, Jellum E, Steen
+ PA.
+
+
+ Thromb Diath Haemorrh Suppl 1968;30:165-9 [Purpura of the premenstrum and climacteric].
+ [Article in German] Stamm H.
+
+
+
+ Toth E, Lajtha A. Glycine potentiates the action of some anticonvulsant drugs in some seizure
+ models. Neurochem Res. 1984; 9:1711-1718.
+
+
+ Sheng Li Ke Xue Jin Zhan. 2000 Jul;31(3):231-3.
+ [The roles of estrogen and progestin in epileptogenesis and their mechanisms of action]
+ [Article in Chinese] Wang Q.
+
+
+ FASEB J. 2000; 14:476-484.
+ Glycine-gated channels in neutrophils attenuate calcium influx and superoxide production.
+ Wheeler M, Stachlewitz RT, Yamashina S, et al.
+
+
+
+ Cell Mol Life Sci.1999; 56:843-856. Glycine: a new anti-inflammatory immunonutrient.
+ Wheeler MD, Ikejema K, Mol Life Sci. Enomoto N, et al.
+
+
+ Nutr Cancer. 2001;40(2):197-204. Endothelial cells contain a glycine-gated chloride channel. Yamashina S, Konno A, Wheeler MD, Rusyn I, Rusyn EV, Cox AD, Thurman RG. "Glycine inhibited growth
+ of B16 melanoma tumors in vivo most likely because of the inhibition of angiogenesis. Here, the
+ hypothesis that the anticancer effect of glycine in vivo is due to expression of a glycine-gated Cl-
+ channel in endothelial cells was tested.
+
+
+ Biull Eksp Biol Med. 1981 Nov;92(11):599-601. [Repair processes in wound tissues of experimental
+ animals following administration of glycine]
+
+ [Article in Russian] Zaidenberg MA, Pisarzhevskii SA, Nosova IM, Kerova AN, Dudnikova GN. A study was made
+ of the effect of glycine given in doses approximating the physiological ones on the repair of processes in
+ rat wound tissues. It was disclosed that in the early periods of wound healing, glycine administration leads
+ to the increased content of cAMP and cAMP/cGMP ratio in the wound muscle and then in the granulation tissue,
+ which appears to promote the intensification of the repair processes manifesting in the changes in tissue
+ metabolism (DNA, collagen), in anti-inflammatory action, as well as in a more rapid maturation of the
+ granulation tissue and wound reduction.. It was also found that the doses of glycine tested do not affect
+ the content of insulin and hydrocortisone in the blood of experimental animals.
+
+
+
+ "In recent years, evidence has mounted in favor of the antiinflammatory, immunomodulatory and
+ cytoprotective effects of the simplest amino acid L-glycine." "Glycine protects against shock caused by
+ hemorrhage, endotoxin and sepsis, prevents ischemia/reperfusion and cold storage/reperfusion injury to a
+ variety of tissues and organs including liver, kidney, heart, intestine and skeletal muscle, and
+ diminishes liver and renal injury caused by hepatic and renal toxicants and drugs. Glycine also protects
+ against peptidoglycan polysaccharide-induced arthritis..." and inhibits gastric secretion "....and
+ protects the gastric mucosa against chemically and stress-induced ulcers. Glycine appears to exert
+ several protective effects, including antiinflammatory, immunomodulatory and direct cytoprotective
+ actions. Glycine acts on inflammatory cells such as macrophages to suppress activation of transcription
+ factors and the formation of free radicals and inflammatory cytokines. In the plasma membrane, glycine
+ appears to activate a chloride channel that stabilizes or hyperpolarizes the plasma membrane potential.
+ As a consequence, .... opening of ... calcium channels and the resulting increases in intracellular
+ calcium ions are suppressed, which may account for the immunomodulatory and antiinflammatory effects of
+ glycine. Lastly, glycine blocks the opening of relatively non-specific pores in the plasma membrane that
+ occurs as the penultimate event leading to necrotic cell death."
+
+
+
+
+ Zhong Z, Wheeler MD, Li X, Froh M, Schemmer P, Yin M, Bunzendaul H, Bradford B, Lemasters JJ.,
+ "L-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent." Curr Opin Clin
+ Nutr Metab Care. 2003 Mar;6(2):229-40. © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
+
+
+
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+
+
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+
+
+
+ Genes, Carbon Dioxide and Adaptation
+
+
+ "Over the oxygen supply of the body carbon dioxide spreads its protecting wings." - Friedrich Miescher,
+ Swiss physiologist, 1885
+
+
+ To reach useful simplicities, we usually have to sift through the accumulated rationalizations previous
+ generations have produced to justify doing things their way. If we could start with an accurate
+ understanding of what life is, and what we are doing here, science could be built up deductively as well as
+ by the accumulation of evidence. But the fact that we have grown up amid false and unworkable models of what
+ life is, means that we have to lean heavily on evidence, building up new models inductively, imaginatively,
+ and scientifically. Textbooks and professional journals can be useful if they are seen as monuments to past
+ beliefs, and not as authorities to be accepted. Examining the dogmatic models of life and the world in which
+ life exists, we can better understand the nature of the existing barriers to constructive work.
+
+
+ The Central Dogma of the molecular geneticists, in their own words, was that information flows only from DNA
+ to RNA, and from RNA to protein, never in the other direction. The Central Dogma was formulated to suppress
+ forever the Lamarckian idea of the inheritance of acquired characters, that Weismann's amputation of the
+ tails of a multitude of mice had attempted to deal with earlier in the history of genetics.
+
+
+ The Central Dogma continues to be influential, even after a series of revisions. Until the 1990s, the only
+ "practical" fruit of genetics had been genocide, but now it has become possible to insert genes into
+ bacteria, and to use the bacteria to produce industrial quantities of specific proteins. In principle, that
+ could be useful, although bovine growth hormone poses a threat to the health of both people and cows, human
+ growth hormone poses a threat to athletes and old people, and human insulin could increase the number of
+ treated diabetics. A deranged culture will put anything cheap to bad use. The ability to make organisms
+ produce foreign proteins confirms that information can flow from DNA to protein, but as that technology was
+ being developed, the discovery of retroviruses showed that the Central Dogma of molecular genetics was
+ wrong, RNA is a very significant template for the production of DNA. And the scrapie prion shows that
+ proteins can be infectious, passing along information without nucleic acids as the agent of transmission.
+ The directed mutations demonstrated by John Cairns and others have thoroughly destroyed the Central Dogma of
+ molecular genetics, even as it applied to the simplest organisms, but molecular genetics survives as an
+ industrial and forensic technology.
+
+
+ Although evidence suggests that about 2% of human diseases involve the inheritance of an abnormal protein,
+ the exact way the disease develops is never as clear as the geneticists would imply. And the major diseases,
+ cancer, diabetes, heart disease, Alzheimer's, epilepsy, depression, etc., that are so often blamed on
+ "genes," are so poorly understood that it is arbitrary and crazy to talk about the way genes "cause" them.
+ People who had never had a problem with diabetes in their culture, very soon suffered from the same rate of
+ diabetes as their neighbors when they immigrated into Israel and began eating the European style diet. The
+ interesting thing about the genetic explanation for disease is how its proponents can believe what they are
+ saying. If you read Konrad Lorenz's writings on racial hygiene, you can imagine that he might have really
+ come to believe what he was saying, even if it was an invention that earned him personal prestige and
+ revenge against people who were reluctant to accept his ideas of cultural excellence and inferiority. When I
+ listened to Gunther Stent praising the doctrine he had taken straight from Konrad Lorenz's original genocide
+ papers, I wondered how a German who had escaped the holocaust with his Jewish family when he was nine years
+ old could talk about those doctrines without anger, and without pointing out the purpose for which they had
+ been created. In the audience, a professor who had been a refugee from Hungary defended the doctrine, saying
+ that a man and his work have nothing to do with each other, though the whole content of the doctrine was
+ that a man and his work are identical, because his behavior is determined by his genes. These were mature,
+ internationally known intellectuals, who made the most amazingly self-contradictory statements without
+ embarrassment, because they were committed, for some deep, mysterious reason, to the doctrine of genetic
+ determinism. If these refugees could espouse the rationale for "racial hygiene" as their own, I suppose it
+ isn't so hard to understand that people can devote their life to studying the genetics of diabetes, even
+ though diabetes has appeared suddenly in one generation of immigrants when their diet was suddenly changed,
+ a massive fact that bluntly contradicts the genetic doctrine. There is something very deep in our culture
+ that loves genetics.
+
+
+ One of the cultural trends that makes genetic determinism attractive is the theory of radical individualism,
+ something that has grown up with protestant christianity, according to some historians. Roger Williams' work
+ in nutrition seemed to be powered by this idea of individual genetic uniqueness, and in his case, the idea
+ led him to some useful insights--he suggested that the environment could be adjusted to suit the highly
+ specific needs of the individual. This idea led to the widespread belief that nutritional supplements might
+ be needed by a large part of the population. Extreme nurturing of the deviant individual is the opposite
+ extreme from the Lorenzian-Hitlerian solution, of eliminating everyone who wasn't a perfect Aryan specimen.
+
+
+ But Williams' genetic doctrine assumed that our nutritional needs were primarily inborn, determined by our
+ unique genes. However, there is a famous experiment in which rats were made deficient in riboflavin, and
+ when their corneal tissue showed evidence of the vitamin deficiency, they were given a standard diet.
+ However, the standard diet no longer met the needs of their eye tissue, and during the remainder of the
+ observation period, only a dose of riboflavin several times higher than normal would prevent the signs of
+ deficiency. A developmental change had taken place in the cornea, making its vitamin B2 requirement
+ abnormally high. If we accept the epigenetic, developmental idea of metabolic requirements, our idea of
+ nurturing environmental support would consider the long-range effects of environmental adequacy, and would
+ consider that much disease could be prevented by prenatal support, and by avoiding extreme deficiencies at
+ any time. Williams himself emphasized the importance of prenatal nutrition in disease prevention, so he
+ wasn't a genetic totalitarian; combining the idea of unique genetic individuality with the recognition that
+ malnutrition causes disease, led him to believe in the necessity for nutitional adequacy, rather than to the
+ extermination of the sick, weak, or different individuals.
+
+
+ The idea of "genetic determinism" says that our traits are the result of the specific proteins that are
+ produced by our specific genes. The doctrine allows for some gradations, such as "half a dose" of a trait,
+ but in practice it becomes a purely subjective accounting for everything in terms of mysterious degrees of
+ "penetrance" of genes, and interactions with unknown factors. Proteins, that supposedly express our genetic
+ constitution, include enzymes, structural proteins, antibodies, and a variety of protein hormones and
+ peptide regulatory molecules. Every protein, including the smallest peptide (except certain cyclic
+ peptides), contains at least one amine group, and usually several. Amine groups react spontaneously with
+ carbon dioxide, to form carbamino groups, and they can also react, nonenzymically, with sugars, in the
+ reaction called glycation or glycosylation. These chemical changes alter the functions of the proteins, so
+ that hormones and their "receptors," tubules and filaments, enzymes and synthetic systems, all behave
+ differently under their influences. (The proteins' electrical charge, relationship to water and fats, and
+ shape, change quickly and reversibly as the concentration of carbon dioxide changes; in the absence of
+ carbon dioxide, these properties tend to change irreversibly under the influence of metabolic stress.)
+
+
+ This is the clearest, and the most powerful, instance of metabolic influence on biological structure. That
+ makes it very remarkable that it has been the subject of so few publications. I think the absence of
+ discussion of this fundamental biological principle can be understood only in relation to the great
+ importance it has for a new understanding of development and inheritance--it is an easily documented process
+ that will invalidate some of the most deeply held beliefs of most of the people who are influential in
+ science and politics.
+
+
+ I will continue discussing some of these implications in newsletters on imprinting, degenerative diseases,
+ heart attacks, high blood pressure, and other special biological questions, but I think the most important
+ work that remains to be done is to work out the exact mechanisms by which metabolic energy, expressed
+ largely by factors such as the ratio of carbon dioxide to lactic acid, guides both development and
+ evolution. These ideas will have to take into account the actual resources of the world, as well as the
+ internal processes and resources of the organism. Each development in the organism, whether it leads to
+ maturation or to degeneration, consists of responses to and interactions with specific environments.
+
+
+ Curiosity, esthetics, creativity, and stimulation are necessarily and deeply linked to metabolic efficiency
+ and structural-anatomical development. For example, the known effects of stimulation and success (or
+ isolation and depression) on brain anatomy and function should be linked meaningfully with metabolic,
+ hormonal and dietary processes. There is a large amount of information available that could be put to
+ practical use, but there are still important ideological barriers to be overcome. Marshalling the
+ information needed to optimize our own development runs counter to the program of our technical-scientific
+ culture, which prefers to believe that degeneration is programmed, while emergent evolution is
+ unforeseeable. But, if an optimization project is presented as a way to forestall the "programmed
+ degeneration," it might succeed in becoming part of the culture.
+
+
+ Vernadsky's idea of the Noosphere differs from the Gaia hypothesis (that the world is a self-regulating
+ organism-like system) in the intrinsic directionality of Vernadsky's Noosphere, which makes the course of
+ human society crucial for the fate of the planet. It proposes that planets, like organisms, are going
+ somewhere. The Gaia hypothesis is increasingly being interpreted as a justification for feeling no
+ responsibility for the effects of technology on the environment, and some people are expressing that view of
+ the world as essentially a justification for any vandalism that may come along. Kary Mullis, for example,
+ says that mass extinctions of organisms have occurred in the past, and so it's just natural for species to
+ become extinct, and it isn't appropriate to be concerned about the extinctions that are being caused by
+ civilization's technological depredations.
+
+
+ In the Noosphere, global warming and increased carbon dioxide would represent an advance toward a higher
+ state of "metabolism" of the world, and this would support the emergence of new biological forms from those
+ existing. But if whole systems of life are destroyed before that happens, the biological achievements of the
+ past could be lost irretrievably; there is no guarantee that the system will continue to work, if major
+ sectors are deleted from the interacting systems. Even in terms of the Gaia conception, that the earth is
+ like an organism, consider what the loss of genetic complexity means for an organism. Sometimes, for
+ example, things that happen to an individual lead to sterility several generations later, although the
+ procedure didn't seem lethal for the individual or its immediate descendants.
+
+
+ The whole idea of "evolution" is that the past is preserved within the present, or that the present is built
+ upon the accomplishments of the past. The idea that evolution has been "random," and that the world is
+ simply self-regulating, might seem liberating to those who hate the idea that they might be intrinsically
+ responsible for anything outside of themselves, but it is liberating only in the way that a vandal's
+ manifesto might be, declaring the world to be their playground.
+
+
+ The problem with such a manifesto of irresponsibility is simply that it is built upon the same system of
+ cultural assumptions that produced Nazi eugenics, and that those assumptions are false. The political
+ assumptions of the people who controlled scientific institutions were built into a set of pseudo-scientific
+ doctrines, which continue to be valued for their political and philosophical implications.
+
+
+ For hundreds or thousands of years, the therapeutic value of carbonated mineral springs has been known. The
+ belief that it was the water's lively gas content that made it therapeutic led Joseph Priestley to
+ investigate ways to make artificially carbonated water, and in the process he discovered oxygen. Carbonated
+ water had its medical vogue in the 19th century, but the modern medical establishment has chosen to define
+ itself in a way that glorifies "dangerous," "powerful" treatments, and ridicules "natural" and mild
+ approaches. The motivation is obvious--to maintain a monopoly, there must be some reason to exclude the
+ general public from "the practice of medicine." Witch doctors maintained their monopoly by working with
+ frightening ghost-powers, and modern medicine uses its technical mystifications to the same
+ purpose.vAlthough the medical profession hasn't lost its legal monopoly on health care, corporate interests
+ have come to control the way medicine is practiced, and the way research is done in all the fields related
+ to medicine.
+
+
+ The fact that carbon dioxide therapy is extremely safe has led to the official doctrine that it can't be
+ effective. The results reviewed by Yandell Henderson in the Cyclopedia of Medicine in 1940 were so
+ impressive that carbon dioxide therapy would have been as commonly used and as well known as oxygen therapy,
+ radiation treatments, sulfa drugs, barbiturates, and digitalis, but it was completely lacking in the
+ thrilling mystique of those dangerous treatments.
+
+
+ Henderson assumed that carbon dioxide use was becoming a permanent part of medicine, to be used with
+ anesthesia to prevent cessation of spontaneous breathing, during recovery from surgery to prevent shock and
+ pneumonia, for stimulating respiration in newborns, and for resuscitating drowning or suffocation victims,
+ as well as for treatment of heart disease and some neurological conditions (see below). However, its use in
+ surgery and resuscitation has probably decreased since he wrote, despite occasional publications pointing
+ out the dangers involved in the use of oxygen without carbon dioxide.
+
+ REFERENCES
+ O. Rahn, "Protozoa need carbon dioxide for growth," Growth 5, 197-199, 1941. "On page 113 of
+ this volume, the statement of Valley and Rettger that all bacteria need carbon dioxide for growth had been shown
+ to apply to young as well as old cells." "...it is possible...to remove it as rapidly as it is produced, and
+ under these circumstances, bacteria cannot multiply."Y. Henderson, "Carbon Dioxide," Cyclopedia of
+ Medicine, 1940. "Before considering these matters, it will be best that the mind be cleared of
+ certain deep rooted misconceptions that have long opposed the truth and impeded its applications. It will be
+ seen that carbon dioxide is truly the breath of life.""The human mind is inherently inclined to take a
+ moralistic view of nature. Prior to the modern scientific era, which only goes back a generation or two, if
+ indeed it can be said as yet even to have begun in popular thought, nearly every problem was viewed as an
+ alternative between good and evil, righteousness and sin, God and the Devil. This superstitious slant still
+ distorts the conceptions of health and disease; indeed, it is mainly derived from the experience of physical
+ suffering. Lavoisier contributed unintentionally to this conception when he defined the life supporting
+ character of oxygen and the suffocating power of carbon dioxide. Accordingly, for more than a century after his
+ death, and even now in the field of respiration and related functions, oxygen typifies the Good and carbon
+ dioxide is still regarded as a spirit of Evil. There could scarcely be a greater misconception of the true
+ biological relations of these gases." "Carbon dioxide is the chief hormone of the entire body; it is the only
+ one that is produced by every tissue and that probably acts on every organ. In the regulation of the functions
+ of the body, carbon dioxide exerts at least 3 well defined influences: (1) It is one of the prime factors in the
+ acid-base balance of the blood. (2) It is the principal control of respiration. (3) It exerts an essential tonic
+ influence upon the heart and peripheral circulation.""A frog's muscle will contract effectively and repeatedly
+ under suitable stimulation in an atmosphere of pure nitrogen. In contraction, a muscle produces lactic acid,
+ partly by reconversion into sugar. In other words, oxygen is not one of the primary factors in muscular work.
+ The reserve store of oxygen in the body is small. Vigorous breathing does not take place before an exertion; the
+ exertion is first made and then the oxygen needed to clear the system in preparation for another exertion is
+ absorbed. The demand for oxygen for this scavenging of waste and restoration of power is termed by A.V. Hill the
+ "oxygen deficit" of exercise.""On the other hand, present knowledge indicates that carbon dioxide is an
+ absolutely essential component of protoplasm. It is one of the factors in the balance of alkali and acid for the
+ maintenance of the normal pH of the tissues. Acapnia, that is diminution of the normal content of carbon
+ dioxide, involves therefore, a disturbance of one of the fundamental conditions of life.""These observations
+ upon the circulation showed also that in animals reduced to a state of shock the carbon dioxide of the blood, or
+ as it now be generally termed, the "alkaline reserve," is greatly reduced. This experimental result was later
+ confirmed by the observations of Cannon upon wounded soldiers during the war.""Catatonia.---Finally, mention may
+ be made of the extraordinary observations reported by the late A.S. Lovenhart, in which he found that inhalation
+ of carbon dioxide to cases of catatonia induced a temporary restoration of intelligence and mental
+ responsiveness. The simplest explanation of the results in these cases is attained by postulating an habitual
+ contraction of blood-vessels in the brain of the catatonic patient, similar to that in the heart and limbs of
+ the cases discussed in the previous section. If this view is correct, the beneficial effects of the inhalation
+ are due to improvement in the circulation in the brain under the influence of carbon dioxide upon the finer
+ blood vessels."Vojnosanit Pregl 1996 Jul-Aug;53(4):261-74. [Carbon dioxide
+ inhibits the generation of active forms of oxygen in human and animal cells and the significance of the
+ phenomenon in biology and medicine]. Boljevic S, Kogan AH, Gracev SV, Jelisejeva SV, Daniljak IGCarbon dioxide (CO2) influence in generation of active oxygen forms (AOF) in human mononuclear cells
+ (blood phagocytes and alveolar macrophages) and animal cells (tissue phagocytes, parenchymal and interstitial
+ cells of liver, kidney, lung, brain and stomach) was investigated. The AOF generation was examined by the
+ methods of chemiluminiscence (CL) using luminol, lucigenin and NBT (nitro blue tetrazolium) reaction. It was
+ established that CO2 in concentrations similar to those in blood (5.1%, pCO2 37.5 mmHg) and at high
+ concentrations (8.2%, pCO2 60 mmHg; 20%, pCO2 146 mmHg) showed pronounced inhibitory effect on the AOF
+ generation in all the studied cells (usually reducing it 2 to 4 times). Those results were obtained not only
+ after the direct contact of isolated cells with CO2, but also after the whole body exposure to CO2. Besides, it
+ was established that venous blood gas mixture (CO2 - 45 mmHg, +O2 - 39 mmHg, + N2 - 646 mmHg) inhibited the AOF
+ generation in cited cells more than the arterial blood gas mixture (CO2 - 40 mmHg, + O2 - 95 mmHg, + N2 - 595
+ mmHg). Carbon dioxide action mechanism was developed partially through the inhibition of the OAF generation in
+ mitochondria and through deceleration of NADPH oxidative activity. Finally, it was established that CO2 led to
+ the better coordination of oxidation and phosphorylation and increased the phosphorylation velocity in liver
+ mitochondria. The results clearly confirmed the general property of CO2 to inhibit significantly the AOF
+ generation in all the cell types. This favors the new explanation of the well-known evolutionary paradox: the
+ Earth life and organisms preservation when the oxygen, that shows toxic effects on the cells through the AOF,
+ occurs in the atmosphere. The results can also be used to explain in a new way the vasodilating effect of CO2
+ and the favorable hypercapnotherapy influence on the course of some bronchial asthma forms. The results are
+ probably significant for the analysis of important bio-ecological problem, such as the increase of CO2
+ concentration in the atmosphere and its effect on the humans and animals.Aviakosm Ekolog Med
+ 1997;31(6):56-9. [Functional activity of peripheral blood neutrophils of rats during combined effects of
+ hypoxia, hypercapnia and cooling]. Baev VI, Kuprava MVFunctional activity of neutrophilic
+ leukocytes was studied in blood of rats immediately following single and repeated gradual increase in carbon
+ dioxide and decrease in oxygen concentrations with the ambient temperature at 2 to 3 degrees C. Phagocytic
+ activity was shown to alter as the number of phagocyticneutrophilic granulocytes, absorptivity or the phagocytic
+ index, and the coefficient of phagocytosis completeness were elevated and levels of oxygen-dependent and
+ oxygen-independent metabolism were reduced.Izv Akad Nauk Ser Biol 1997 Mar-Apr;(2):204-17. [Carbon
+ dioxide--a universal inhibitor of the generation of active oxygen forms by cells]. Kogan AKh, Grachev SV,
+ Eliseeva SV, Bolevich SStudies were carried out on blood phagocytes and alveolar macrophages of 96
+ humans, on the cells of the viscera and tissue phagocytes (liver, brain, myocardium, lungs, kidneys, stomach,
+ and skeletal muscle), and liver mitochondria of 186 random bred white mice. Generation of the active oxygen
+ forms was determined using different methods after direct effect of CO2 on the cells and biopsies and indirect
+ effect of CO2 on the integral organism. The results obtained suggest that CO2 at a tension close to that
+ observed in the blood (37.0 mm Hg) and high tensions (60 or 146 mm Hg) is a potent inhibitor of generation of
+ the active oxygen forms by the cells and mitochondria of the human and tissues. The mechanism of CO2 effect
+ appears to be realized, partially, through inhibition of the NADPH-oxidase activity. The results are important
+ for deciphering of a paradox of evolution, life preservation upon appearance of oxygen in the atmosphere and
+ succession of anaerobiosis by aerobiosis, and elucidation of some other problems of biology and medicine, as
+ well as analysis of the global bioecological problem, such as ever increasing CO2 content in the
+ atmosphere.Ukr Biokhim Zh 1978 Mar-Apr;50(2):150-4.. [Content of adenine nucleotides and
+ creatinephosphate in brain, myocardium, liver and skeletal muscle under combined action of hypercapnia,
+ hypoxia and cooling]. Baev VI, Drukina MACooling of rats under conditions of hypercapina and
+ hypoxia induced no changes in the content of adenine nucleotides in the brain and skeletal muscles and decreased
+ their concentration in the liver and myocardium. The content of creatine phosphate increased in the brain, but
+ had no changes in the other tissues. 48 hours after cooling the amount of adenine nucleotides in the brain was
+ higher as compared with the initial values, that was due to an increase in the ATP concentration; in the other
+ tissues the contents of adenine nucleotides did not differ from that of the intact rats. The repeated action (48
+ hours after the first influences) caused no changes in the contents of adenine nucleotides in skeletal muscles
+ and decreased them in the myocardium and liver. In the brain their amount and the content of creatinephosphate
+ were increased as related to the intact rats. In the brain and myocardium the level of NADPH decreased after the
+ first action and 48 hours after impact it restored up to the inital values. After repeated impact the level of
+ NADPH in the brain restored up to initial values, in the myocardium it was increased.Fiziol Zh SSSR 1978
+ Oct;64(10):1456-62. [Role of CO2 fixation in increasing the body's resistance to acute hypoxia]. Baev VI,
+ Vasil'ev VV, Nikolaeva ENIn rats, the phenomenon of considerable increase in resistance to acute
+ hypoxia observed after 2-hour stay under conditions of gradually increasing concentration of CO2, decreasing
+ concentration of O2, And external cooling at 2--3 degrees seems to be based mainly on changes in concentration
+ of CO2 (ACCORDINGLY, PCO2 and other forms of CO2 in the blood). The high resistance to acute hypoxia develops as
+ well after subcutaneous or i.v. administration of 1.0 ml of water solution (169.2 mg/200 g) NaHCO2, (NH4)2SO4,
+ MgSO4, MnSO4, and ZnSO4 (in proportion: 35 : 5 : 2 : 0.15 : 0.15, resp.) or after 1-hour effect of increased
+ hypercapnia and hypoxia without cooling.Vopr Med Khim 1976 Jan-Feb;22(1):37-41 [Pyridine nucleotide
+ content in the brain and myocardium of rats under combined effect of hypercapnia, hypoxia and cooling]. Baev
+ VI, Drukina MAIn experiments with rats, subjected to single and repeated simultaneous effect of
+ hypercapnia, hypoxia and cooling, contents of pyridine nucleotides (NAD, NADP, NAD-H2 and NADP-H2) and
+ macroergic substances were studied and also the activity of dehydrogenases of the pentose pathway was determined
+ in brain and myocardium. In brain NADP was not practically determined and in heart its content was increased
+ after the first and the second treatments. Content of NADP-H2 was distinctly decreased in both tissues after the
+ single treatment. NAD was not altered in the tissues in all the periods studied. The amount of NAD-H2 was
+ decreased in brain after the single treatment and it was increased in myocardium after the repeated one. In the
+ activity of dehydrogenases marked alterations were not observed. Total macroergic substances were not altered in
+ brain after the single treatment and after the repeated one they were increased mainly due to the ATP increase.
+ In myocardium total macroergic substances were decreased after the both treatments.
+ ASTHMA: Buteyko's Cure.
+
+
+ © Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com
+
+
+
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+
+ Glucose and sucrose for diabetes
+
Diabetes has been known since ancient times as a wasting disease in which sugar was lost in the urine, but
+ more recently the name has been used to describe the presence of more than the normal amount of glucose in the
+ blood, even in the absence of glucose in the urine. Some of the medical ideas regarding the original form of the
+ condition have been applied to the newer form. Cultural "paradigms" or ideologies are so convenient that people
+ often don't bother to doubt them, and they are sometimes so rigorously enforced that people learn to keep their
+ doubts to themselves. Public concern about diabetes has been growing for decades, but despite the introduction
+ of insulin and other drugs to treat it, and massive campaigns to "improve" eating habits, mortality from
+ diabetes has been increasing during the last 100 years. Diabetes ("type 1") has been increasing even among
+ children (Barat, et al., 2008).A basic meaning of homeopathic medicine is the support of the organism's ability
+ to heal itself; the essence of allopathy is that the physician fights "a disease" to cure the patient, e.g., by
+ cutting out tumors or killing germs. Confidence in the organism's essential rationality led the doctors with a
+ homeopathic orientation to see a fever as part of a recuperative process, while their allopathic opponents
+ sometimes saw fever as the essence of the sickness to be cured. Homeopaths concentrated on the nature of the
+ patient; allopaths concentrated on a disease entity in itself, and were likely to ignore the patient's
+ idiosyncrasies and preferences.Diabetes was named for the excessive urination it causes, and for the sugar in
+ the urine. It was called the sugar disease, and physicians were taught that sugar was the problem. Patients were
+ ordered to avoid sweet foods, and in hospitals they were sometimes locked up to keep them from finding sweets.
+ The practice was derived from ideology, not from any evidence that the treatment helped.In 1857, M. Piorry in
+ Paris and William Budd in Bristol, England, reasoned that if a patient was losing a pound of sugar every day in
+ 10 liters of urine, and was losing weight very rapidly, and had an intense craving for sugar, it would be
+ reasonable to replace some of the lost sugar, simply because the quick weight loss of diabetes invariably led to
+ death. Keeping patients from eating what they craved seemed both cruel and futile. After Budd's detailed reports
+ of a woman's progressive recovery over a period of several weeks when he prescribed 8 ounces of sugar every day,
+ along with a normal diet including beef and beef broth, a London physician, Thomas Williams, wrote sarcastically
+ about Budd's metaphysical ideas, and reported his own trial of a diet that he described as similar to Budd's.
+ But after two or three days he decided his patients were getting worse, and stopped the experiment. Williams'
+ publication was presented as a scientific refutation of Budd's deluded homeopathic ideas, but Budd hadn't
+ explained his experiment as anything more than an attempt to slow the patient's death from wasting which was
+ sure to be the result of losing so much sugar in the urine. The following year Budd described another patient, a
+ young man who had become too weak to work and who was losing weight at an extreme rate. Budd's prescription
+ included 8 ounces of white sugar and 4 ounces of honey every day, and again, instead of increasing the amount of
+ glucose in the urine, the amount decreased quickly as the patient began eating almost as much sugar as was being
+ lost initially, and then as the loss of sugar in the urine decreased, the patient gained weight and recovered
+ his strength. Drs. Budd and Piorry described patients recovering from an incurable disease, and that has usually
+ been enough to make the medical profession antagonistic. Even when a physician has himself diagnosed diabetes
+ and told a patient that it would be necessary to inject insulin for the rest of his life, if that patient
+ recovers by changing his diet, the physician will typically say that the diagnosis was wrong, because diabetes
+ is incurable.Twenty-five years ago, some rabbits were made diabetic with a poison that killed their
+ insulin-secreting pancreatic beta-cells, and when some of them recovered from the diabetes after being given
+ supplemental DHEA, it was found that their beta-cells had regenerated. The more recent interest in stem cells
+ has led several research groups to acknowledge that in animals the insulin-producing cells are able to
+ regenerate. It is now conceivable that there will be an effort to understand the factors that damage the
+ beta-cells, and the factors that allow them to regenerate. The observations of Budd and Piorry would be a good
+ place to start such a reconsideration. For many years, physicians have been taught that diabetes is either
+ "genetic" or possibly caused by a viral infection, that might trigger an "autoimmune reaction," but the study of
+ cellular respiration and energy metabolism and endocrinology has provided more convincing explanations. The
+ antibodies that are found in the "autoimmune" conditions are evidence of tissue damage, but the damage may have
+ been done by metabolic toxins, with the immune system's involvement being primarily the removal of defective
+ cells. In the 1940s, Bernardo Houssay found that coconut oil protected animals from poison-induced diabetes,
+ while a lard-based diet failed to protect them. Later, glucose itself was found to protect the pancreatic
+ beta-cells from poisons.In 1963, P.J. Randle clearly described the inhibition of glucose oxidation by free fatty
+ acids. Later, when lipid emulsions came into use for intravenous feeding in hospitals, it was found that they
+ blocked glucose oxidation, lowered the metabolic rate, suppressed immunity, and increased lipid peroxidation and
+ oxidative stress.Estrogen and stress are both known to create some of the conditions of diabetes, while
+ increasing fat oxidation and inhibiting glucose oxidation. Emotional stress, overwork, trauma, and infections
+ have been known to initiate diabetes. Estrogen increases free fatty acids and decreases glycogen storage, and
+ when birth control pills were becoming popular, some researchers warned that they might cause diabetes. But the
+ food oil industry and the estrogen industry were satisfied with the medical doctrine that diabetes was caused by
+ eating too much sugar.If the essence of diabetes is the presence of too much sugar, then it seems reasonable to
+ argue that it is the excess sugar that's responsible for the suffering and death associated with the disease,
+ otherwise, how would the prohibition of sugar in the diet be justified? In fact, the argument is made (e.g.,
+ Muggeo, 1998) that it is the hyperglycemia that causes problems such as hypertension, kidney failure, heart
+ failure, neuropathy, blindness, dementia, and gangrene.As information about the many physiological and
+ biochemical events associated with diabetes has accumulated, the basic doctrine that "sugar causes diabetes" has
+ extended itself to whatever the topic of discussion is: "Glucose causes" the death of
+ beta-cells, glucose causes blood vessels to become leaky, glucose causes cells to be unable to absorb glucose,
+ glucose causes the formation of free radicals, glucose impairs immunity and wound healing, but causes
+ inflammation while preventing the "respiratory burst" in which free radicals are produced by cells that cause
+ inflammation, it disturbs enzyme functions, impairs nerve conduction and muscle strength, etc., and it is also
+ addictive, causing people to irrationally seek the very material that is poisoning them. Tens of thousands of
+ publications describe the pathogenic effects of sugar. To prove their point, they grow cells in a culture dish,
+ and find that when they are exposed to excess glucose, often 5 times the normal amount, they deteriorate. In the
+ artificial conditions of cell culture, the oversupply of glucose causes lactic acid to accumulate, leading to
+ toxic effects. But in the organism, the hyperglycemia is compensating for a sensed deficiency of glucose, a need
+ for more energy. If diabetes means that cells can't absorb or metabolize glucose, then any cellular function
+ that requires glucose will be impaired, despite the presence of glucose in the blood. It is the intracellular
+ absence of glucose which is problematic, rather than its extracellular excess. Neuroglycopenia (or
+ neuroglucopenia) or intracellular glycopenia refers to the deficit of glucose in cells. When the brain senses a
+ lack of glucose, nerves are activated to increase the amount of glucose in the blood, to correct the problem. As
+ long as the brain senses the need for more glucose, the regulatory systems will make the adjustments to the
+ blood glucose level. The antagonism between fat and sugar that Randle described can involve the suppression of
+ sugar oxidation when the concentration of fats in the bloodstream is increased by eating fatty food, or by
+ releasing fats from the tissues by lipolysis, but it can also involve the suppression of fat oxidation by
+ inhibiting the release of fatty acids from the tissues, when a sufficient amount of sugar is eaten. When a
+ normal person, or even a "type 2 diabetic," is given a large dose of sugar, there is a suppression of lipolysis,
+ and the concentration of free fatty acids in the bloodstream decreases, though the suppression is weaker in the
+ diabetic (Soriguer, et al., 2008). Insulin, released by the sugar, inhibits lipolysis, reducing the supply of
+ fats to the respiring cells.Free fatty acids suppress mitochondrial respiration (Kamikawa and Yamazaki, 1981),
+ leading to increased glycolysis (producing lactic acid) to maintain cellular energy. The suppression of
+ mitochondrial respiration increases the production of toxic free radicals, and the decreased carbon dioxide
+ makes the proteins more susceptible to attack by free radicals. The lactate produced under the influence of
+ excessive fat metabolism stimulates the release of endorphins, which are lipolytic, releasing more free fatty
+ acids from the tissues. Acting through cytokines such as interleukin-6, lactate shifts the balance toward the
+ catabolic hormones, leading to tissue wasting.Lactic acid itself, and the longer chain fatty acids, inhibit the
+ regulatory enzyme pyruvate dehydrogenase (which is activated by insulin), reducing the oxidative production of
+ energy. Drugs to activate this enzyme are being studied by the pharmaceutical industry as treatments for
+ diabetes and cancer (for example, DCA, dichloroacetate).Oxidative damage of proteins is often described as
+ glycation or glycosylation, but it really consists of many addition and crosslinking reactions, most often onto,
+ or between, lysine groups. Carbon dioxide normally associates with lysine groups, so the destructive reactions
+ are favored when carbon dioxide is displaced by lactic acid. The reactive fragments of polyunsaturated fatty
+ acids are much more often the source of the protein-damaging radicals than the carbohydrates are. The importance
+ of the fats in causing type-2 diabetes is coming to be accepted, for example Li, et al., recently (2008) said
+ "The cellular link between fatty acids and ROS (reactive oxygen species) is essentially the mitochondrion, a key
+ organelle for the control of insulin secretion. Mitochondria are the main source of ROS and are also the primary
+ target of oxidative attacks."But much earlier (Wright, et al., 1988) it had been demonstrated that a deficiency
+ of the "essential fatty acids" prevents toxin-induced diabetes and greatly increases resistance to inflammation
+ (Lefkowith, et al., 1990). The lack of those so-called "essential fatty acids" also prevents autoimmune diabetes
+ in a strain of diabetic mice (Benhamou, et al., 1995),Suppressing fatty acid oxidation improves the contraction
+ of the heart muscle and increases the efficiency of oxygen use (Chandler, et al., 2003). Various drugs are being
+ considered for that purpose, but niacinamide is already being used to improve heart function, since it lowers
+ the concentration of free fatty acids.The antimetabolic and toxic effects of the polyunsaturated fatty acids can
+ account for the "insulin resistance" that characterizes type-2 diabetes, but similar actions in the pancreatic
+ beta-cells can impair or kill those cells, creating a deficiency of insulin, resembling type-1 diabetes.The
+ suppression of mitochondrial respiration causes increased free radical damage, and the presence of
+ polyunsaturated fatty acids in the suppressed cell increases the rate of fat decomposition and production of
+ toxins.Increasing the rate of respiration by replacing the fats with glucose reduces the availability of
+ electrons that can trigger lipid peroxidation and produce toxic free radicals, and the shift of fuel also
+ increases the amount of carbon dioxide produced, which can protect the protein amino groups such as lysine from
+ glycation and lipoxidation.While it's clear that it is the excessive oxidation of fat that damages cells in the
+ "diabetic" state in which cells aren't able to use glucose, it's important to look at some of the situations in
+ which so many researchers are blaming problems on hyperglycemia.Important problems in diabetes are slow wound
+ healing, excessive permeability or leakiness of blood vessels which allows molecules such as albumin to be
+ extravasated, and the impaired function and survival of pancreatic beta-cells.During the healing of a wound in a
+ diabetic individual, the local concentration of glucose decreases and then entirely disappears, as healing
+ stops. Applying glucose and insulin topically to the wound, it heals quickly. The very old practice of treating
+ deep wounds with honey or granulated sugar has been studied in controlled situations, including the treatment of
+ diabetic ulcers, infected deep wounds following heart surgery, and wounds of lepers. The treatment eradicates
+ bacterial infections better than some antiseptics, and accelerates healing without scarring, or with minimal
+ scarring. The sugar regulates the communication between cells, and optimizes the synthesis of collagen and
+ extracellular matrix. An excess of insulin, causing hypoglycemia, can cause blood vessels, for example in the
+ brain and kidneys, to become leaky, and this has been claimed to be an effect of insulin itself. However, the
+ same leakiness can be produced by an analog of glucose that can't be metabolized, so that intracellular
+ glycopenia is produced. The harmful effect that has been ascribed to excessive insulin can be prevented by
+ maintaining an adequate supply of glucose (Uezu and Murakami, 1993), showing that it is the lack of glucose,
+ rather than the excess insulin, that causes the vascular malfunction. Fructose also reduces the leakiness of
+ blood vessels (Plante, et al., 2003). Many of the complications of diabetes are caused by increased vascular
+ leakiness (Simard, et al., 2002).Sugar can protect the beta-cells from the free fatty acids, apparently in the
+ same ways that it protects the cells of blood vessels, restoring metabolic energy and preventing damage to the
+ mitochondria. Glucose suppresses superoxide formation in beta-cells (Martens, et al., 2005) and apparently in
+ other cells including brain cells. (Isaev, et al., 2008).The beta-cell protecting effect of glucose is
+ supported by bicarbonate and sodium. Sodium activates cells to produce carbon dioxide, allowing them to regulate
+ calcium, preventing overstimulation and death. For a given amount of energy released, the oxidation of glucose
+ produces more carbon dioxide and uses less oxygen than the oxidation of fatty acids. The toxic excess of
+ intracellular calcium that damages the insulin-secreting cells in the relative absence of carbon dioxide is
+ analogous to the increased excitation of nerves and muscles that can be produced by hyperventilation.In every
+ type of tissue, it is the failure to oxidize glucose that produces oxidative stress and cellular damage. Even
+ feeding enough sucrose to cause fat deposition in the liver can protect the liver from oxidative stress
+ (Spolarics and Meyenhofer, 2000), possibly by mechanisms such as those involved in the treatment of alcoholic
+ liver disease with saturated fats.The active thyroid hormone, T3, protects the heart by supporting the oxidation
+ of glucose (Liu, et al., 1998). The amount of T3 produced by the liver depends mainly on the amount of glucose
+ available.Animals that have been made diabetic with relatively low doses of the poison streptozotocin can
+ recover functional beta-cells spontaneously, and the rate of recovery is higher in pregnant animals (Hartman, et
+ al., 1989). Pregnancy stabilizes blood sugar at a higher level, and progesterone favors the oxidation of glucose
+ rather than fats.A recent study suggests that recovery of the pancreas can be very fast. A little glucose was
+ infused for 4 days into rats, keeping the blood glucose level normal, and the mass of beta-cells was found to
+ have increased 2.5 times. Cell division wasn't increased, so apparently the additional glucose was preventing
+ the death of beta-cells, or stimulating the conversion of another type of cell to become insulin-secreting
+ beta-cells (Jetton, et al., 2008).That study is very important in relation to stem cells in general, because it
+ either means that glandular cells are turning over ("streaming") at a much higher rate than currently recognized
+ in biology and medicine, or it means that (when blood sugar is adequate) stimulated cells are able to recruit
+ neighboring cells to participate in their specialized function. Either way, it shows the great importance of
+ environmental factors in regulating our anatomy and physiology."Diabetologists" don't regularly measure their
+ patients' insulin, but they usually make the assumption that insulin is the main factor regulating blood sugar.
+ In one study, it was found that the insulin molecule itself, immunoreactive insulin, accounted for only about 8%
+ of the serum's insulin-like action. The authors of that study believed that potassium was the main other factor
+ in the serum that promoted the disposition of glucose. Since potassium and glucose are both always present in
+ the blood, their effects on each other have usually been ignored. Cellular activation (by electrical, nervous,
+ chemical, or mechanical stimulation) causes glucose to be absorbed and oxidized, even in the absence of insulin
+ and in otherwise insulin-resistant individuals. I think this local interaction between the need for energy and
+ the production of energy predominates in good health, with insulin and other hormones facilitating the process
+ in times of stress. A variety of local tissue regulators, including GABA and glutamate, probably participate in
+ these interactions, in the brain, endocrine glands, muscles, and other tissues, and are probably involved in the
+ relaxing and analgesic actions of the sugars. The GABA system (GABA is highly concentrated in the beta-cells) is
+ involved in regulating blood sugar, inhibiting the release of glucagon when glucose isn't needed, and apparently
+ allowing the beta cells to discriminate between amino acids and glucose (Gu, et al., 1993) and acting as a
+ survival and growth factor for neighboring cells (Ligon, et al., 2007). The damaged beta-cells lose the enzyme
+ (glutamate dehydrogenase) that makes GABA, and their ratio of linoleic acid to saturated and monounsaturated fat
+ increases, a change that corresponds to a decreased metabolism of glucose.The free intracellular calcium that
+ can become toxic is normally bound safely by well-energized mitochondria, and in the bloodstream it is kept
+ safely complexed with carbon dioxide. The thyroid hormone, producing carbon dioxide, helps to sustain the level
+ of ionized calcium (Lindblom, et al., 2001). In a vitamin D deficiency, or a calcium deficiency, the parathyroid
+ hormone increases, and this hormone can contribute to many inflammatory and degenerative processes, including
+ diabetes. Consuming enough calcium and vitamin D to keep the parathyroid hormone suppressed is important to
+ protect against the degenerative conditions.When animals were fed an otherwise balanced diet lacking vitamin D,
+ with the addition of either 68% sucrose or 68% starch, the bones of those on the starch diet failed to develop
+ normally, as would be expected with a vitamin D deficiency, and their serum calcium was low. However, the bones
+ of those on the diet with sucrose developed properly, and didn't show evidence of being calcium deficient,
+ though they weren't quite as heavy as those that also received an adequate amount of vitamin D (Artus, 1975).
+ This study suggests that the famous dietetic emphasis on the "complex carbohydrates," i.e., starches, has made
+ an important contribution to the prevalence of osteoporosis, as well as obesity and other degeneration
+ conditions.Both vitamin D and vitamin K, another important calcium-regulating nutrient, are now known to prevent
+ diabetes. Both of these vitamins require carbon dioxide for disposing of calcium properly, preventing its
+ toxicity. When carbon dioxide is inadequate, for example from simple hyperventilation or from hypothyroidism,
+ calcium is allowed to enter cells, causing inappropriate excitation, sometimes followed by calcification.Keeping
+ an optimal level of carbon dioxide (for example, when adapted to high altitude) causes calcium to be controlled,
+ resulting in lowered parathyroid hormone, an effect similar to supplementing with calcium, vitamin D, and
+ vitamin K. (E.g., Nicolaidou, et al, 2006.) Glycine, like carbon dioxide, protects proteins against oxidative
+ damage (Lezcano, et al., 2006), so including gelatin (very rich in glycine) in the diet is probably protective.
+ The contribution of PTH to inflammation and degeneration is just being acknowledged (e.g., Kuwabara, 2008), but
+ the mechanism undoubtedly involves the fact that it is lipolytic, increasing the concentration of free fatty
+ acids that suppress metabolism and interfere with the use of glucose.When we talk about increasing the metabolic
+ rate, and the benefits it produces, we are comparing the rate of metabolism in the presence of thyroid, sugar,
+ salt, and adequate protein to the "normal" diet, containing smaller amounts of those "stimulating" substances.
+ It would be more accurate if we would speak of the suppressive nature of the habitual diet, in relation to the
+ more optimal diet, which provides more energy for work and adaptation, while minimizing the toxic effects of
+ free radicals.Feeding animals a normal diet with the addition of Coca-Cola, or with a similar amount of sucrose,
+ has been found to let them increase their calorie intake by 50% without increasing their weight gain
+ (Bukowiecki, et al., 1983). Although plain sucrose can alleviate the metabolic suppression of an average diet,
+ the effect of sugars in the diet is much more likely to be healthful in the long run when they are associated
+ with an abundance of minerals, as in milk and fruit, which provide potassium and calcium and other protective
+ nutrients. Avoiding the starches such as cereals and beans, and using fruits as a major part of the diet helps
+ to minimize the effects of the polyunsaturated fats. Celiac disease or gluten sensitivity is associated with
+ diabetes and hypothyroidism. There is a cross reaction between the gluten protein molecule and an enzyme which
+ is expressed under the influence of estrogen. This is another reason for simply avoiding cereal
+ products.Brewers' yeast has been used traditionally to correct diabetes, and its high content of niacin and
+ other B vitamins and potassium might account for its beneficial effects. However, eating a large quantity of it
+ is likely to cause gas, so some people prefer to extract the soluble nutrients with hot water. Yeast contains a
+ considerable amount of estrogen, and the water extract probably leaves much of that in the insoluble starchy
+ residue. Liver is another rich source of the B vitamins as well as the oily vitamins, but it can suppress
+ thyroid function, so usually one meal a week is enough.The supplements that most often help to correct
+ diabetes-like conditions are niacinamide, thiamine, thyroid, and progesterone or pregnenolone. Vitamins D and K
+ are clearly protective against developing diabetes, and their effects on many regulatory processes suggest that
+ they would also help to correct existing hyperglycemia.Drinking coffee seems to be very protective against
+ developing diabetes. Its niacin and magnesium are clearly important, but it is also a rich source of
+ antioxidants, and it helps to maintain normal thyroid and progesterone production. Chocolate is probably
+ protective too, and it is a good source of magnesium and antioxidants.A recent study (Xia, et al., 2008) showed
+ that inhibition of cholesterol synthesis by beta-cells impairs insulin synthesis, and that replenishing
+ cholesterol restores the insulin secretion. Green tea contains this type of inhibitor, but its use has
+ nevertheless been associated with a reduced risk of diabetes. Caffeine is likely to be the main protective
+ substance in these foods. Although antioxidants can be protective against diabetes, not all things sold as
+ "antioxidants" are safe; many botannical "antioxidants" are estrogenic. Hundreds of herbal products can lower
+ blood sugar, but many of them are simply toxic, and the reduction of blood glucose can make some problems
+ worse.The supplements I mention above--including caffeine--have antiinflammatory, antioxidative and
+ energy-promoting effects. Inflammation, interfering with cellular energy production, is probably the essential
+ feature of the things called diabetes.Aspirin has a very broad spectrum of antiinflammatory actions, and is
+ increasingly being recommended for preventing complications of diabetes. One of the consequences of inflammation
+ is hyperglycemia, and aspirin helps to correct that (Yuan, et al., 2001), while protecting proteins against
+ oxidative damage (Jafarnejad, et al, 2001).If Dr. Budd's thinking (and results) had been more widely accepted
+ when his publications appeared, thinking about "diabetes" might have led to earlier investigation of the
+ syndromes of stress and tissue wasting, with insulin being identified as just one of many regulatory substances,
+ and a large amount of useless and harmful activity treating hyperglycemia as the enemy, rather than part of an
+ adaptive reaction, might have been avoided.
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+ experience in Aquitaine. Barat P, Valade A, Brosselin P, Alberti C, Maurice-Tison S, L"vy-Marchal
+ C.Pancreas. 1995 Jul;11(1):26-37. Essential fatty acid deficiency prevents autoimmune diabetes in
+ nonobese diabetic mice through a positive impact on antigen-presenting cells and Th2 lymphocytes.
+ Benhamou PY, Mullen Y, Clare-Salzler M, Sangkharat A, Benhamou C, Shevlin L, Go VL.The Retrospect of Medicine,
+ XXXVII January-June, 1858 Edited by W. Braithwaite, p. 122: SUGAR AND DIABETES: A CASE. By Dr. William Budd,
+ Senior Physician to the Bristol Royal Infirmary.Am J Physiol. 1983 Apr;244(4):R500-7. Effects of
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+ fatty acids in insulin resistance of subjects with non-insulin-dependent diabetes, Girard J.
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+ chronic exposure of pancreatic beta cells to elevated plasma free fatty acid levels." [This direct effect of
+ free fatty acids on the beta cells is extremely important. Estrogen--probably via GH--increases free fatty
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+ storage. Free fatty acids impair mitochondrail energy production.]Med Sci (Paris). 2005 Dec;21 Spec No:19-25.
+ [Contribution of free fatty acids to impairment of insulin secretion and action. mechanism of beta-cell
+ lipotoxicity] Girard J.Acta Diabetologica 32(1), 44-48, 1995.Effect of lipid oxidation on
+ the regulation of glucose utilization in obese patients, Golay A., et al., [Free fatty acids
+ strongly and quickly depress the ability to oxidize or store glucose.]Life Sci. 1993;52(8):687-94. Suppressive effect of GABA on insulin secretion from the pancreatic beta-cells in the rat. Gu XH,
+ Kurose T, Kato S, Masuda K, Tsuda K, Ishida H, Seino Y.Exp Clin Endocrinol 1989 May;93(2-3):225-30. Spontaneous recovery of streptozotocin diabetes in mice. Hartmann K, Besch W, Zuhlke H.Proc. Nat.
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+ Impaired wound healing in an acute diabetic pig model and the effects of local hyperglycemia.
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+ S, Svensson H, Yao F, Eriksson E.Proc Natl Acad Sci U S A. 1988 Aug;85(16):6137-41. Essential fatty acid
+ deficiency prevents multiple low-dose streptozotocin-induced diabetes in CD-1 mice.Wright JR Jr,
+ Lefkowith JB, Schreiner G, Lacy PE.Endocrinology. 2008 Oct;149(10):5136-45. Inhibition of cholesterol
+ biosynthesis impairs insulin secretion and voltage-gated calcium channel function in pancreatic beta-cells.
+ Xia F, Xie L, Mihic A, Gao X, Chen Y, Gaisano HY, Tsushima RG.Science. 2001 Aug
+ 31;293(5535):1673-7.
+ Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta.
+ Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE.
+
+ © Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com
+
+
+
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+
+ Glycemia, starch, and sugar in context
+
+
+ Glycemia, starch, and sugar in context
+
+
+
+
+
+
+
+
+ Monosaccharide -- a simple sugar; examples, glucose,
+
+ fructose, ribose, galactose (galactose is also called cerebrose, brain sugar).
+
+
+ Disaccharide -- two monosaccharides bound together; examples, sucrose, lactose, maltose.
+
+
+ Oligosaccharide -- a short chain of monosaccharides, including disaccharides and slightly longer
+ chains.
+
+ Polysaccharide -- example, starch, cellulose, glycogen.
+ Glycation -- the attachment of a sugar to a protein.
+
+
+ Lipolysis - the liberation of free fatty acids from triglycerides, the neutral form in which
+ fats are stored, bound to glycerine.
+
+
+
+
+
+
+ In the 1920s, "diabetes" was thought to be a disease of insulin deficiency. Eventually, measurements of
+ insulin showed that "diabetics" often had normal amounts of insulin, or above-normal amounts. There are now
+ "two kinds of diabetes," with suggestions that "the disease" will soon be further subdivided.
+
+
+ The degenerative diseases that are associated with hyperglycemia and commonly called diabetes, are only
+ indirectly related to insulin, and as an approach to understanding or treating diabetes, the "glycemic
+ index" of foods is useless. Physiologically, it has no constructive use, and very little meaning.
+
+
+ Insulin is important in the regulation of blood sugar, but its importance has been exaggerated because of
+ the diabetes/insulin industry. Insulin itself has been found to account for only about 8% of the
+ "insulin-like activity" of the blood, with potassium being probably the largest factor. There probably isn't
+ any process in the body that doesn't potentially affect blood sugar.
+
+
+
+ Glucagon, cortisol, adrenalin, growth hormone and thyroid tend to increase the blood sugar, but it is common
+ to interpret hyperglycemia as "diabetes," without measuring any of these factors. Even when "insulin
+ dependent diabetes" is diagnosed, it isn't customary to measure the insulin to see whether it is actually
+ deficient, before writing a prescription for insulin. People resign themselves to a lifetime of insulin
+ injections, without knowing why their blood sugar is high.
+
+
+ Insulin release is also stimulated by amino acids such as leucine, and insulin stimulates cells to absorb
+ amino acids and to synthesize proteins. Since insulin lowers blood sugar as it disposes of amino acids,
+ eating a large amount of protein without carbohydrate can cause a sharp decrease in blood sugar. This leads
+ to the release of adrenalin and cortisol, which raise the blood sugar. Adrenalin causes fatty acids to be
+ drawn into the blood from fat stores, especially if the liver's glycogen stores are depleted, and cortisol
+ causes tissue protein to be broken down into amino acids, some of which are used in place of carbohydrate.
+ Unsaturated fatty acids, adrenaline, and cortisol cause insulin resistance.
+
+
+
+
+
+
+ "Professional opinion" can be propagated about 10,000 times faster than research can evaluate it, or, as C.
+ H. Spurgeon said, "A lie travels round the world while Truth is putting on her boots."
+
+
+ In the 1970s, dietitians began talking about the value of including "complex carbohydrates" in the diet.
+ Many dietitians (all but one of the Registered Dietitians that I knew of) claimed that starches were more
+ slowly absorbed than sugars, and so should be less disruptive to the blood sugar and insulin levels. People
+ were told to eat whole grains and legumes, and to avoid fruit juices.
+
+
+ These recommendations, and their supporting ideology, are still rampant in the culture of the United States,
+ fostered by the U.S. Department of Agriculture and the American Dietetic Association and the American
+ Diabetes Association and innumerable university departments of home economics, dietetics, or nutrition.
+
+
+ Judging by present and past statements of the American Dietetic Association, I think some kind of
+ institutional brain defect might account for their recommendations. Although the dietetic association now
+ feebly acknowledges that sugars don't raise the blood sugar more quickly than starches do, they can't get
+ away from their absurd old recommendations, which were never scientifically justified: "Eat
+ more starches, such as bread, cereal, and starchy vegetables--6 servings a day or more. Start the day with
+ cold (dry) cereal with nonfat/skim milk or a bagel with one teaspoon of jelly/jam. Put starch center
+ stage--pasta with tomato sauce, baked potato with chili, rice and stir-fried beef and vegetables. Add cooked
+ black beans, corn, or garbanzo beans (chickpeas) to salads or casseroles."
+
+
+
+ The Dietetic Association's association with General Mills, the breakfast cereal empire, (and Kellog,
+ Nabisco, and many other food industry giants) might have something to do with their starchy opinions.
+ Starch-grain embolisms can cause brain damage, but major money can also make people say stupid things.
+
+
+ In an old experiment, a rat was tube-fed ten grams of corn-starch paste, and then anesthetized. Ten minutes
+ after the massive tube feeding, the professor told the students to find how far the starch had moved along
+ the alimentary canal. No trace of the white paste could be found, demonstrating the speed with which starch
+ can be digested and absorbed. The very rapid rise of blood sugar stimulates massive release of insulin, and
+ rapidly converts much of the carbohydrate into fat.
+
+
+ It was this sort of experiment that led to the concept of "glycemic index," that ranks foods according to
+ their ability to raise the blood sugar. David Jenkins, in 1981, knew enough about the old studies of starch
+ digestion to realize that the dietitians had created a dangerous cult around the "complex carbohydrates,"
+ and he did a series of measurements that showed that starch is more "glycemic" than sucrose. But he simply
+ used the amount of increase in blood glucose during the first two hours after ingesting the food sample,
+ compared to that following ingestion of pure glucose, for the comparison, neglecting the physiologically
+ complex facts, all of the processes involved in causing a certain amount of glucose to be present in the
+ blood during a certain time. (Even the taste of sweetness, without swallowing anything, can stimulate the
+ release of glucagon, which raises blood sugar.)
+
+
+ More important than the physiological vacuity of a simple glycemic measurement was the ideology within which
+ the whole issue developed, namely, the idea that diabetes (conceived as chronic hyperglycemia) is caused by
+ eating too much sugar, i.e., chronic hyperglycemia the illness is caused by the recurrent hyperglycemia of
+ sugar gluttony. The experiments of Bernardo Houssay (1947 Nobel laureate) in the 1940s, in which sugar and
+ coconut oil protected against diabetes, followed by Randle's demonstration of the antagonism between fats
+ and glucose assimilation, and the growing recognition that polyunsaturated fatty acids cause insulin
+ resistance and damage the pancreas, have made it clear that the dietetic obsession with sugar in relation to
+ diabetes has been a dangerous diversion that has retarded the understanding of degenerative metabolic
+ diseases.
+
+
+
+ Starting with the insulin industry, a culture of diabetes and sugar has been fabulized and expanded and
+ modified as new commercial industries found ways to profit from it. Seed oils, fish oils, breakfast cereals,
+ soybean products, and other things that were never eaten by any animal in millions of years of evolution
+ have become commonplace as "foods," even as "health foods."
+
+
+ Although many things condition the rate at which blood sugar rises after eating carbohydrates, and affect
+ the way in which blood glucose is metabolized, making the idea of a "glycemic index" highly misleading, it
+ is true that blood sugar and insulin responses to different foods have some meaningful effects on physiology
+ and health.
+
+
+ Starch and glucose efficiently stimulate insulin secretion, and that accelerates the disposition of glucose,
+ activating its conversion to glycogen and fat, as well as its oxidation. Fructose inhibits the
+ stimulation of insulin by glucose, so this means that eating ordinary sugar, sucrose (a disaccharide,
+ consisting of glucose and fructose), in place of starch, will reduce the tendency to store fat.
+ Eating "complex carbohydrates," rather than sugars, is a reasonable way to promote obesity. Eating starch,
+ by increasing insulin and lowering the blood sugar, stimulates the appetite, causing a person to eat more,
+ so the effect on fat production becomes much larger than when equal amounts of sugar and starch are eaten.
+ The obesity itself then becomes an additional physiological factor; the fat cells create something analogous
+ to an inflammatory state. There isn't anything wrong with a high carbohydrate diet, and even a high starch
+ diet isn't necessarily incompatible with good health, but when better foods are available they should be
+ used instead of starches. For example, fruits have many advantages over grains, besides the difference
+ between sugar and starch. Bread and pasta consumption are strongly associated with the occurrence of
+ diabetes, fruit consumption has a strong inverse association.
+
+
+ Although pure fructose and sucrose produce less glycemia than glucose and starch do, the different effects
+ of fruits and grains on the health can't be reduced to their effects on blood sugar.
+
+
+
+ Orange juice and sucrose have a lower glycemic index than starch or whole wheat or white bread, but it is
+ common for dietitians to argue against the use of orange juice, because its index is the same as that of
+ Coca Cola. But, if the glycemic index is very important, to be rational they would have to argue that Coke
+ or orange juice should be substituted for white bread.
+
+
+ After decades of "education" to promote eating starchy foods, obesity is a bigger problem than ever, and
+ more people are dying of diabetes than previously. The age-specific incidence of most cancers is increasing,
+ too, and there is evidence that starch, such as pasta, contributes to breast cancer, and possibly other
+ types of cancer.
+
+
+ The epidemiology would appear to suggest that complex carbohydrates cause diabetes, heart disease, and
+ cancer. If the glycemic index is viewed in terms of the theory that hyperglycemia, by way of
+ "glucotoxicity," causes the destruction of proteins by glycation, which is seen in diabetes and old age,
+ that might seem simple and obvious.
+
+
+
+
+
+
+
+
+
+
+
+ But there are many reasons to question that theory.
+
+
+ Oxidation of sugar is metabolically efficient in many ways, including sparing oxygen consumption. It
+ produces more carbon dioxide than oxidizing fat does, and carbon dioxide has many protective functions,
+ including increasing Krebs cycle activity and inhibiting toxic damage to proteins. The glycation of proteins
+ occurs under stress, when less carbon dioxide is being produced, and the proteins are normally protected by
+ carbon dioxide.
+
+
+ When sugar (or starch) is turned into fat, the fats will be either saturated, or in the series derived from
+ omega -9 monounsaturated fatty acids. When sugar isn't available in the diet, stored glycogen will provide
+ some glucose (usually for a few hours, up to a day), but as that is depleted, protein will be metabolized to
+ provide sugar. If protein is eaten without carbohydrate, it will stimulate insulin secretion, lowering blood
+ sugar and activating the stress response, leading to the secretion of adrenalin, cortisol, growth hormone,
+ prolactin, and other hormones. The adrenalin will mobilize glycogen from the liver, and (along with other
+ hormones) will mobilize fatty acids, mainly from fat cells. Cortisol will activate the conversion of protein
+ to amino acids, and then to fat and sugar, for use as energy. (If the diet doesn't contain enough protein to
+ maintain the essential organs, especially the heart, lungs, and brain, they are supplied with protein from
+ the skeletal muscles. Because of the amino acid composition of the muscle proteins, their destruction
+ stimulates the formation of additional cortisol, to accelerate the movement of amino acids from the less
+ important tissues to the essential ones.)
+
+
+
+ The diabetic condition is similar in many ways to stress, inflammation, and aging, for example in the
+ chronic elevation of free fatty acids, and in various mediators of inflammation, such as tumor necrosis
+ factor (TNF).
+
+
+ Rather than the sustained hyperglycemia which is measured for determining the glycemic index, I think the
+ "diabetogenic" or "carcinogenic" action of starch has to do with the stress reaction that follows the
+ intense stimulation of insulin release. This is most easily seen after a large amount of protein is eaten.
+ Insulin is secreted in response to the amino acids, and besides stimulating cells to take up the amino acids
+ and convert them into protein, the insulin also lowers the blood sugar. This decrease in blood sugar
+ stimulates the formation of many hormones, including cortisol, and under the influence of cortisol both
+ sugar and fat are produced by the breakdown of proteins, including those already forming the tissues of the
+ body. At the same time, adrenalin and several other hormones are causing free fatty acids to appear in the
+ blood.
+
+
+ Since the work of Cushing and Houssay, it has been understood that blood sugar is controlled by antagonistic
+ hormones: Remove the pituitary along with the pancreas, and the lack of insulin doesn't
+ cause hyperglycemia. If something increases cortisol a little, the body can maintain normal blood sugar by
+ secreting more insulin, but that tends to increase cortisol production. A certain degree of glycemia is
+ produced by a particular balance between opposing hormones.
+
+
+ Tryptophan, from dietary protein or from the catabolism of muscles, is turned into serotonin which activates
+ the pituitary stress hormones, increasing cortisol, and intensifying catabolism, which releases more
+ tryptophan. It suppresses thyroid function, which leads to an increased need for the stress hormones.
+ Serotonin impairs glucose oxidation, and contributes to many of the problems associated with diabetes.
+
+
+ "Diabetes" is often the diagnosis, when excess cortisol is the problem. The hormones have traditionally not
+ been measured before diagnosing diabetes and prescribing insulin or other chemical to lower the blood sugar.
+ Some of the worst effects of "diabetes," including retinal damage, are caused or exacerbated by insulin
+ itself.
+
+
+
+ Antiserotonin drugs can sometimes alleviate stress and normalize blood sugar. Simply eating sucrose was
+ recently discovered to restrain the stress hormone system ("A new perspective on glucocorticoid
+ feedback: relation to stress, carbohydrate feeding and feeling better," J Neuroendocrinol
+ 13(9), 2001, KD Laugero).
+
+
+ The free fatty acids released by the stress hormones serve as supplemental fuel, and increase the
+ consumption of oxygen and the production of heat. (This increased oxygen demand is a problem for the heart
+ when it is forced to oxidize fatty acids. [A. Grynberg, 2001]) But if the stored fats happen to be
+ polyunsaturated, they damage the blood vessels and the mitochondria, suppress thyroid function, and cause
+ "glycation" of proteins. They also damage the pancreas, and impair insulin secretion.
+
+
+ A repeated small stress, or overstimulation of insulin secretion, gradually tends to become amplified by the
+ effects of tryptophan and the polyunsaturated fatty acids, with these fats increasing the formation of
+ serotonin, and serotonin increasing the liberation of the fats.
+
+
+ The name, "glycation," indicates the addition of sugar groups to proteins, such as occurs in diabetes and
+ old age, but when tested in a controlled experiment, lipid peroxidation of polyunsaturated fatty
+ acids produces the protein damage about 23 times faster than the simple sugars do
+ (Fu, et al., 1996). And the oxidation of fats rather than glucose means that the proteins won't have as much
+ protective carbon dioxide combined with their reactive nitrogen atoms, so the real difference in the
+ organism is likely to be greater than that seen by Fu, et al.
+
+
+
+ These products of lipid peroxidation, HNE, MDA, acrolein, glyoxal, and other highly reactive aldehydes,
+ damage the mitochondria, reducing the ability to oxidize sugar, and to produce energy and protective carbon
+ dioxide.
+
+
+ Fish oil, which is extremely unstable in the presence of oxygen and metals such as iron, produces
+ some of these dangerous products very rapidly.
+ The polyunsaturated "essential fatty acids" and their products, arachidonic acid and many of the
+ prostaglandin-like materials, also produce them.
+
+
+ When glucose can't be oxidized, for any reason, there is a stress reaction, that mobiles free fatty acids.
+ Drugs that oppose the hormones (such as adrenalin or growth hormone) that liberate free fatty acids have
+ been used to treat diabetes, because lowering free fatty acids can restore glucose oxidation.
+
+
+ Brief exposures to polyunsaturated fatty acids can damage the insulin-secreting cells of the pancreas, and
+ the mitochondria in which oxidative energy production takes place. Prolonged exposure causes progressive
+ damage. Acutely, the free polyunsaturated fatty acids cause capillary permeability to increase, and this can
+ be detected at the beginning of "insulin resistance" or "diabetes." After chronic exposure, the leakiness
+ increases and albumin occurs in the urine, as proteins leak out of the blood vessels. The retina and brain
+ and other organs are damaged by the leaking capillaries.
+
+
+ The blood vessels and other tissues are also damaged by the chronically increased cortisol, and at least in
+ some tissues (the immune system is most sensitive to the interaction) the polyunsaturated fats increase the
+ ability of cortisol to kill the cells.
+
+
+
+ When cells are stressed, they are likely to waste glucose in two ways, turning some of it into lactic acid,
+ and turning some into fatty acids, even while fats are being oxidized, in place of the sugar that is
+ available. Growth hormone and adrenalin, the stress-induced hormones, stimulate the oxidation of fatty
+ acids, as well as their liberation from storage, so the correction of energy metabolism requires the
+ minimization of the stress hormones, and of the free fatty acids. Prolactin, ACTH, and estrogen also cause
+ the shift of metabolism toward the fatty acids.
+
+
+ Sugar and thyroid hormone (T3, triiodothyronine) correct many parts of the problem. The conversion of T4
+ into the active T3 requires glucose, and in diabetes, cells are deprived of glucose. Logically, all
+ diabetics would be functionally hypothyroid. Providing T3 and sugar tends to shift energy metabolism away
+ from the oxidation of fats, back to the oxidation of sugar.
+
+
+ Niacinamide, used in moderate doses, can safely help to restrain the excessive production of free fatty
+ acids, and also helps to limit the wasteful conversion of glucose into fat. There is evidence that diabetics
+ are chronically deficient in niacin. Excess fatty acids in the blood probably divert tryptophan from niacin
+ synthesis into serotonin synthesis.
+
+
+ Sodium, which is lost in hypothyroidism and diabetes, increases cellular energy. Diuretics, that cause loss
+ of sodium, can cause apparent diabetes, with increased glucose and fats in the blood. Thyroid,
+ sodium, and glucose work very closely together to maintain cellular energy and stability.
+
+
+ In Houssay's experiments, sugar, protein, and coconut oil protected mice against developing diabetes. The
+ saturated fats of coconut oil are similar to those we synthesize ourselves from sugar. Saturated fats, and
+ the polyunsaturated fats synthesized by plants, have very different effects on many important physiological
+ processes. In every case I know about, the vegetable polyunsaturated fats have harmful effects on our
+ physiology.
+
+
+
+ For example, they bind to the "receptor" proteins for cortisol, progesterone, and estrogen, and to all of
+ the major proteins related to thyroid function, and to the vesicles that take up nerve transmitter
+ substances, such as glutamic acid.
+
+
+ They allow glutamic acid to injure and kill cells through excessive stimulation; this process is similar to
+ the nerve damage done by cobra venom, and other toxins.
+
+
+ Excess cortisol makes nerve cells more sensitive to excitotoxicity, but the cells are protected if they are
+ provided with an unusually large amount of glucose.
+
+
+ The cells of the thymus gland are very sensitive to damage by stress or cortisol, but they too can be
+ rescued by giving them enough extra glucose to compensate for the cortisol. Polyunsaturated fatty acids have
+ the opposite effect, sensitizing the thymus cells to cortisol. This partly accounts for the
+ immunosuppressive effects of the polyunsaturated fats. (AIDS patients have increased cortisol and
+ polyunsaturated fatty acids in their blood.[E.A. Nunez, 1988.])
+
+
+ Unsaturated fatty acids activate the stress hormones, sugar restrains them.
+
+
+ Simply making animals "deficient" in the unsaturated vegetable oils (which allows them to synthesize their
+ own series of animal polyunsaturated fats, which are very stable), protects them against "autoimmune"
+ diabetes, and against a variety of other "immunological" challenges. The "essential fatty acid" deficiency
+ increases the oxidation of glucose, as it increases the metabolic rate generally.
+
+
+
+ Saturated fats improve the insulin-secreting response to glucose.
+
+
+ The protective effects of sugar, and the harmful effects of excessive fat metabolism, are now being widely
+ recognized, in every field of physiology. The unsaturated vegetable fats, linoleic and linolenic acid and
+ their derivatives, such as arachidonic acid and the long chain fish oils, have excitatory, stress promoting
+ effects, that shift metabolism away from the oxidation of glucose, and finally destroy the respiratory
+ metabolism altogether. Since cell injury and death generally involve an imbalance between excitation and the
+ ability to produce energy, it is significant that the oxidation of unsaturated fatty acids seems to consume
+ energy, lowering cellular ATP (Clejan, et al, 1986).
+
+
+ The bulk of the age-related tissue damage classified as "glycation end-products" (or "advanced glycation
+ end-products," AGE) is produced by decomposition of the polyunsaturated fats, rather than by sugars, and
+ this would be minimized by the protective oxidation of glucose to carbon dioxide.
+
+
+ Protein of the right kind, in the right amount, is essential for reducing stress. Gelatin, with its
+ antiinflammatory amino acid balance, helps to regulate fat metabolism.
+
+
+ Aspirin's antiinflammatory actions are generally important when the polyunsaturated fats are producing
+ inflammatory and degenerative changes, and aspirin prevents many of the problems associated with diabetes,
+ reducing vascular leakiness. It improves mitochondrial respiration (De Cristobal, et al., 2002) and helps to
+ regulate blood sugar and lipids (Yuan, et al., 2001). Aspirin's broad range of beneficial effects is
+ probably analogous to vitamin E's, being proportional to protection against the broad range of toxic effects
+ of the polyunsaturated "essential" fatty acids.
+
+
+ REFERENCES
+
+
+ Diabetes Care 1993 Sep;16(9):1301-5. Metabolic effects of dietary sucrose in type II diabetic
+ subjects. Bantle JP, Swanson JE, Thomas W, Laine DC "CONCLUSIONS--A high sucrose diet did not adversely
+ affect glycemia or lipemia in type II diabetic subjects."
+
+
+ Am J Physiol 1997 Nov;273(5 Pt 1):C1732-8. Glycolysis inhibition by palmitate in renal cells
+ cultured in a two-chamber system. Bolon C, Gauthier C, Simonnet H ""palmitate promoted a
+ long-term decrease in lactate production and sustained excellent cellular growth. After 4 days of contact,
+ decreased glycolysis was maintained even in the absence of carnitine"."
+
+
+ Diabetes 1989 Oct;38(10):1314-9. Effects of fish oil supplementation on glucose and lipid metabolism
+ in NIDDM. Borkman M, Chisholm DJ, Furler SM, Storlien LH, Kraegen EW, Simons LA, Chesterman CN.
+ Garvan "In summary, dietary fish oil supplementation adversely affected glycemic control in NIDDM
+ subjects without producing significant beneficial effects on plasma lipids. The effect of safflower oil
+ supplementation was not significantly different from fish oil,
+ suggesting that the negative effects on glucose metabolism may be related to the extra energy or
+ fat intake." Randomized Controlled Trial
+
+
+
+ Ann Clin Lab Sci 1988 Jul-Aug;18(4):337-43. Effects of peroxidized polyunsaturated fatty acids on
+ mitochondrial function and structure: pathogenetic implications for Reye's syndrome. Brown RE,
+ Bhuvaneswaran C, Brewster M. "Linoleic acid, a polyunsaturated fatty acid, is a constituent of
+ margosa oil which has been implicated as a cause of Reye's syndrome (RS) in infants. Increased
+ concentrations of polyunsaturated fatty acids have been found in sera from patients with RS." Isolated
+ rat liver mitochondria exposed to the peroxidized (but not unperoxidized) methyl esters of
+ linoleic (C18:2) or linolenic (C18:3) acids showed decreases in state 3 and uncoupled respiratory rates and
+ in respiratory control and ADP/O ratios. In addition, they caused mitochondrial swelling as demonstrated
+ spectrophotometrically. Between the two, the peroxidized methyl ester of linolenic acid was more toxic and
+ was capable of inducing high amplitude swelling ultrastructurally similar to that seen in the hepatocytes of
+ RS victims. The ability of rat liver mitochondria to oxidize glutamate was inversely related to the peroxide
+ concentration in the medium."
+
+
+ J Neurochem 1982 Feb;38(2):525-31.
+ Phospholipid degradation and cellular edema induced by free radicals in brain cortical slices.
+
+ Chan PH, Yurko M, Fishman RA. "These data suggest that lipases are activated by free radicals and
+ lipid peroxides in the pathogenesis of cellular swelling."
+
+
+
+ J Neurochem 1988 Apr;50(4):1185-93. Induction of intracellular superoxide radical formation by
+ arachidonic acid and by polyunsaturated fatty acids in primary astrocytic cultures. Chan PH,
+ Chen SF, Yu AC. "Other PUFAs, including linoleic acid, linolenic acid, and docosahexaenoic acid, were also
+ effective in stimulating NBF formation in astrocytes, whereas saturated palmitic acid and monounsaturated
+ oleic acid were ineffective. Similar effects of these PUFAs were observed in malondialdehyde formation in
+ cells and lactic acid accumulation in incubation medium. These data indicate that both membrane integrity
+ and cellular metabolism were perturbed by arachidonic acid and by other PUFAs."
+
+
+ Can J Biochem 1978 Feb;56(2):111-6. Uncoupling activity of endogenous free fatty acids in rat liver
+ mitochondria. Chan SH, Higgins E Jr.
+
+
+ J Neurochem 1980 Oct;35(4):1004-7. Transient formation of superoxide radicals in polyunsaturated
+ fatty acid-induced brain swelling.
+
+ Chan PH, Fishman RA. "The polyunsaturated fatty acids linoleic acid (18:2), linolenic acid (18:3),
+ arachidonic acid (20:4), and docosahexaenoic acid (22:6) caused brain swelling concomitant with increases in
+ superoxide and membrane lipid
+ peroxidation. Palmitic acid (16:0) and oleic acid (18:1) had no such effect." "These in vitro
+ data support the hypothesis that both superoxide radicals and lipid peroxidation are involved in the
+ mechanism of polyunsaturated fatty acid-induced brain edema."
+
+
+
+ Arch Biochem Biophys 1986 May 1;246(2):820-8. Effect of growth hormone on fatty acid oxidation:
+ growth hormone increases the activity of 2,4-dienoyl-CoA reductase in mitochondria.
+ Clejan S, Schulz H. "Rates of respiration supported by polyunsaturated fatty
+ acylcarnitines, in contrast to rates observed with palmitoylcarnitine or oleoylcarnitine, were slightly
+ lower in hypophysectomized rats than in normal rats, but were higher in hypophysectomized rats treated
+ with growth hormone. The effects were most pronounced with docosahexaenoylcarnitine, the substrate with
+ the highest degree of unsaturation.
+ Since uncoupling of mitochondria with 2,4-dinitrophenol resulted in lower rates of
+ docosahexaenoylcarnitine-supported respiration, while substitution of ATP for ADP yielded higher rates, it
+ appears that
+ energy is required for the effective oxidation of polyunsaturated
+ fatty acids. Growth hormone treatment of hypophysectomized rats caused a threefold increase in t`he activity
+ of 2,4-dienoyl-CoA reductase or 4-enoyl-CoA reductase (EC 1.3.1.34) in mitochondria, but not in
+ peroxisomes." "Rates of acetoacetate formation from linolenoylcarnitine, but not from palmitoylcarnitine,
+ were stimulated by glutamate in mitochondria from hypophysectomized rats and hypophysectomized rats treated
+ with growth hormone. All data together lead to the conclusion that the mitochondrial oxidation of
+ highly polyunsaturated fatty acids is limited by the availability of NADPH
+ and the activity of 2,4-dienoyl-CoA reductase which is induced by growth hormone treatment."
+
+
+ V. Coiro, et al., "Low-dose ovine corticotropin-releasing hormone stimulation test in diabetes mellitus with
+ or without neuropathy," Metabolism--Clinical and Experimental 44(4), 538-542, 1995.
+ "...basal and CRH-induced cortisol levels were significantly higher in diabetics than in normal
+ controls." "...even uncomplicated diabetes mellitus is associated with adrenal hyperfunction."
+
+
+ Stroke 2002 Jan;33(1):261-7.
+ Inhibition of glutamate release via recovery of ATP levels accounts for a neuroprotective effect of
+ aspirin in rat cortical neurons exposed to oxygen-glucose deprivation. De Cristobal J, Cardenas
+ A, Lizasoain I, Leza JC, Fernandez-Tome P, Lorenzo P, Moro MA. "Aspirin is preventive against stroke not
+ only because of its antithrombotic properties but also by other direct effects." "Aspirin inhibited
+ OGD-induced neuronal damage at concentrations lower (0.3 mmol/L) than those reported to act via inhibition
+ of the transcription factor nuclear factor-kappaB (which are >1 mmol/L), an effect that correlated with the inhibition caused by aspirin on glutamate release. This effect was shared by
+ sodium salicylate but not by indomethacin, thus excluding the involvement of cyclooxygenase. A
+ pharmacological dissection of the components involved indicated that aspirin selectively inhibits the
+ increase in extracellular glutamate concentration that results from reversal of the glutamate transporter, a
+ component of release that is due to ATP depletion. Moreover, aspirin-afforded neuroprotection occurred in
+ parallel with a lesser decrease in ATP levels after OGD. Aspirin elevated ATP levels not only in
+ intact cortical neurons but also in isolated brain mitochondria, an effect concomitant with an increase
+ in NADH-dependent respiration by brain submitochondrial particles." "Taken together, our
+ present findings show a novel mechanism for the neuroprotective effects of aspirin, which takes place at
+ concentrations in the antithrombotic-analgesic range, useful in the management of patients with high risk of
+ ischemic events."
+
+
+
+ Diabetes 2002 Jun;51(6):1825-33. The composition of dietary fat directly influences
+ glucose-stimulated insulin secretion in rats. Dobbins RL, Szczepaniak LS, Myhill J, Tamura Y,
+ Uchino H, Giacca A, McGarry JD. "Insulin responses during hyperglycemic clamps were augmented by
+ saturated but not unsaturated fat (580 +/- 25, 325 +/- 30, and 380 +/- 50 pmol x l(-1) x min(-1) in
+ Lard, Soy, and Low-Fat groups, respectively)."
+ "These data indicate that prolonged exposure to saturated fat enhances GSIS (but this does not entirely
+ compensate for insulin resistance), whereas unsaturated fat, given in the diet or by infusion, impairs
+ GSIS."
+
+
+ C. Douillet and M. Ciavatti, "Effect of vitamin E treatment on tissue fatty acids and cholesterol
+ content in experimental diabetes,"
+ J. Nutr. Biochem. 6(6), 319-326, 1995.
+ "Diabetes induced a decrease of monounsaturated fatty acids and particularly palmitoleic acid in all
+ studied tissues: liver, aorta, plasma." "C18:3 n-6 and C20:4 n-6 were increased by diabetes."
+
+
+
+ Diabetologia 1992 Feb;35(2):165-72. Long-term effects of linoleic-acid-enriched diet on albuminuria
+ and lipid levels in type 1 (insulin-dependent) diabetic patients with elevated urinary albumin
+ excretion. Dullaart RP, Beusekamp BJ, Meijer S, Hoogenberg K, van Doormaal JJ, Sluiter WJ. "We
+ conducted a 2-year prospective randomised study to investigate the effects of a linoleic-acid-enriched diet
+ on albuminuria and lipid levels in Type 1 (insulin-dependent) diabetic patients with elevated urinary
+ albumin excretion (overnight urinary albumin excretion rate between 10 and 200 micrograms/min)." "Clinical
+ characteristics,
+ albuminuria, blood pressure, glomerular filtration rate, metabolic control and dietary composition were
+ similar in the two groups at baseline. In the high linoleic acid diet group, linoleic intake rose from 7 +/-
+ 4 to 11 +/- 2 energy % and polyunsaturated:saturated fatty acids ratio rose from 0.60 +/- 0.28 to 0.96 +/-
+ 0.16 (p less than 0.001 compared to usual diet group). The median increase albuminuria was 58% (95%
+ confidence interval, 13 to 109) during the first year (p less than 0.02) and 55% (95% confidence interval,
+ 11 to 127) (p less than 0.01) during the second year."
+
+
+ J Biol Chem 1996 Apr 26;271(17):9982-6. The advanced glycation end product,
+ Nepsilon-(carboxymethyl)lysine, is a product of both lipid peroxidation and glycoxidation
+ reactions.
+ Fu MX, Requena JR, Jenkins AJ, Lyons TJ, Baynes JW, Thorpe SR. Nepsilon-(Carboxymethyl)lysine (CML) is an
+ advanced glycation end product formed on protein by combined nonenzymatic glycation and oxidation
+ (glycoxidation) reactions. We now report that CML is also formed during metal-catalyzed oxidation of
+ polyunsaturated fatty acids in the presence of protein. During copper-catalyzed oxidation in vitro, the CML
+ content of low density lipoprotein increased in concert with conjugated dienes but was independent of the
+ presence
+ of the Amadori compound, fructoselysine, on the protein. CML was also formed in a time-dependent manner
+ in RNase incubated under aerobic conditions in phosphate buffer containing arachidonate or linoleate;
+ only trace amounts of CML were formed from oleate. After 6 days of incubation the yield of CML in RNase
+ from arachidonate was approximately 0.7 mmol/mol lysine compared with only 0.03 mmol/mol lysine for
+ protein incubated under the same conditions with glucose. Glyoxal, a known precursor of CML,
+ was also formed during incubation of Rnase with arachidonate. These results suggest that lipid peroxidation,
+ as well as glycoxidation, may be an important source of CML in tissue proteins in vivo and that CML may be a
+ general marker of oxidative stress and long term damage to protein in aging, atherosclerosis, and diabetes.
+
+
+
+ J Nutr 2000 Oct;130(10):2503-7. A high carbohydrate versus a high monounsaturated fatty acid diet
+ lowers the atherogenic potential of big VLDL particles in patients with type 1 diabetes.
+ Georgopoulos A, Bantle JP, Noutsou M, Hoover HA. "A high (25%) monounsaturated fatty acid (Mono) diet and a
+ high (61%) carbohydrate (CHO) diet were provided for 4 wk in a randomized crossover design to 19
+ normolipidemic, nonobese patients with type 1 diabetes. The two diets were matched for protein,
+ polyunsaturated/saturated fatty acids, cholesterol and fiber content." "We conclude that a high CHO diet
+ might be preferable to a high Mono diet, on the basis of the premise that more big VLDL particles could
+ increase the atherosclerotic risk in patients with diabetes."
+
+
+ J. Girard, "Role of free fatty acids in insulin resistance of subjects with non-insulin-dependent diabetes,"
+ Diabetes Metab. 21(2), 79-88, 1995. "Studies performed in the rat suggest that impaired
+ glucose-induced insulin secretion could also be related to chronic exposure of pancreatic beta cells to
+ elevated plasma free fatty acid levels."
+
+
+ Ann Intern Med 1988 May;108(5):663-8. Adverse metabolic effect of omega-3 fatty acids in
+ non-insulin-dependent diabetes mellitus.
+
+
+
but unchanged glucose disposal rates. Caution should be used when recommending
+ omega-3 fatty acids in type II diabetic persons."
+
+
+ A. Golay, et al., "Effect of lipid oxidation on the regulation of glucose utilization in obese patients,"
+ Acta Diabetologica 32(1), 44-48, 1995. [Free fatty acids strongly and quickly depress the ability to
+ oxidize or store glucose.]
+
+
+ Biol Neonate 1985;47(6):343-9. Increased maternal-fetal transport of fat in diabetes assessed by
+ polyunsaturated fatty acid content in fetal lipids.
+ Goldstein R, Levy E, Shafrir E. The distribution of fatty acids was determined by gas-liquid chromatography
+ in total lipid and triglyceride fraction of extracts of several tissues of streptozotocin-diabetic rats and
+ their fetuses on day 20 of pregnancy. In maternal rats, diabetes did not significantly affect fatty acid
+ distribution apart from small changes in the relative content of linoleate in adipose tissue and liver. In
+ the placenta, the fetal carcass and the fetal liver the
+ triglyceride content increased approximately 2-fold as a result of maternal diabetes, in association
+ with the elevation in triglycerides and free fatty
+
+ acids in the maternal circulation. A pronounced increase in the relative content
+ of linoleate was recorded in the total lipid and triglyceride extracts of placenta (35 and 59%), fetal
+ carcass (56 and 66%) and fetal liver (100 and 205%). Small increases in arachidonate proportion were
+ also seen in some fetal tissues. The large increase in fetal hepatic linoleate indicates that
+ this tissue is an important uptake target of maternal lipids transported in excess into the
+ fetus. The results confirm the previous observations on increased transplacental fat passage in diabetes by
+ demonstrating that the increment in the essential fatty acid, linoleate, parallels the diabetes-induced
+ triglyceride accumulation in the fetoplacental unit.
+
+
+ A. Gomes, et al., "Anti-hyperglycemic effect of black tea (Camellia sinensis) in rat," J. of
+ Ethnopharmacology 45(3), 223-226, 1995.
+ It "was found to possess both preventive and curative effects on experimentally produced diabetes in
+ rats."
+
+
+ J Endocrinol 2002 Apr;173(1):73-80. Acute effects of fatty acids on insulin secretion from rat and
+ human islets of Langerhans. Gravena C, Mathias PC, Ashcroft SJ. "Long-chain fatty
+ acids (palmitate and stearate) were more effective than medium-chain (octanoate). Saturated fatty acids
+ (palmitate, stearate) were more effective than unsaturated (palmitoleate, linoleate, elaidate)."
+
+
+
+ Diabetes Metab 2001 Nov;27(5 Pt 2):S12-9. [Modifications in myocardial energy metabolism in diabetic
+ patients]] [Article in French] Grynberg A. "Because FA is the main heart fuel (although
+ the most expensive one in oxygen, and prompt to induce deleterious effects), this process is based on a
+ balanced fatty acid (FA) metabolism. Several pathological situations are associated with an
+ accumulation of FA or derivatives, or with an excessive b-oxidation. The diabetic cardiomyocyte is
+ characterised by an over consumption of FA. The control of the FA/glucose balance clearly appears as a new
+ strategy for cytoprotection, particularly in diabetes and requires a reduced FA contribution to ATP
+ production. Cardiac myocytes can control FA mitochondrial entry, but display weak ability to control FA
+ uptake, thus the fate of non beta-oxidized FA appear as a new impairment for the cell." "Sudden death,
+ hypercatecholaminemia, diabetes and heart failure have been associated with an altered PUFA content in
+ cardiac membranes."
+
+
+ Diabetologia 1996 Mar;39(3):251-5. Acceleration of experimental diabetic retinopathy in the rat by
+ omega-3 fatty Acids. Hammes HP, Weiss A, Fuhrer D, Kramer HJ, Papavassilis C, Grimminger F.
+ Omega-3 fatty acids exert several important biological effects on factors that may predispose to diabetic
+ retinopathy. Potential pathogenetic mechanisms include platelet dysfunction, altered eicosanoid production,
+ increased blood viscosity in association with impaired cell deformability and pathologic
+ leucocyte/endothelium interaction. Therefore, we tested whether a 6-month administration of fish oil (750 mg
+ Maxepa, 5 times per week), containing 14% eicosapentaenoic acid (EPA) and 10% docosahexaenic acid, could
+ inhibit the development of experimental retinopathy of the streptozotocin-diabetic rat. The efficiency of
+ fish oil supplementation was evaluated by measuring EPA concentrations in total, plasma and membrane fatty
+ acids and by measuring the generation of lipid mediators (leukotrienes and thromboxanes). Retinal digest
+ preparations were quantitatively analysed for pericyte loss, and the formation of acellular capillaries.
+ Omega-3 fatty acid administration to diabetic rats resulted in a twofold increase of EPA 20:5 in total fatty
+ acids, and a reduction of the thromboxane ratio from 600 (untreated diabetic rats) to 50 (treated diabetic
+ rats). Despite these biochemical changes, diabetes-associated pericyte loss remained unaffected and the
+ formation of acellular, occluded capillaries was increased by 75% in the fish oil treated diabetic group
+ (115.1 +/- 26.8; untreated diabetic 65.2 +/- 15.0 acellular capillary segments/mm2 of retinal area). We
+ conclude from this study that dietary fish oil supplementation may be harmful for the diabetic
+ microvasculature in the retina.
+
+
+ Y. Hattori, et al., "Phorbol esters elicit Ca++-dependent delayed contractions in diabetic rat aorta," Eur.
+ J. Pharmacol. 279(1), 51-58, 1995. [Diabetic tissue is more responsive to activation of protein
+ kinase C by phorbol esters.]
+
+
+
+ Nutr Metab 1975;18(1):41-8. Adipose tissue metabolism in essential fatty acid deficienty. Effects of
+ prostaglandin e1, epinephrine, and ACTH.
+ Hazinski TA, Barr M, Hertelendy F. In an effort to better define some of the metabolic changes that
+ accompany essential fatty acid deficiency (EFAD), we studied glucose metabolism in adipose tissue of EFAD
+ and normal mice under basal conditions and in the presence of prostaglandin E1 (PGE1), epinephrine, and
+ ACTH1-18. Isolated fat cells were incubated in Krebs-Ringer bicarbonate medium containing glucose 1(-14C) or
+ 6(-14C), and the incorporation of radioactive carbon into CO2, total fat, fatty acids, and
+ glyceride-glycerol was determined. It was found that EFAD increased glucose uptake over controls
+ which could be attributed to increased oxidation to CO2 and fatty acid synthesis. The contribution of
+ the pentose cycle to glucose oxidation was 50-80% higher in EFAD adipocytes as compared to controls.
+ ACTH1-18 (0.1 mug/ml) suppressed this by 18 and 30% in the control and EFAD groups,
+ respectively, while epinephrine decreased pentose cycle activity by 83 and 55% in the two groups,
+ respectively. PGE1 alone had no significant effect, but in combination with epinephrine it abolished the
+ inhibitory action of the catecholamine in both groups."
+
+
+ J Neurosci Res 1989 Oct;24(2):247-50. Brain mitochondrial swelling induced by arachidonic acid and
+ other long chain free fatty acids. Hillered L, Chan PH. "Polyunsaturated fatty acids
+ (PUFAs), arachidonic acid in particular, are well known, potent inducers of edema in the brain, while
+ monounsaturated and saturated long chain fatty acids do not possess this quality."
+ "ATP-MgCl2 both prevented and reversed this swelling, while binding of the 20:4 by the addition of
+ bovine serum albumin could only prevent but not reverse the swelling." "Moreover, reversal of the
+ swelling occurred without recovery of respiratory function."
+
+
+
+
+ J Neurosci Res 1988 Aug;20(4):451-6.
+ Role of arachidonic acid and other free fatty acids in mitochondrial dysfunction in brain ischemia.
+
+ Hillered L, Chan PH.
+
+
+ B. A. Houssay and C. Martinez, "Experimental diabetes and diet,"
+ Science 105, 548-549, 1947. [Mortality was zero on the high coconut oil diet, 100% on the high lard
+ diet. It was 90% on the low protein diet, and 33% on the high protein diet. With a combination of
+ coconut oil and lard, 20%.]
+
+
+ B. A. Houssay, et al., "Accion de la administracion prolongada de glucosa sobre la diabetes de la
+ rata," Rev. Soc. argent. de biol. 23, 288-293, 1947.
+
+
+
+ S. Ikemoto, et al., "High fat diet-induced hyperglycemia: Prevention by low level expression of a
+ glucose transporter (GLUT4) minigene in transgenic mice," Proc. Nat. Acad. Sci. USA 92(8),
+ 3096-3099, 1995.
+ "...mice fed a high-fat (safflower oil) diet develop defective glycemic control, hyperglycemia, and
+ obesity."
+
+
+ M. Inaba, et al., "Influence of high glucose on 1,25-dihydroxyvitamin D-3-induced effect on human
+ osteoblast-like MG-63 cells," J. Bone Miner. Res. 10(7), 1050-1056, 1995.
+
+
+ J. S. Jensen, et al., "Microalbuminuria reflects a generalized transvascular albumin leakiness in
+ clinically healthy subjects,"
+
+ Clin. Sci. 88(6), 629-633, 1995.
+
+
+ J Am Geriatr Soc 1984 May;32(5):375-9.
+ Low triiodothyronine and raised reverse triiodothyronine levels in patients over fifty years of age who
+ have type II diabetes mellitus: influence of metabolic control, not age. Kabadi UM,
+ Premachandra BN. "Several studies have demonstrated that the uncontrolled diabetic state in both type I as
+ well as type II diabetes mellitus is characterized by altered thyroid hormone metabolism, which results in
+ the
+ lowering of serum triiodothyronine (T3) levels and a reciprocal elevation of T3 (rT3) levels."
+
+ "Serum T3 levels declined and rT3 levels rose in the diabetic patients with worsening of the metabolic
+ control."
+
+
+ Metabolism 1989 Mar;38(3):278-81. The effect of fatty acids on the vulnerability of lymphocytes to
+ cortisol. Klein A, Bruser B, Malkin A. "We have shown previously that cortisol-sensitive
+ lymphocytes (thymocytes) have a much lower capacity than cortisol-resistant cells to catabolize cortisol and
+ that linoleic acid inhibits the catabolism of cortisol by lymphocytes and modulates the sensitivity
+ of lymphocytes to cortisol." "Measuring the effect of fatty acids on cortisol catabolism by
+ lymphocytes indicated that the polyunsaturated fatty acids, linoleate, arachidonate, and
+ eicosapentaenoic, inhibit cortisol catabolism by lymphocytes." "Examining the effect of fatty acids on
+ the vulnerability of lymphocytes to cortisol, we noted that saturated fatty acids had no significant
+ effect, whereas the aforementioned polyunsaturated fatty acids make lymphocytes more sensitive to
+ cortisol."
+
+
+
+ Jpn J Pharmacol 1978 Apr;28(2):277-87. Relationship between cerebral energy failure and free fatty
+ acid accumulation following prolonged brain ischemia.
+ Kuwashima J, Nakamura K, Fujitani B, Kadokawa T, Yoshida K, Shimizu M. "Mitochondria isolated from the
+ ischemic brain showed an impairment of oxidative phosphorylation. The ischemic
+ brain was also characterized by remarkable accumulation of free fatty acids known to have properties as
+ an uncoupling factor." "These results indicate that cerebral energy failure in the ischemic brain is
+ related to the accumulation of free fatty acids, which are derived from endogenous brain
+ lipids."
+
+
+ Probl Endokrinol (Mosk) 1992 Nov-Dec; 38(6):53-4. [Effect of protein content in rat diet on
+ water-soluble vitamin metabolism in streptozotocin-induced diabetes]
+ [Article in Russian] Kodentsova VM, Sadykova RE, Dreval' AV, Vrzhesinskaia OA, Sokol'nikov AA,
+ Beketova NA. Water-soluble group B vitamins metabolism was studied over the course of streptozotocin-induced
+ diabetes mellitus in rats fed semisynthetic isocaloric diets containing 18 and 50% of protein. A
+ high-protein diet in diabetes mellitus does not influence riboflavin metabolism disordered in this disease
+ but reduced 4-pyridoxyl acid excretion to the level characteristic of healthy animals. The observed trend to
+ an increase of liver nicotinamide coenzymes levels and of 1-methylnicotinamide urinary excretion reflects
+ increased niacin synthesis from
+ the diet protein tryptophan, for niacin level is reduced in diabetes.
+
+
+ M. Kusunoki, et al., "Amelioration of high fat feeding-induced insulin resistance in skeletal muscle
+ with the antiglucocorticoid RU486,"
+
+
+ Diabetes 44(6), 718-720, 1995. "These results suggest that glucocorticoids play, in a
+ tissue-specific manner, a role in the maintenance and/or production of insulin resistance produced by
+ high-fat feeding."
+
+
+ J Neuroendocrinol 2001 Sep;13(9):827-35. A new perspective on glucocorticoid feedback: relation to
+ stress, carbohydrate feeding and feeling better.
+ Laugero KD. "In this review, I discuss findings that have led us to view glucocorticoid feedback in
+ the HPA axis in a new light. Much of what has precipitated this view comes from a very surprising finding in
+ our laboratory; sucrose ingestion normalizes feeding, energy balance and central corticotropin releasing
+ factor expression in adrenalectomized (ADX) rats." "Taken together, recent findings of the well-known
+ importance of glucocorticoids to feeding and energy balance, and the modulatory actions of carbohydrate
+ ingestion on both basal and stress-induced activity in the HPA axis, strongly suggest that many metabolic
+ (e.g. obesity) and psychological (e.g. depression) pathologies, which often present together and have been
+ associated with stress and HPA dysregulation, might, in part, be understood in light of our new view of
+ glucocorticoid feedback."
+
+
+ Endocrinology 2001 Jul;142(7):2796-804. Sucrose ingestion normalizes central expression of
+ corticotropin-releasing-factor messenger ribonucleic acid and energy balance in adrenalectomized rats: a
+ glucocorticoid-metabolic-brain axis?
+ Laugero KD, Bell ME, Bhatnagar S, Soriano L, Dallman MF. "Both CRF and norepinephrine (NE) inhibit food
+ intake and stimulate ACTH secretion and sympathetic outflow. CRF also increases anxiety; NE increases
+ attention and cortical arousal. Adrenalectomy (ADX) changes CRF and NE activity in brain, increases ACTH
+ secretion and sympathetic outflow and reduces food intake and weight gain; all of these effects are
+ corrected by administration of adrenal steroids. Unexpectedly, we recently found that ADX rats drinking
+ sucrose, but not saccharin, also have normal caloric intake, metabolism, and ACTH." "Voluntary
+ ingestion of sucrose restores CRF and dopamine-beta-hydroxylase messenger RNA expression in brain, food
+ intake, and caloric efficiency and fat deposition, circulating triglyceride, leptin, and insulin to
+ normal."
+
+
+ A. Lazarow, "Protection against alloxan diabetes," Anat. Rec. 97, 353, 1947.
+
+
+
+ A. Lazarow, "Protective effect of glutathione and cysteine against alloxan diabetes in the rat," Proc. Soc.
+ Exp. Biol. & Med. 61, 441-447, 1946. [While certain doses of cysteine, glutathione, and
+ thioglycolic acid completely prevented alloxan diabetes, it was interesting that all of the rats
+ receiving ascorbic acid became diabetic. To me, this argues for the free radical cause of diabetes,
+ rather than just the sulfhydryl oxidation. Lazarow suggested that succinic dehydrogenase, and various
+ other sulfhydryl enzymes, including those involved in fatty acid oxidation, might be involved.]
+
+
+ Minerva Endocrinol 1990 Oct-Dec;15(4):273-7.
+ [Postprandial thermogenesis and obesity: effects of glucose and fructose].
+ [Article in Italian] Macor C, De Palo C, Vettor R, Sicolo N, De Palo E, Federspil G. "Energy expenditure was
+ calculated both in basal conditions and during the test (resting metabolic rate: RMR) using indirect
+ calorimetry expressed per kg of lean weight, as assessed using bioimpedance measurement techniques. Blood
+ samples were collected to assay glycemia and insulinemia. Results show that increased RMR induced by glucose
+ was significantly reduced in the group of obese subjects compared to controls. In the same group of
+ obese subjects, RMR was found to be significantly higher following fructose in comparison to the glucose
+ response but did not differ from that in controls. Data confirm the existence of reduced
+ thermogenesis in obese subjects induced by glucose. The fact that this phenomenon was not recorded in the
+ same subjects following the fructose tolerance test, whose metabolism is insulin-independent, supports the
+ hypothesis that reduced glucose-induced thermogenesis in obese subjects may depend on insulin resistance."
+
+
+
+ Diabetes Care 2000 Oct;23(10):1472-7. Dietary unsaturated fatty acids in type 2 diabetes: higher
+ levels of postprandial lipoprotein on a linoleic acid-rich sunflower oil diet compared with an oleic
+ acid-rich olive oil diet. Madigan C, Ryan M, Owens D, Collins P, Tomkin GH.
+
+
+ Proc Natl Acad Sci U S A 1990 Nov;87(22):8845-9. Incorporation of marine lipids into mitochondrial
+ membranes increases susceptibility to damage by calcium and reactive oxygen species: evidence for
+ enhanced activation of phospholipase A2 in mitochondria enriched with n-3 fatty Acids.
+ Malis CD, Weber PC, Leaf A, Bonventre JV. "Mitochondrial site 1 (NADH coenzyme Q reductase) activity was
+ reduced to 45 and 85% of control values in fish-oil- and beef-tallow-fed groups, respectively. Exposure to Ca2+ and reactive oxygen species enhance the release of polyunsaturated fatty acids enriched at
+ the sn-2 position of phospholipids from mitochondria of fish-oil-fed rats when compared with similarly
+ treated mitochondria of beef-tallow-fed rats." "Phospholipase A2 activity and
+ mitochondrial damage are enhanced when mitochondrial membranes are enriched with n-3 fatty
+ acids."
+
+
+ FEBS Lett 1998 Oct 16:437(1-2):24-8. Generation of protein carbonyls by glycoxidation and
+ lipoxidation reactions with autoxidation products of ascorbic acid and polyunsaturated fatty acids.
+
+
+ Miyata T, Inagi R, Asahi K, Yamada Y, Horie K, Sakai H, Uchida K, Kurokawa K. "In vitro incubation of
+ proteins with ascorbic acid accelerated the production of protein carbonyls as well as CML and pentosidine,
+ and incubation with arachidonate accelerated the production of protein carbonyls as well as CML, MDA, and
+ HNE. By contrast, incubation of proteins with glucose resulted in the production of CML and pentosidine, but
+ not protein carbonyls." "The present study suggests that ascorbate and polyunsaturated fatty acids,
+ but not glucose, represent potential sources of protein carbonyls, and that both the glycoxidation and
+ lipoxidation reactions contribute to protein carbonyl formation in aging and various diseases."
+
+
+ Chem Phys Lipids 1996 Jan 25;79(1):47-53. Previously unknown aldehydic lipid peroxidation compounds
+ of arachidonic acid.
+
+ Mlakar A, Spiteller G. Lehrstuhl fr Organische Chemie I, "Arachidonic acid was oxidized by iron ascorbate."
+ "The main aldehydic lipid peroxidation product was found to be the well-known 4-hydroxy-2-nonenal
+ (HNE), but 2-hydroxy heptanal (HH) -- a previously unknown lipid peroxidation product of arachidonic
+ acid -- was detected to be nearly equally abundant. Malondialdehyde (MDA), glyoxal and
+ 2-hydroxy-4-decenal (HDE) were detected to be produced in up to 100 times lower amounts compared to
+ HNE.". . . . "Since this and analogous hydroxy acids (LOHs) are the main biological
+ degradation
+ products of hydroperoxides of unsaturated acids (LOOHs) their further peroxidation seems to be a main
+ source of toxic aldehydes."
+
+
+ J Clin Endocrinol Metab 2000 Dec;85(12):4515-9. Acute fructose administration decreases the glycemic
+ response to an oral glucose tolerance test in normal adults. Moore MC, Cherrington AD, Mann SL,
+ Davis SN. "In animal models, a small (catalytic) dose of fructose administered with glucose decreases the
+ glycemic response to the glucose load." "In conclusion, low dose fructose improves the glycemic
+ response to an oral glucose load in normal adults without significantly enhancing the insulin or
+ triglyceride response. Fructose appears most effective in those normal individuals who have the poorest
+ glucose tolerance."
+
+
+
+ Tumour Biol 1988;9(5):225-32. Modulation of cell-mediated immune response by steroids and free fatty
+ acids in AIDS patients: a critical survey.
+ Nunez EA. "The overall data presented in this review show that cortisol and free fatty acids, in
+ particular long-chain polyunsaturated fatty acids, each have immunoinhibitory properties on
+ lymphoblastic transformation of certain T lymphocytes. This effect is enhanced when the two factors are
+ associated. These data could explain in part the immunosuppression observed in acquired immunodeficiency
+ syndrome (AIDS) patients where enhanced concentrations of cortisol and polyunsaturated fatty acids
+ have been observed." "These new weapons could be the administration of diets or treatments
+ (liposomes) modifying the lipid profile of circulating cells and/or viruses and the utilization of hormonal
+ therapy in AIDS and in some types of cancer which often present a biologic picture similar to that of AIDS."
+
+
+ Diabetes Care 1984 Sep-Oct;7(5):465-70. Effect of protein ingestion on the glucose and insulin
+ response to a standardized oral glucose load.
+ Nuttall FQ, Mooradian AD, Gannon MC, Billington C, Krezowski P. "The plasma glucose area above the baseline
+ following a glucose meal was reduced 34% when protein was given with the glucose." "The insulin area
+ following glucose was only modestly greater than with a protein meal (97 +/- 35, 83 +/- 19 microU X h/ml,
+ respectively)." "When various amounts of protein were given with 50 g glucose, the insulin area response was
+ essentially first order. Subsequently, subjects were given 50 g glucose or 50 g glucose with 50 g protein as
+ two meals 4 h apart in random sequence. The insulin areas were not significantly different for each meal but
+ were higher when protein + glucose was given. After the second glucose meal the plasma glucose area was 33%
+ less than after the first meal. Following the second glucose + protein meal the plasma glucose area was
+ markedly reduced, being only 7% as large as after the first meal. These data indicate that protein
+ given with glucose will increase insulin secretion and reduce the plasma glucose rise in at least some
+ type II diabetic persons." Randomized Controlled Trial
+
+
+
+ Biochem J 1985 Sep 1;230(2):329-37. Inhibitory effects of some long-chain unsaturated fatty acids on
+ mitochondrial beta-oxidation. Effects of streptozotocin-induced diabetes on mitochondrial beta-oxidation
+ of polyunsaturated fatty acids. Osmundsen H, Bjornstad K.
+ "Evidence showing that some unsaturated fatty acids, and in particular docosahexaenoic acid, can be
+ powerful inhibitors of mitochondrial beta-oxidation is presented. This inhibitory property is, however,
+ also observed with the cis- and trans-isomers of the C18:1(16) acid. Hence it is probably the position
+ of the double bond(s), and not the degree of unsaturation, which confers the inhibitory property. It is
+ suggested that the inhibitory effect is caused by accumulation of 2,4-di- or 2,4,7-tri-enoyl-CoA esters
+ in the mitochondrial matrix."
+
+
+
+ Free Radic Biol Med 1999 Oct;27(7-8):901-10. Thyroid status modulates glycoxidative and lipoxidative
+ modification of tissue Proteins.
+
+ Pamplona R, Portero-Otin M, Ruiz C, Bellmunt MJ, Requena JR, Thorpe SR, Baynes JW, Romero M, Lopez-Torres M,
+ Barja G. Steady state protein modification by carbonyl compounds is related to the rate of carbonyl adduct
+ formation and the half-life of the protein. Thyroid hormones are physiologic modulators of both
+ tissue oxidative stress and protein degradation.
+ The levels of the glycation product
+ N(epsilon)-fructoselysine (FL) and those of the oxidation products,
+
+ N(epsilon)-(carboxymethyl)lysine (CML) and malondialdehyde-lysine
+ (MDA-lys), identified by GC/MS in liver proteins, decreased significantly in hyperthyroid
+ rats, as well as (less acutely) in hypothyroid animals. Immunoblotting of liver proteins for
+ advanced glycation end-products (AGE) is in agreement with the results obtained by GC/MS. Cytosolic
+ proteolytic activity against carboxymethylated foreign proteins measured in vitro was significantly
+ increased in hypo- and hyperthyroidism. Oxidative damage to DNA, estimated as
+ 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxodG), did not show significant differences between groups. The
+ results suggests that the steady state levels of these markers depend on the levels of thyroid hormones,
+ presumably through their
+ combined effects on the rates of protein degradation and oxidative stress, whereas DNA is more
+ protected from oxidative damage.
+
+
+ Metabolism 1999 Mar;48(3):406-9. The blood vessel, linchpin of diabetic lesions.
+
+ Plante GE, Alfred J, Chakir M. "The morbidity and mortality associated with diabetes mellitus are
+ essentially related to the vascular lesions that develop over time in this condition. Both the
+ macrocirculation and microcirculation are involved, and as a consequence, vital organs such as the brain,
+ retina, heart, and kidney and the limbs become damaged." "Changes in the structure of conduit arteries,
+ partly responsible for the alteration in compliance characteristics, could well be related to the way these
+ arteries are fed by the vasa vasorum system." "Preliminary results indicate that the size of terminal
+ arterioles of the vasa vasorum (increased diameter) and the capillary permeability to albumin (markedly
+ enhanced) in this specialized network are profoundly affected in the thoracic aorta obtained from diabetic
+ animals. Albumin extravasation into the interstitial fluid compartment of the aorta is likely to lead to
+ structural and physicochemical changes: in fact, removal of interstitial macromolecules via lymphatic
+ drainage is poor in the blood vessel wall of large arteries."
+
+
+ Metabolism 2001 Dec;50(12):1472-8.
+ Serum phospholipid fatty acid composition and insulin action in type 2 diabetic patients.
+ Pelikanova T, Kazdova L, Chvojkova S, Base J. "Increased contents of highly unsaturated n-6
+ family FA (P <.01), arachidonic acid in particular . . . were found in all groups of diabetics
+ compared with HS [healthy subjects], while lower levels of linoleic acid were seen in DMN (P
+ <.001) and DMH (P <.05). The contents of saturated FA and monounsaturated FA were comparable in HS,
+ DMN, and DMD."
+
+
+ J Clin Invest 2002 Mar;109(6):805-15. Acute intensive insulin therapy exacerbates diabetic
+ blood-retinal barrier breakdown via hypoxia-inducible factor-1alpha and VEGF. Poulaki V, Qin W,
+ Joussen AM, Hurlbut P, Wiegand SJ, Rudge J, Yancopoulos GD, Adamis AP. "Here we demonstrate that acute
+ intensive insulin therapy markedly increases VEGF mRNA and protein levels in the retinae of diabetic rats."
+ "Blood-retinal barrier breakdown is markedly increased with acute intensive insulin therapy. . . ." "To our knowledge, these data are the first to identify a specific mechanism for the transient worsening of
+ diabetic retinopathy, specifically blood-retinal barrier breakdown, that follows the institution of
+ intensive insulin therapy."
+
+
+
+ Acta Endocrinol (Copenh) 1992 Apr;126(4):378-80. Lipid peroxidation in early experimental diabetes
+ in rats: effects of diabetes and insulin.
+ Rungby J, Flyvbjerg A, Andersen HB, Nyborg K. "In the kidney, lipid
+ peroxidation was increased after one week of diabetes; insulin treatment reduced the level of lipid
+ peroxidation to levels lower than seen in controls. In the liver, diabetes caused an increased lipid
+ peroxidation, which could be reversed by insulin; no additional effect of insulin was found. In heart
+ and pancreas no effects of diabetes or insulin were demonstrated. The present paper provides
+ evidence that lipid peroxidation is increased in the early stages of
+ experimental diabetes and is reversible by insulin treatment. Hyperinsulinaemia may, in itself,
+ counteract lipid peroxidation in kidney."
+
+
+ Br J Nutr 1997 Sep;78(3):459-67. Influence of dietary protein and fat on serum lipids and metabolism
+ of essential fatty acids in rats. Ratnayake WM, Sarwar G, Laffey P. A "In general, the
+ concentrations of serum triacylglycerols and
+ total cholesterol and liver phospholipid levels of arachidonic acid (AA) and docosahexaenoic acid (DHA)
+ were higher in rats fed on casein diets compared with those fed on the gelatin diets. These effects were
+ more pronounced in rats fed on the high-casein (300 g/kg)-high-fat (150 g/kg) diet. Gelatin was hypocholesterolaemic and also suppressed the liver phospholipid levels of AA and DHA (reported
+ for the first time). The difference in the amino acid composition between casein and gelatin
+ may be responsible for the observed effects. Casein contains higher levels of glutamic acid, methionine,
+ phenylalanine and tyrosine, while gelatin contains higher levels of arginine, glycine and hydroxyproline."
+
+
+
+ Br Med J 1979 Jun 30;1(6180):1753-6. Improved glucose control in maturity-onset diabetes treated
+ with high-carbohydrate-modified fat diet. Simpson RW, Mann JI, Eaton J, Moore RA, Carter R,
+ Hockaday TD. "Fourteen patients with established maturity-onset diabetes were treated as outpatients with a
+ high-carbohydrate-(about 60% of total daily energy requirements)-modified fat diet (ratio of polyunsaturated
+ fatty acids to other fatty acids greater than or equal to 1:1) for six weeks." "The findings suggest
+ that it is no longer justifiable to prescribe a low-carbohydrate diet for maturity-onset
+ diabetes."
+
+
+ Postgrad Med J 1981 Aug;57(670):511-5. Severe hypertriglyceridaemia responding to insulin and
+ nicotinic acid therapy. Smith SR. "Treatment with insulin and restriction of dietary
+ carbohydrate led to a 50% reduction in the triglyceride concentration, and the addition of nicotinic acid in
+ modest doses led ultimately to a complete normalization of the patient's lipid values. A close
+ correlation
+ was noted between the falling triglyceride concentration and the rising serum sodium concentration
+ during the course of successful therapy. Overall, it is felt likely that this patient's severe and
+ reversible hypertriglyceridaemia was on the basis of excessively rapid lipolysis
+ leading to high concentrations of very low density lipoprotein production."
+
+
+ Am J Clin Nutr 1993 Nov;58(5 Suppl):766S-770S. Fructose and dietary thermogenesis. Tappy L,
+ Jequier E. "Fructose ingestion induces a greater thermogenesis than does glucose. This can be
+ explained by the hydrolysis of 3.5-4.5 mol ATP/mol fructose stored as glycogen, vs 2.5 mol ATP/mol
+ glucose stored. Therefore the large thermogenesis of fructose corresponds essentially to an increase in
+ obligatory thermogenesis. Obese individuals and obese patients with non-insulin-dependent
+ diabetes mellitus commonly have a decrease in glucose-induced thermogenesis. These individuals in
+ contrast display a normal thermogenesis after ingestion of fructose.
+
+ This may be explained by the fact that the initial hepatic fructose metabolism is independent of insulin."
+
+
+ Diabetes 2002 Jun;51(6):1772-8.
+ Inhibition of interleukin-1beta-induced COX-2 and EP3 gene expression by sodium salicylate enhances
+ pancreatic islet beta-cell function.
+ Tran PO, Gleason CE, Robertson RP.
+
+
+ Proc Natl Acad Sci U S A 1998 Apr 28;95(9):4882-7. Protein-bound acrolein: potential markers for
+ oxidative stress.
+
+
+ Here we show that this notorious aldehyde is not just a pollutant, but also a lipid peroxidation product
+ that could be ubiquitously generated in biological systems. Upon incubation with BSA, acrolein was
+ rapidly incorporated into the protein and generated the protein-linked carbonyl derivative, a putative
+ marker of oxidatively modified proteins under oxidative stress." "Immunohistochemical analysis
+ of atherosclerotic lesions from a human aorta demonstrated that antigenic materials recognized by mAb5F6
+ indeed constituted the lesions, in which intense positivity was associated primarily with macrophage-derived
+ foam cells and the thickening neointima of arterial walls. The observations that (i) oxidative
+ modification of low-density lipoprotein with Cu2+ generated the acrolein-low-density lipoprotein adducts
+ and (ii) the iron-catalyzed oxidation of arachidonate in the presence of protein
+
+ resulted in the formation of antigenic materials suggested that
+ polyunsaturated fatty acids are sources of acrolein that cause the production of protein-bound acrolein.
+ These data suggest that the protein-bound acrolein represents potential markers of oxidative stress and
+ long-term damage to protein in aging, atherosclerosis, and diabetes."
+
+
+ J Intern Med 1990 Aug;228(2):165-71. Dietary supplementation with n-3 fatty acids may impair glucose
+ homeostasis in patients with non-insulin-dependent diabetes mellitus. Vessby B, Boberg M. "The
+ blood glucose concentration
+ tended to increase during MaxEPA treatment, and to decrease during the placebo period, the changes under
+ the two regimes being significantly different (P less than 0.01). In addition, the rate constant for
+ glucose disappearance (k value) for the intravenous insulin-tolerance test, which reflected the
+ peripheral insulin sensitivity, tended to decrease during MaxEPA treatment and increase during
+ administration of the placebo, there being a significant difference (P less than 0.03) between the changes
+ during the two treatments. The reason for the observed changes in blood glucose concentration and peripheral
+ insulin sensitivity is still unclear."
+
+
+ Diabet Med 1992 Mar;9(2):126-33. Polyunsaturated fatty acids may impair blood glucose control in
+ type 2 diabetic Patients. Vessby B, Karlstrom B, Boberg M, Lithell H, Berne C. "
+
+
+
+ Drugs 1999;58 Suppl 1:31-9; discussion 75-82. The antihyperglycaemic effect of metformin:
+ therapeutic and cellular mechanisms. Wiernsperger NF, Bailey CJ "Other effects involved in the
+ blood
+ glucose-lowering effect of metformin include an insulin-independent suppression of fatty acid oxidation
+ and a reduction in hypertriglyceridaemia. These effects reduce the energy supply for gluconeogenesis and
+ serve to balance the glucose-fatty acid (Randle) cycle."
+
+
+
+ J Biol Chem 2001 Mar 30;276(13):9800-7. Polyunsaturated fatty acids suppress hepatic sterol
+ regulatory element-binding protein-1 expression by accelerating transcript decay.
+ Xu J, Teran-Garcia M, Park JH, Nakamura MT, Clarke SD. "Our initial studies
+ indicated that the induction of SREBP-1 expression by insulin and glucose was blocked by PUFA. Nuclear
+ run-on assays suggested PUFA reduced SREBP-1 mRNA by post-transcriptional mechanisms." "Although the mechanism by which PUFA accelerate SREBP-1 mRNA decay remains to be determined,
+ cloning and sequencing of the 3'-untranslated region for the rat SREBP-1 transcript revealed the presence of
+ an A-U-rich region that is characteristic of a destablizing element."
+
+
+
+ Recent Adv Stud Cardiac Struct Metab 1976 May 26-29;12:271-7. Arrhythmogenic effects of acute free
+ fatty acid mobilization on ischemic heart.
+ Yamazaki N, Suzuki Y, Kamikawa T, Ogawa K, Mizutani K, Kakizawa N, Yamamoto M.
+
+
+ Science 1978 Jul 28;201(4353):358-60. Brain edema: induction in cortical slices by polyunsaturated
+ fatty acids.
+
+ Chan PH, Fishman RA The presence of polyunsaturated and saturated fatty acids in leukocytic membranes
+ prompted study of their possible role in the induction of brain edema. Polyunsaturated fatty acids including
+ sodium arachidonate, sodium linoleate, sodium linolenate, and docasahexaenoic acids induced edma in slices
+ of rat brain cortex. This cellular edema was specific, since neither saturated fatty acids nor a
+ fatty acid containing a single double bond had such effect.
+
+
+ J Neurochem 1986 Oct;47(4):1181-9. Effects of arachidonic acid on glutamate and gamma-aminobutyric
+ acid uptake in primary cultures of rat cerebral cortical astrocytes and neurons. Yu AC, Chan
+ PH, Fishman RA. "Arachidonic acid inhibited glutamate uptake in both astrocytes and neurons. The inhibitory
+ effect was observed within 10 min of incubation with arachidonic acid and reached approximately 80% within
+ 120 min in both types of culture. The arachidonic acid effect was not only time-dependent, but also
+ dose-related. Arachidonic acid, at concentrations of 0.015 and 0.03 mumol/mg protein, significantly
+ inhibited glutamate uptake in neurons, whereas 20 times higher concentrations were required for astrocytes.
+ The effects of arachidonic acid were not as deleterious on GABA uptake as on glutamate uptake in both
+ astrocytes and neurons." "Other polyunsaturated fatty acids, such as docosahexaenoic acid, affected
+ amino acid uptake in a manner similar to arachidonic acid in both astrocytes and neurons. However,
+ saturated fatty acids, such as palmitic acid, exerted no such effect."
+
+
+
+ © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
+
+
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+
+
+
+
+
+
+ Growth hormone: Hormone of Stress, Aging, & Death?
+
+
+ The name "growth hormone" is misleading; stress produces somatic growth, in a process called
+ "hormesis." Exercise produces muscle edema, to a degree similar to that produced by GH;
+ edema stimulates growth, but GH effect isn't limited to bone and muscle.
+
+
+ Identity of GH: Molecular ambiguity, complex modifications change one substance
+ into many; its evolution suggests a role in water regulation. Doctrine of a
+ "specific molecule" and "specific receptor" and specific effects is a
+ myth.
+
+
+ The osmoregulatory problem--keeping water under control--is centrally involved
+ in stress.
+
+
+ In mammals, the kidneys and bowel are the main regulators of water
+ balance.
+
+
+ GH is a stress hormone. Its effects can be produced osmotically, for example
+ inducing milk production and cartilage growth, by osmotic (dilution)
+ shock.
+
+
+ Estrogen produces increased GH, and increases its production in stress.
+
+
+ Nitric oxide is a pro-aging free radical induced by estrogen, releasing GH; all
+ three produce edema.
+
+
+ Behind edema, hypoxia, hypocarbia; free fatty acids, diabetes, vascular
+ leakiness, degenerative kidney changes, connective tissue changes,
+ thickened.basement membrane, retinal degeneration. The same changes occur in
+ aging: increased permeability; kidney disease, connective tissue
+ changes.
+
+
+ The absence of GH protects kidneys against degeneration. Osteoarthritis, a
+ characteristic aging condition, is caused by estrogen and GH.
+
+
+ Some studies found that heart failure and bone repair aren't improved by GH; GH
+ is very high during heart failure, in which edema contributes to the
+ problem; carpal tunnel syndrome, myalgia, tumor growth, gynecomastia, and
+ many other problems have been produced by GH treatments.
Bovine Growth Hormone is used to make cows give more milk.Human Growth Hormone is supposed to make men lean and muscular, not to increase
+ their milk production.
+
+
+
Recently I heard Robert
+ Sapolsky interviewed, and he was describing the changes that prepare the body
+ for short-term stress. He said the energy-mobilizing hormones, adrenalin and
+ cortisol, increase, while the hormones that don't contribute to meeting the
+ immediate problem, including the sex hormones and growth hormone, are
+ suppressed, to save energy; growth and reproductive processes can be suspended
+ for the few minutes of acute stress, to make the body more able to meet its
+ acute needs. He reiterated: Growth hormone is suppressed by stress.
+
+
+ Sapolsky has done very interesting work on the suppression of testosterone by
+ stress, and on the way in which brain cells are killed by prolonged exposure to
+ glucocorticoids. He showed that if extra glucose is supplied, the brain cells
+ can survive their exposure to cortisol. In the body, adrenalin and the
+ glucocorticoids increase the availability of glucose.
+
+
+ In the radio interview, he didn't have time for much detail, but it seemed to me
+ that he wasn't talking about the same growth hormone that I have been reading
+ about, and trying to understand, for years. Since people have asked me to write
+ about the current anti-aging uses of GH, and its use in the dairy industry,
+ Sapolsky's statements made me decide to think about some of the issues around
+ the hormone.*
+
+
+ ________________________________________________________________________________*If Sapolsky had been talking about just mice and rats, his statement
+ would have been generally accurate. Adrenaline stimulates rat pituitary cells to
+ secrete GH, and since both increase the amount of free circulating fatty acids,
+ it could be that rats' GH is suppressed by a fatty acid excess.
+
+
+ The "growth hormone" was named long before it was actually found, and the substance
+ with that name turns out to be involved in many processes other than growth. It
+ is being given to cows to make them produce more milk, and it is being given to
+ people with the purpose of making them lean and muscular, and with the hope of
+ building stronger bones.It isn't
+ surprising that the Growth Hormone helps breasts develop and promotes milk
+ production, since it is very similar to prolactin. GH and prolactin are members
+ of a family of proteins that have diverged from each other in evolution, but
+ they still have many overlapping effects.
+
+
+ When GH is treated as a drug, it is supposed to have a discrete identity, based on
+ the sequence of its amino acids. But the natural hormone (disregarding the
+ existence of a variety of closely related peptides with slightly different amino
+ acid composition) varies with time, being chemically modified even before it is
+ secreted. For example, its acidic amino acids may be methylated, and its lysine
+ groups may combine with sugars or carbon dioxide. The history of the protein in
+ the body determines its exact structure, and therefore its biological
+ effects.
+
+
+ Male animals secrete GH in pulses, but females secrete it more steadily. This
+ pattern of secretion "masculinizes" or "feminizes" the liver (and other organs),
+ determining the pattern of enzyme activity. It would be possible (though very
+ difficult) to arrange a system for delivering doses in a pulsed, intermittent
+ manner. In cows, this apparently isn't necessary, since the purpose of the
+ growth hormone is presumably to "feminize" the milk-producing system. But the
+ normal pattern of secretion is much more complex than simply being "pulsed" or
+ "continuous," since it, like prolactin secretion, is responsive to changes in
+ thyroid, estrogen, diet, stress, and many other factors.For example, hormones in this family are, as far back in evolution as
+ they have been studied, involved in the regulation of water and minerals. It is
+ well established that increased water (hypotonicity) stimulates prolactin, and
+ increased sodium inhibits its secretion. Growth hormone is also closely involved
+ with the regulation of water and salts.
+
+
+ One of the best known metabolic effects of GH is that, like adrenalin, it mobilizes
+ fatty acids from storage. GH is known to antagonize insulin, and one of the ways
+ it does this is simply by the ability of increased free fatty acids to block the
+ oxidation of glucose. At puberty, the increased GH creates a mild degree of
+ diabetes-like insulin resistance, which tends to increase progressively with
+ age.
+
+
+ In his book, Why Zebras Don't Get Ulcers, Sapolsky acknowledges some situations in
+ which GH is increased by stress in humans, but I think he misses the real ways
+ in which it operates in stress. One of the interesting features of cortisol,
+ which Sapolsky showed killed brain cells by making them unable to use glucose
+ efficiently, is that it makes cells take up unsaturated fatty acids more easily,
+ interfering with their energy production. Since growth hormone also has this
+ kind of "diatebetogenic" action, it might be desirable to suppress its secretion
+ during stress, but in fact, there are several kinds of stress that clearly
+ increase its secretion, and in animals as different as fish, frogs, cows, and
+ people it can be seen to play roles in water and salt regulation, growth and
+ development, stress, and starvation.
+
+
+ Heat, hypoglycemia, running, and some types of shock are known to stimulate growth
+ hormone secretion, sometimes to levels ten or twenty times higher than normal.
+ (Two kinds of stress that usually don't increase GH are cold and
+ stimulus-deprivation.) I consider the growth hormone to be, almost as much as
+ prolactin, a stress-inducible hormone. That's why I reasoned that, if an
+ endocrinologist as good as Sapolsky can misunderstand GH to that degree, the
+ public is even more likely to misunderstand the nature of the material, and to
+ believe that it somehow acts just on muscle, fat, and bones.
+
+
+ And the normally functioning pituitary appears to be unnecessary to grow to normal
+ height. (Kageyama, et al., 1998.)
+
+
+ W. D. Denckla discovered that the pituitary hormones are in some way able to
+ accelerate the process of aging. They block the actions of thyroid hormone,
+ decreasing the ability to consume oxygen and produce energy. The diabetes-like
+ state that sets in at puberty involves the relative inability to metabolize
+ glucose, which is an oxygen-efficient energy source, and a shift to fat
+ oxidation, in which more free radicals are produced, and in which mitochondrial
+ function is depressed. Diabetics, even though it is supposedly an inability of
+ their cells to absorb glucose that defines their disease, habitually waste
+ glucose, producing lactic acid even when they aren't "stressed" or exerting
+ themselves enough to account for this seemingly anaerobic metabolism. It was
+ noticing phenomena of this sort, occurring in a great variety of animal species,
+ in different phyla, that led Denckla to search for what he called DECO
+ (decreasing consumption of oxygen) or "the death hormone." (Vladimir Dilman
+ noticed a similar cluster of events, but he consistently interpreted everything
+ in terms of a great genetic program, and he offered no solution beyond a
+ mechanistic treatment of the symptoms.)
+
+
+ Simply increasing the amount of free fatty acids in the blood will act like DECO or
+ "the death hormone," but growth hormone has more specific metabolic effects than
+ simply increasing our cells' exposure to fatty acids. The hormone creates a bias
+ toward oxidizing of the most unsaturated fatty acids (Clejan and Schulz), in a
+ process that appears to specifically waste energy.Growth hormone plays an important role in puberty, influencing ovarian
+ function, for example.
+
+
+ Removing animals' pituitaries, Denckla found that their aging was drastically
+ slowed. He tried to isolate the death hormone from pituitary extracts. He
+ concluded that it wasn't prolactin, although prolactin had some of its
+ properties. In the last publication of his that I know of on that subject, he
+ reported that he was unable to isolate the death hormone, but that it was "in
+ the prolactin fraction." Since rats have at least 14 different peptides in their
+ prolactin family, not counting the multitude of modifications that can occur
+ depending on the exact conditions of secretion, it isn't surprising that
+ isolating a single factor with exactly the properties of the chronically
+ functioning aging pituitary hasn't been successful.
+
+
+ Denckla's experiments are reminiscent of many others that have identified changes
+ in pituitary function as driving forces in aging and degenerative diseases.
+
+
+ Menopause, for example, is the result of overactivity of the pituitary gonatropins,
+ resulting from the cumulatively toxic effects of estrogen in the
+ hypothalamus.
+
+
+ A. V. Everitt, in his book on the hypothalamus and pituitary in aging, reported on
+ studies in which estrogen caused connective tissues to lose their elasticity,
+ and in which progesterone seemed to be an antiestrogenic longevity factor.
+ Later, he did a series of experiments that were very similar to Denckla's, in
+ which removal of the pituitary slowed the aging process. Several of his
+ experiments strongly pointed to the prolactin-growth hormone family as the aging
+ factors. Removal of the pituitary caused retardation of aging similar to food
+ restriction. These pituitary hormones, especially prolactin, are very responsive
+ to food intake, and the growth hormone is involved in the connective tissue and
+ kidney changes that occur in diabetes and aging.
+
+
+ A mutant dwarf mouse, called "little," has only 5% to 10% as much growth hormone as
+ normal mice, and it has an abnormally long lifespan.
+
+
+ Many experiments show that prolactin and estrogen have synergistic effects in
+ causing tissue degeneration, including cancerization, and that their effects
+ tend to operate with fewer protective restraining influences in old age.
+ Estrogen stimulates both prolactin and growth hormone secretion. Thirty years
+ ago, people were warning that estrogen contraceptives might produce diabetes,
+ because they caused chronic elevation of growth hormone and free fatty
+ acids.Since estrogen causes a
+ slight tendency to retain water while losing sodium, producing hypotonic body
+ fluids, and since hypotonicity is a sufficient stimulus to cause prolactin
+ secretion, I have proposed that it is estrogen's effect on the body fluids which
+ causes it to stimulate prolactin. In pregnancy, the fetus is exposed to fluids
+ more hypotonic than can be accounted for by estrogen and prolactin alone; since
+ GH lowers the salt concentration of fish when they enter the ocean from
+ freshwater, it seems to be a candidate for this effect in pregnancy.
+
+
+ Growth itself is an intrinsic property of all cells, but the growth hormone does
+ have its greatest influence on certain tissues, especially cartilage. Gigantism
+ and acromegaly were what originally made people interested in looking for a
+ growth hormone, and these are characterized by continued, exaggerated
+ enlargement of bones and cartilage. In old age, cartilaginous structures such as
+ the bones and ears keep enlarging. The fact that simply diluting the culture
+ medium is sufficient to stimulate the growth of cartilage suggests that the
+ growth hormone might be acting by its effects on water metabolism. In fish which
+ enter fresh water from the ocean, pituitary hormones of this family help them to
+ balance salts in this new environment, but in the process, they develop
+ osteoporosis and skeletal deformity, of the sort that occur more gradually in
+ other animals with aging.
+
+
+ Growth hormone clearly causes edema, and this is probably involved in the
+ pathological processes that it can produce. The expansion of extracellular water
+ has been reported, but others have concluded that the increased weight of
+ muscles following GH treatment must be the result of "growth," "because
+ microscopic examination didn't show edema." Statements of that sort give
+ incompetence a bad name, because any student of biology or biochemistry has to
+ know, before he does almost any experiment, that the way to determine the water
+ content of a tissue is to compare the wet weight to the weight after thorough
+ drying. Looking for water under a microscope is the sort of thing they do at
+ drug companies to pretend that they have done something.
+
+
+ Estrogen, growth hormone, and nitric oxide, which tend to work as a system, along
+ with free fatty acids, all increase the permeability of blood vessels. The
+ leaking of albumin into the urine, which is characteristic of diabetes, is
+ promoted by GH. In diabetes and GH treatment, the basement membrane, the
+ jelly-like material that forms a foundation for capillary cells, is thickened.
+ The reason for this isn't known, but it could be a compensatory"anti-leak"
+ response tending to reduce the leakage of proteins and fats.
+
+
+ Besides being involved in kidney degeneration, vascular leakiness contributes to
+ brain edema, and probably contributes to the "autoimmune" diseases.
+
+
+ Whatever the exact mechanism may be, it is clearly established that GH contributes
+ to kidney degereration, and the lack of GH, even the removal of the pituitary,
+ is protective against kidney degeneration.
+
+
+ Denckla's and Everitt's experiments can be interpreted much more clearly now that
+ GH's essential contribution to kidney degeneration is known. Growth Hormone may
+ not be precisely the Death Hormone that Denckla was looking for, but it is very
+ close to it. Anti-thyroid effects have been seen, and possibly even anti-growth
+ effects during gestation, and in kidney disease. In newborns, high GH is
+ associated with smaller size and slower growth; in one study, this was
+ associated wtith rapid breathing, presumably hyperventilation which is
+ associated with stress. The shift to the diabetes-like fatty acid oxidation
+ would be expected to inhibit respiration, and the chronic elevation of serum
+ free fatty acids will have a generalized antithyroid effect. Under the influence
+ of GH, the proportion of unsaturated fatty acids is increased, as occurs under
+ the influence of estrogen.
+
+
+ Growth hormone blocks gonadotropin-stimulated progesterone production, and this
+ could also affect thyroid and respiratory metabolism.
+
+
+ The increase of GH during sleep might seem to be utterly incompatible with the idea
+ that it is a stress hormone, but in fact the other stress hormones, adrenalin,
+ cortisol, and prolactin also tend to increase during night-time sleep. Thyroid
+ function and progesterone function decrease at night. As I have argued
+ previously darkness is one of our major stressors. Considering GH's tendency to
+ cause edema, tissue swelling, it could play a role in the nocturnal increase of
+ the viscosity of blood, as the volume of blood is decreased by the leakage of
+ fluid into the tissues. Another process with potentially deadly results that
+ increase withaging and stress, is the passage of bacteria from the intestine
+ into the blood stream; this process is increased under the influence of GH.
+
+
+ Acute, short term studies definitely show growth hormone to be a stress hormone
+ with some destabilizing effects. Over a lifetime, it is possible that such
+ things as chronically increased levels of unsaturated fatty acids in the blood,
+ and increased leakiness of the blood vessels, could cumulatively produce the
+ effects that Denckla ascribed to the Death Hormone.REFERENCES
Intern Med 1998 May;37(5):472-5. A hypopituitary patient who attained tall
+ stature without growth hormone. Kageyama K, Watanobe H, Nasushita R, Nishie M,
+ Horiba N, Suda T. "We describe an unusual patient with hypopituitarism who
+ attained tall stature even without growth hormone (GH)." Pediatr. Pulmonol. 1998 26(4):241-9. Sleep, respiratory rate, and growth
+ hormone in chronic neonatal lung disease, D. Fitzgerald, et al."Insulin resistance in puberty [editorial]," Anonymousm Lancet, 1991 May
+ 25, 337:8752, 1259-60. "The
+ gonadotropic function of insulin," Poretsky L; Kalin MF, Endocr Rev, 1987 May,
+ 8:2, 132-4.1.
Circulation 1991 Jun;83(6):1880-7. Pathogenesis of edema in constrictive
+ pericarditis. Studies of body water and sodium, renal function, hemodynamics,
+ and plasma hormones before and after pericardiectomy. Anand IS, Ferrari R, Kalra
+ GS, Wahi PL, Poole-Wilson PA, Harris PC. "BACKGROUND. The pathogenesis of sodium
+ and water accumulation in chronic constrictive pericarditis is not well
+ understood and may differ from that in patients with chronic congestive heart
+ failure due to myocardial disease. This study was undertaken to investigate some
+ of the mechanisms. METHODS AND RESULTS. Using standard techniques, the
+ hemodynamics, water and electrolyte spaces, renal function, and plasma
+ concentrations of hormones were measured in 16 patients with untreated
+ constrictive pericarditis and were measured again in eight patients after
+ pericardiectomy. The average hemodynamic measurements were as follows: cardiac
+ output, 1.98 l/min/m2; right atrial pressure, 22.9 mm Hg; pulmonary wedge
+ pressure, 24.2 mm Hg; and mean pulmonary artery pressure 30.2 mm Hg. The
+ systemic and pulmonary vascular resistances (36.3 +/- 2.5 and 3.2 +/- 0.3 mm
+ Hg.min.m2/l, respectively) were increased. Significant increases occurred in
+ total body water (36%), extracellular volume (81%), plasma volume (53%), and
+ exchangeable sodium (63%). The renal plasma flow was only moderately decreased
+ (49%), and the glomerular filtration rate was normal. Significant increases also
+ occurred in plasma concentrations of norepinephrine (3.6 times normal), renin
+ activity (7.2 time normal), aldosterone (3.4 times normal), cortisol (1.4 times
+ normal), growth hormone (21.8 times normal), and atrial natriuretic peptide (5
+ times normal)." "The arterial pressure is maintained more by the expansion of
+ the blood volume than by an increase in the peripheral vascular
+ resistance." J Clin
+ Endocrinol Metab 1991 Apr;72(4):768-72 Expansion of extracellular volume and
+ suppression of atrial natriuretic peptide after growth hormone administration in
+ normal man. Moller J, Jorgensen JO, Moller N, Hansen KW, Pedersen EB,
+ Christiansen JS. University Department of Endocrinology and Internal Medicine,
+ Aarhus Kommunehospital, Denmark. "Sodium retention and symptoms and signs of
+ fluid retention are commonly recorded during GH administration in both
+ GH-deficient patients and normal subjects." "GH caused a significant increase in
+ ECV (L): 20.45 +/- 0.45 (GH), 19.53 +/- 0.48 (placebo) (P less than 0.01),
+ whereas plasma volume (L) remained unchanged 3.92 +/- 0.16 (GH), 4.02 +/- 0.13
+ (placebo)."Edema of cardiac
+ origin. Studies of body water and sodium, renal function, hemodynamic indexes,
+ and plasma hormones in untreated congestive cardiac failure. Anand IS, Ferrari
+ R, Kalra GS, Wahi PL, Poole-Wilson PA, Harris PC. "This study provides data on
+ plasma hormone levels in patients with severe clinical congestive cardiac
+ failure who had never received therapy and in whom the presence of an
+ accumulation of excess water and sodium had been established." "Total body water
+ content was 16% above control, extracellular liquid was 33% above control,
+ plasma volume was 34% above control, total exchangeable sodium was 37% above
+ control, renal plasma flow was 29% of control, and glomerular filtration rate
+ was 65% of control. Plasma norepinephrine was consistently increased (on average
+ 6.3 times control), whereas adrenaline was unaffected. Although plasma renin
+ activity and aldosterone varied widely, they were on average above normal (renin
+ 9.5 times control, aldosterone 6.4 times control). Plasma atrial natriuretic
+ peptide (14.3 times control) and growth hormone (11.5 times control) were
+ consistently increased. Cortisol was also increased on average (1.7 times
+ control). Vasopressin was increased only in one patient." J Pediatr Endocrinol 1994 Apr-Jun;7(2):93-105. Studies on the renal
+ kinetics of growth hormone (GH) and on the GH receptor and related effects in
+ animals. Krogsgaard Thomsen M, Friis C, Sehested Hansen B, Johansen P, Eschen C,
+ Nowak J, Poulsen K. "Growth hormone (GH) is filtered through the kidney, and may
+ exert effects on renal function when presented via the circulation.
+ Investigations on kidney-related aspects of GH are increasing in number." "Short
+ term administration of GH to rats and humans elicited electrolyte and water
+ retention that may cause edema in adults."Mech Ageing Dev 1983 Jul-Aug;22(3-4):233-51 The anti-aging action of
+ hypophysectomy in hypothalamic obese rats: effects on collagen aging,
+ age-associated proteinuria development and renal histopathology. Everitt AV,
+ Wyndham JR, Barnard DL Hypophysectomy in young male Wistar rats aged 70 days,
+ like food restriction begun at the same age, retarded the life-long rate of
+ collagen aging in tail tendon fibres and inhibited the development of
+ age-associated proteinuria and renal histopathology. Hypothalamic lesions which
+ increased the food intake of hypophysectomized rats from 7 g to 15 g/day and
+ produced obesity did not alter the rate of either collagen aging or proteinuria
+ development, nor reduce life expectancy, but increased the incidence of abnormal
+ glomeruli. In the intact rats elevation of food intake from 7 g to 15 g/day
+ increased the rate of proteinuria development, but did not affect the rate of
+ collagen aging. Hypophysectomy was found to have a greater anti-collagen aging
+ effect than food restriction, when food intakes were the same in both groups.
+ These studies suggest a pituitary-hormonal effect on collagen aging and a
+ food-pituitary-hormone-mediated effect on the development of age-associated
+ proteinuria. Growth Dev
+ Aging 1992 Summer;56(2):85-93. Morphometrical analysis of the short-term effects
+ of hypophysectomy and food restriction on skeletal muscle fibers in relation to
+ growth and aging changes in the rat. Shorey CD, Manning LA, Grant AL, Everitt
+ AV.Metabolism of glomerular
+ basement membrane in normal, hypophysectomized, and growth-hormone-treated
+ diabetic rats," Reddi AS, Exp Mol Pathol, 1985 Oct, 43:2, 196-208. "The in vivo
+ synthesis of the renal glomerular basement membrane (GBM) collagen was studied
+ in normal, hypophysectomized (hypox), diabetic, and growth-hormone (GH)-treated
+ diabetic rats...." "A significant decrease in both proline and hydroxyproline
+ specific activities were observed in GBM of hypox rats at all periods of study.
+ Administration of GH to hypox rats returned the GBM collagen synthesis to
+ normal. Diabetic GBM had higher proline and hydroxyproline specific activities
+ when compared to normal rats. Treatment of diabetic rats with GH for 10 days
+ further increased both proline and hydroxyproline specific activities when
+ compared either to diabetic or normal rats treated with GH. The activity of
+ glucosyltransferase, an enzyme involved in the biosynthesis of the disaccharide
+ unit of GBM collagen was found to be decreased in glomeruli of hypox rats. In
+ contrast, the activity of N-acetyl-beta-glucosaminidase, a
+ glycoprotein-degrading enzyme, was found to be significantly increased in hypox
+ rats. GH treatment restored both enzyme activities to normal. The results of the
+ present study show that GBM collagen synthesis is decreased in hypox rats and
+ increased in diabetic rats. ....not only normalized GBM collagen synthesis in
+ hypox rats but also caused significant increase in diabetic rats. This suggests
+ that the renal GBM metabolism is influenced by GH, and this may be of particular
+ significance in view of GH involvement in diabetic microvascular
+ complications."Ciba Found Symp
+ 1982;(90):263-78 Prolactin and growth hormone receptors. Friesen HG, Shiu RP,
+ Elsholtz H, Simpson S, Hughes J The two hormones prolactin and growth hormone
+ exhibit considerable structural homology as well as exerting similar biological
+ effects, especially the primate hormones. One effect of prolactin that deserves
+ greater attention is its action on the immune system including the stimulation
+ of growth of experimental lymphomas, both in vivo and in vitro." N Engl J Med 1999 Sep 9;341(11):785-92. Increased mortality associated
+ with growth hormone treatment in critically ill adults.
+
+
+
+
+ © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com
+
+
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+ Heart and hormones The heart's unique behavior has given cardiologists a
+ particularly mechanical perspective on biology. If a cardiologist and an oncologist have anything to talk
+ about, it's likely to be about why cancer treatments cause heart failure; a cardiologist and an
+ endocrinologist might share an interest in "cardioprotective estrogen" and "cardiotoxic obesity." Cell
+ physiology and bioenergetics aren't likely to be their common interest. Each specialty has its close
+ involvement with the pharmaceutical industry, shaping its thinking.
+
+
+ The drug industry has been lowering the numbers for cholesterol, blood pressure, and
+ blood glucose that are considered to be the upper limit of normal, increasing the number of customers
+ for their prescription drugs. Recently, publications have been claiming that the upper limit of the
+ normal range of heart rates should be lower than 100 beats per minute; this would encourage doctors to
+ prescribe more drugs to slow hearts, but the way the evidence is being presented, invoking the
+ discredited "wear and tear" theory of aging, could have many unexpected harmful consequences. It would
+ reinforce existing misconceptions about heart functions.
+ A few decades ago, diuretics to lower blood pressure and digitalis/digoxin to increase
+ the heart's strength of contraction were the main treatments for heart disease. In 1968, the annual
+ number of deaths in the US from congestive heart failure (in which the heart beats more weakly, pumping
+ less blood) was 10,000. By 1993 the number had increased to 42,000 per year. More recently, the annual
+ number of deaths in which heart failure is the primary cause was more than 55,000. During these decades,
+ many new drugs for treating heart disease were introduced, and the use of digoxin has decreased
+ slightly. People with heart failure usually live with the condition for several years; at present about
+ 5.7 million people in the US live with heart failure. The prevalence of, and mortality from, other
+ cardiovascular diseases (such as hypertension and abnormalities of the coronary arteries) are higher,
+ but congestive heart failure is especially important to understand, because it involves defective
+ function of the heart muscle itself.
+ Although Albert Szent-Gyorgyi is known mostly for his discovery of vitamin C and
+ his contribution to understanding the tricarboxylic acid or Krebs cycle, his main interest was in
+ understanding the nature of life itself, and he focused mainly on muscle contraction and cancer growth
+ regulation. In one of his experiments, he compared the effects of estrogen and progesterone on rabbit
+ hearts. A basic property of the heart muscle is that when it beats more frequently, it beats more
+ strongly. This is called the staircase effect, from the way a tracing of its motion rises, beat by beat,
+ as the rate of stimulation is increased. This is a logical way to behave, but sometimes it fails to
+ occur: In shock, and in heart failure, the pulse rate increases, without increasing the volume of blood
+ pumped in each contraction.
+ Szent-Gyorgyi found that estrogen treatment decreased the staircase effect, while
+ progesterone treatment increased the staircase. He described the staircase as a situation in which
+ function (the rate of contraction) builds structure (the size of the contraction). Progesterone allowed
+ "structure" to be built by the contraction, and estrogen prevented that.
+ (It's interesting to compare these effects of the hormones to the more general idea of anabolic and
+ catabolic hormones, in which more permanent structures in cells are affected.)
+ The rapid and extensive alternation of contraction and relaxation made possible by
+ progesterone is also produced by testosterone (Tsang, et al., 2009). Things that increase the force of
+ contraction are called inotropic, and the things that promote relaxation are called lusitropic;
+ progesterone and testosterone are both positively inotropic and lusitropic, improving contraction and
+ relaxation. Estrogen is a negative lusitropic hormone (Filice, et al., 2011), and also a negative
+ inotropic hormone (Sitzler, et al., 1996), that is, it impairs both relaxation and
+ contraction.
+ Another standard term describing heart function is chronotropy, referring to the
+ frequency of contraction. Because of the staircase interaction of frequency and force, there has been
+ some confusion in classifying drugs according to chronotropism. In a state of shock or estrogen
+ dominance, an inotropic drug will slow the heart rate by increasing the amount of blood pumped. This
+ relationship caused digitalis' effect to be thought of as primarily slowing the rate of contraction
+ (Willins and Keys, 1941), though its main effect is positively inotropic. It was traditionally used to
+ treat edema, by stimulating diuresis, which is largely the result of its inotropic action. Progesterone
+ and testosterone's inotropic action can also slow the heart beat by strengthening it.
+ I think it was a little before Szent-Gyorgyi's heart experiment that Hans Selye had
+ discovered that a large dose of estrogen created a shock-like state. Shock and stress cause estrogen to
+ increase, and decrease progesterone and testosterone.
+ About 30 years after Szent-Gyorgyi's work, people began to realize that digoxin and other
+ heart stimulating molecules can be found in animals and humans, as metabolites of progesterone and
+ possibly DHEA (Somogyi, et al., 2004).
+ The regulatory proteins that are involved in estrogen's negative lusi- and inotropic
+ actions (decreasing pumping action) have been known for over 20 years to be regulated by the thyroid
+ hormone to produce positive lusi- and inotropic actions on the heart (increasing its pumping action),
+ and thyroid's beneficial effects on heart and skeletal muscle have been known empirically for 100 years.
+ However, drug centered cardiologists, reviewing the currently available drugs approved by the FDA, have
+ typically concluded that "drugs targeted to achieve these objectives are not available" (Chatterjee,
+ 2002).
+ When a muscle or nerve is fatigued, it swells, retaining water. When the swelling
+ is extreme, its ability to contract is limited. Excess water content resembles a partly excited state,
+ in which increased amounts of sodium and calcium are free in the cytoplasm. Energy is needed to
+ eliminate the sodium and calcium, or to bind calcium, allowing the cell to extrude excess water and
+ return to the resting state. Thyroid hormone allows cells' mitochondria to efficiently produce energy,
+ and it also regulates the synthesis of the proteins (phospholamban and calcisequestrin) that control the
+ binding of calcium. When the cell is energized, by the mitochondria working with thyroid, oxygen, and
+ sugar, these proteins rapidly change their form, binding calcium and removing it from the contractile
+ system, allowing the cell to relax, to be fully prepared for the next contraction. If the calcium isn't
+ fully and quickly bound, the cell retains extra water and sodium, and isn't able to fully relax.
+ Heart failure is described as "diastolic failure" when the muscle isn't able to fully
+ relax. In an early stage, this is just a waterlogged (Iseri, et al., 1952), fatigued condition, but when
+ continued, the metabolic changes lead to fibrosis and even to calcification of the heart muscle.
+ Many children approaching puberty, as estrogen is increasing and interfering with thyroid
+ function, have "growing pains," in which muscles become tense and sore after prolonged activity. When
+ hypothyroidism is severe, it can cause myopathy, in which the painful swollen condition involves the
+ leakage of muscle proteins (especially myoglobin) into the blood stream, allowing it to be diagnosed by
+ a blood test. The combination of hypothyroidism with fatigue and stress can lead to the breakdown and
+ death of muscle cells, rhabdomyolysis.
+ The blood lipid lowering drugs, statins and fibrates, impair mitochondrial respiration
+ (Satoh, et al., 1995, 1994; Brunmair, et al., 2004), and increase the incidence of rhabdomyolysis
+ (Barker, et al., 2003; Wu, et al., 2009; Fallah, et al., 2013). Interference with coenzyme Q10 is not
+ the only mechanism by which they can cause myopathy (Nakahara, et al., 1998). The harmful effect of
+ lowering cholesterol seems to be relevant to heart failure: "In light of the association between high
+ cholesterol levels and improved survival in HF, statin or other lipid-lowering therapy in HF remains
+ controversial (Horwich, 2009).
+ Heart muscle and skeletal muscle are similar in their structural responses to
+ interference with mitochondrial functions, namely, swelling, reduced contractile ability, and
+ dissolution. When myoglobin has been found in the blood and urine, it has been assumed to come from
+ skeletal muscles, but the heart's myoglobin has been found to be depleted in a patient with
+ myoglobinuria (Lewin and Moscarello, 1966). When heart failure is known to exist, similar changes can be
+ found in the skeletal muscles (van der Ent, et al., 1998).
+ Stress, in the form of pressure-overload (Zhabyeyev, et al., 2013), or overactivity of
+ the renin-angiotensin system (Mori, et al., 2013) and sympathetic nervous system or adrenergic chemicals
+ (Mori, et al., 2012), or a failure of energy caused by diabetes, insulin deficiency, or hypothyroidism,
+ causes a shift of energy production from the oxidation of glucose to the oxidation of fatty acids, with
+ the release, rather than oxidation, of the lactic acid produced from glucose. This sequence, from
+ reduced efficiency of energy production to heart failure, can be opposed by agents that reduce the
+ availability of fatty acids and promote the oxidation of glucose. Niacinamide inhibits the release of
+ free fatty acids from the tissues, and thyroid sustains the oxidation of glucose. This principle is now
+ widely recognized, and the FDA has approved a drug that inhibits the oxidation of fatty acids
+ (raloxazine, 2006), but which has serious side effects. Glucose oxidation apparently is necessary for
+ preventing the intracellular accumulation of free calcium and fatty acids (Jeremy, et al., 1992; Burton,
+ et al., 1986; Ivanics, et al., 2001). The calcium binding protein which is activated by thyroid and
+ inhibited by estrogen seems to be activated by glucose and inhibited by fatty acids (Zarain-Herzberg and
+ Rupp, 1999).
+ Diabetes or fasting increases free fatty acids, and forces cells to shift from oxidation
+ of glucose to oxidation of fatty acids, inhibiting the binding of calcium (McKnight, et al., 1999).
+ Providing a small amount of sugar (0.8% sucrose in their drinking water) restored the calcium binding
+ and heart function, without increasing either thyroid hormone or insulin (Rupp, et al., 1988, 1999,
+ 1994). Serum glucose was lowered, as the ability to oxidize sugar was restored by lowering free fatty
+ acids. Activity of the sympathetic nervous system is lowered as efficiency is increased.
+ Digoxin stimulates mitochondrial energy production in skeletal and heart muscle
+ (Tsyganil, et al., 1982), increasing the oxidation of glucose, rather than fatty acids, supporting the
+ effect of thyroid hormone. The statins have the opposite effect, decreasing the oxidation of
+ glucose.
+ One of estrogen's effects is to chronically increase the circulation of free fatty acids,
+ and to favor the long chain polyunsaturated fatty acids, such as EPA and DHA. These fatty acids, which
+ slow the heart rate (Kang and Leaf, 1994), extend the excited state (action potential: Li, et al.,
+ 2011), and are negatively inotropic (Dhein, et al., 2005; Macleod, et al., 1998; Negretti, et al.,
+ 2000), are being proposed as heart protective drugs. (EPA and alpha-linoleic acid also prolong the QT
+ interval: Dhein, et al., 2005).
+ Many publications still promote estrogen as a cardioprotective drug, but there is now
+ increased recognition of its role in heart failure and sudden cardiac death. A prolonged excited state
+ (action potential) and delayed relaxation (QT interval) are known to increase the risk of arrhythmia and
+ sudden death, and estrogen, which causes those changes in humans, causes sudden cardiac death in
+ susceptible rabbits, with an adrenergic stimulant increasing the arrhythmias, and progesterone and
+ androgen preventing them (Odening et al., 2012). Progesterone's protective effect seems to be the result
+ of accelerating recovery of the resting state (Cheng, et al., 2012).
+ Estrogen's interactions with adrenalin in promoting blood vessel constriction has been
+ known for many years (for example, Cheng and Gruetter, 1992). Progesterone blocks that effect of
+ estrogen (Moura and Marcondes, 2001). Environmental estrogens such as BPA can exacerbate ventricular
+ arrhythmia caused by estrogen (Yan, et al., 2013). The hearts of mice genetically engineered to lack
+ aromatase, the enzyme that synthesizes estrogen, were more resistant to damage by being deprived of
+ blood for 25 minutes (Bell, et al., 2011), leading the authors to suggest that aromatase inhibition
+ might be helpful for heart disease.
+ In the stressed, energy depleted failing heart, muscle cells die and are replaced by
+ connective tissue cells. The growth produced by over-exposure to adrenergic stimulation leads to
+ stiffening and reduced functioning. However, under the influence of thyroid hormone a high work load
+ leads to functional enlargement, which simply increases the pumping ability. Because of the traditional
+ belief that heart cells can't replicate, this functional growth was believed to be produced purely by
+ the enlargement of cells, but in recent years the existence of stem cells able to create new heart
+ muscle has been recognized. Thyroid is likely to be one of the hormones responsible for allowing stem
+ cells to differentiate into cardiomyocytes.
+ In this context, of cellular differentiation as a life-long process, we can see the
+ changes of a failing heart as a differentiation which is forced to take an inappropriate course. The
+ calcification of blood vessels caused by phosphate excess and vitamin K deficiency involves the
+ expression of a protein which has its proper place in the skeleton. The replacement of heart muscle by
+ fibrous connective tissue and even bone is a basic biological problem of differentiation, and the
+ responsible factors--stress, increased estrogen, deficient thyroid hormone, suppression of glucose
+ oxidation by fatty acids, etc.--are involved in the problems of differentiation that occur in other
+ degenerative processes, such as sarcopenia, dementia, and cancer.
+ There have been arguments about the nature of wound healing and regeneration, regarding
+ the origin of the new cells--whether they are from the dedifferentiation of local cells, or the
+ migration of stem cells. The evidence is that both can occur, depending on the tissue and the situation.
+ The deterioration of an organ is probably not a question of a lack of stem cells, but of changed
+ conditions causing them to differentiate into something inappropriate for the full functioning of that
+ organ.
+ Various stresses can cause cells to dedifferentiate, but hypoxia is probably a common
+ denominator. In the absence of estrogen, hypoxia can activate the "estrogen receptor." Estrogen is
+ in some situations a hormone of dedifferentiation, facilitating the formation of new cells in stressed
+ tissues, as aromatase is induced. However, the presence of polyunsaturated fats, tending to increase in
+ concentration with age, causes the processes of renewal to produce exaggerated inflammation, with
+ prostaglandins participating in the processes of development and differentiation. Estrogen, by
+ increasing the concentration of free fatty acids, especially polyunsaturated fatty acids, contributes to
+ the metabolic shift away from glucose oxidation, toward the formation of lactic acid, and away from the
+ full organ-specific differentiation.
+ This perspective puts heart failure, cancer, and the other degenerative diseases onto the
+ same biological basis, and shows why certain conditions and therapies can be appropriate for all of
+ them.
+ Problems that seem relatively trivial become more meaningful when they are seen in terms
+ of these mechanisms. Some problems that become very common by middle age are "palpitations," orthostatic
+ hypotension, orthostatic tachycardia, and varicose veins. The negative inotropic effect of estrogen in
+ the heart has a parallel in the smooth muscle of veins, in which the muscles are weakened, and their
+ distensibility increased, when estrogen isn't sufficiently opposed by progesterone. This allows the
+ veins in the lower part of the body to be distended abnormally when standing, reducing the amount of
+ blood returning to the heart, so that the volume pumped with each stroke is small, requiring faster
+ beating. The reduced blood volume reaching the brain can cause fainting. When it becomes chronic, it can
+ lead to the progressive distortion of the veins. An excess of estrogen is associated with varicose veins
+ in men, as well as women. (Raj, 2006; Ciardullo, et al., 2000; Kendler, et al., 2009; Asciutto, et al.,
+ 2010; Raffetto, et al., 2010).
+ The simplicity of things such as supplementing thyroid, progesterone, and sugar, avoiding
+ an excess of phosphate in relation to calcium, and avoiding polyunsaturated fats, makes it possible for
+ people to take action themselves, without having to depend on the medical system. Most physicians still
+ warn their patients of the dangers of thyroid supplements, especially the active T3 hormone, for their
+ heart, but in at least one specialty, its value is recognized. Heart transplant surgeons have discovered
+ that administering T3 to the brain-dead heart donor before removing the heart improves its viability and
+ function in the recipient (Novitzky, 1996). Around this time, the manufacturers of Cytomel conceived the
+ idea of marketing it as a "heart drug," which would make it much more profitable.
+ Another technique that is easy to use to lower blood pressure and improve heart rhythm is
+ to breathe into a paper bag for a minute or two at a time, to increase the carbon dioxide content of the
+ blood. This has a vasodilating effect, reducing the force required to circulate the blood, and reduces
+ anxiety. Rhubarb and emodin (a chemical found in rhubarb and cascara) have been found to have heart
+ protective actions. A considerable amount of research showed that vitamin K is effective for treating
+ hypertension, but again, most doctors warn against its use, because of its reputation as a clot forming
+ vitamin. Recently, the value of the "blood thinner" warfarin, a vitamin K antagonist, has been
+ questioned for people with heart failure (An, et al., 2013; Lee, et al., 2013). There have been several
+ recent warnings about the production of arrhythmia by drugs that increase serotonin's effects (e.g.,
+ Stillman, et al., 2013).
+ Measuring the speed of relaxation of the Achilles tendon reflex twitch is a
+ traditional method for judging thyroid function, because in hypothyroidism the relaxation is visibly
+ delayed. This same retardation can be seen in the electrocardiogram, as a prolonged QT interval, which
+ is associated with arrhythmia and sudden death. Insomnia, mania, and asthma are other conditions in
+ which defective relaxation is seen, under the influence of low thyroid function, and an insufficiently
+ opposed influence of estrogen.
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+ reductase inhibitors on mitochondrial respiration in rat liver during ischemia. Satoh K, Nakai T,
+ Ichihara K.
+
+ Br J Pharmacol. 1997 Oct;122(4):772-8. Imbalance between the endothelial cell-derived contracting
+ factors prostacyclin and angiotensin II and nitric oxide/cyclic GMP in human primary varicosis.
+ Schuller-Petrovic S, Siedler S, Kern T, Meinhart J, Schmidt K, Brunner F.
+ J Clin Invest. 1996 Nov 15;98(10):2244-50. Glucose plus insulin regulate fat oxidation by controlling
+ the rate of fatty acid entry into the mitochondria. Sidossis LS, Stuart CA, Shulman GI, Lopaschuk GD,
+ Wolfe RR.
+ Orv Hetil. 2004 Feb 8;145(6):259-66. [New steroid hormone family: endogenous cardiac glycosides and
+ their role in physiologic and pathologic conditions]. [Article in Hungarian] Somogyi J, Szalay J,
+ Pándics T, Rosta K, Csermely P, Vér A.
+ Headache. 2013 Jan;53(1):217-24. QT prolongation, Torsade de Pointes, myocardial ischemia from
+ coronary vasospasm, and headache medications. Part 2: review of headache medications, drug-drug
+ interactions, QTc prolongation, and other arrhythmias. Stillman MJ, Tepper DE, Tepper SJ, Cho L.
+ Am J Physiol Cell Physiol. 2009 Apr;296(4):C766-82. Testosterone-augmented contractile responses to
+ alpha1- and beta1-adrenoceptor stimulation are associated with increased activities of RyR, SERCA, and
+ NCX in the heart. Tsang S, Wong SS, Wu S, Kravtsov GM, Wong TM.
+ Farmakol Toksikol. 1982 Jan-Feb;45(1):30-2. [Effect of digoxin, strophanthin and isolanid on oxygen
+ absorption, oxidative phosphorylation and the amount of cytochromes in the myocardial mitochondria and
+ their ATPase activity]. Tsyganiĭ AA, Medvinskaia NA, Rudenko AF.
+ Eur Heart J. 1998 Jan;19(1):124-31. A non-invasive selective assessment of type I fibre mitochondrial
+ function using 31P NMR spectroscopy. Evidence for impaired oxidative phosphorylation rate in
+ skeletal muscle in patients with chronic heart failure. van der Ent M, Jeneson JA, Remme WJ, Berger R,
+ Ciampricotti R, Visser F.
+ Withering W. An account of the foxglove and some of its medical uses, with practical remarks on
+ dropsy, and other diseases. In Willins FA, Keys TE, eds. Classics of Cardiology. Volume I. New York, NY:
+ Henry Schuman, Dover Publications; 1941: 231–252.
+ Eur J Clin Pharmacol. 2009 Dec;65(12):1169-74. Rhabdomyolysis associated with fibrate therapy: review
+ of 76 published cases and a new case report. Wu J, Song Y, Li H, Chen J.
+ Cardiovasc Res (2013) 97 (4): 676-685. Pressure-overload-induced heart failure induces a selective
+ reduction in glucose oxidation at physiological afterload. Zhabyeyev P, Gandhi M, Mori J, Basu R.,
+ Kassiri Z, Clanachan A., Lopaschuk GD, Oudit GY.
+
+
+ © Ray Peat Ph.D. 2015. All Rights Reserved. www.RayPeat.com
+
+
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+
+
+
+
+
+
+
+ Hot flashes, energy, and aging
+
+
+
+ Around the time that menstruation and fertility are ending, certain biological problems are more
+ likely to occur. Between the ages of 50 and 55, about 60% of women experience repeated episodes
+ of flushing and sweating. Asthma, migraine, epilepsy, arthritis, varicose veins, aneurysms,
+ urticaria, reduced lung function, hypertension, strokes, and interstitial colitis are some of
+ the other problems that often begin or get worse at the menopause, but that normally aren't
+ considered to be causally related to it.
+
+
+
+ Recently, hot flashes are being taken more seriously, because of their association with increased
+ inflammation, heart disease, and risk of dementia. Around the same age, late 40s to mid-50s, men
+ begin to have a sudden increase of some of the same health problems, including night sweats,
+ anxiety, and insomnia. In both sexes, the high incidence of depression in this age group has
+ usually been explained "psychologically," rather than biologically.
+
+
+
+ When the estrogen industry began concentrating on women of menopausal age (after the disastrous
+ years of selling it as a fertility drug), "estrogen replacement" therapy was promoted as a cure
+ for the problems associated with menopause, including hot flashes, which were explained as the
+ result of a deficiency of estrogen. However, in recent years, the phrase "estrogen deficiency"
+ has begun to be replaced by the phrase "estrogen withdrawal," because it has been found that
+ women with hot flashes don't necessarily have less estrogen in their blood stream than women who
+ don't have hot flashes.
+
+
+
+ Associated with this change of terminology, there has been a recognition that changes in the
+ temperature regulating system in the brain, rather than changes in the amount of estrogen, are
+ responsible for the hot flashes, but mainstream medicine has carefully avoided the investigation
+ of this subject. The effects of estrogen on the thermoregulatory system are very clear, but the
+ standard medical view is that the physiology of hot flashes simply isn't understood.
+
+
+
+ Since the medical literature boldly describes the mechanisms of the circulatory system and the
+ causes of major problems such as heart attacks, high blood pressure, and strokes, it's odd that
+ it doesn't have an explanation for "hot flashes."
+
+
+ But looking at this historically, I think this selective ignorance is necessary, for the protection
+ of some doctrines that have become very important for conventional medicine.
+
+
+
+ When doctors are talking about diseases of the heart and circulatory system, it's common for them
+ to say that estrogen is protective, because it causes blood vessels to relax and dilate,
+ improving circulation and preventing hypertension. The fact that estrogen increases the
+ formation of nitric oxide, a vasodilator, is often mentioned as one of its beneficial effects.
+ But in the case of hot flashes, dilation of the blood vessels is exactly the problem, and
+ estrogen is commonly prescribed to prevent the episodic dilation of blood vessels that
+ constitutes the hot flash. Nitric oxide increases in women in association with the menopause
+ (Watanabe, et al., 2000), and it is increased by inflammation, and hot flushes are associated
+ with various mediators of inflammation, but, as far as I can tell, no one has measured the
+ production of nitric oxide during a hot flash. Inhibitors of nitric oxide formation reduce
+ vasodilation during hot flushes (Hubing, et al., 2010).
+
+
+
+ Starting in the 1940s, the doctrine that menopause is the result of changes in the ovaries,
+ involving a depletion of eggs and an associated loss of estrogen production, was widely taught
+ to medical students. By the 1970s, the taboo against discussing menopause publicly was fading,
+ and the mass media began teaching the public that hot flashes are the result of an estrogen
+ deficiency, and that "estrogen replacement" is the most appropriate and effective treatment, and
+ in the next 20 years almost half the women in the US began taking it around the time of
+ menopause. This practice became routine at a time when "evidence based medicine" was being
+ promoted as a new standard, but there was no evidence that women experiencing hot flashes were
+ deficient in estrogen (in fact, there was evidence that they weren't), and there was evidence
+ that hot flashes began when the first menstrual period was missed, which coincided with, and
+ resulted from, a failure to produce a functional corpus luteum, preventing the production of a
+ normal amount of progesterone. But the silly old doctrine of deficiency is often restated by
+ professors, as if there was no doubt about it (for example, Rance, 2009; Bhattacharya and
+ Keating, 2012).
+
+
+
+ This extremely persistent disregard for important evidence about the nature of menopause and its
+ symptoms was guided by the estrogen industry, which began in the 1930s to call estrogen "the
+ female hormone," disregarding the facts about the biological roles of estrogen and progesterone,
+ because chemicals with estrogenic effects were numerous and cheap, while progesterone was
+ expensive, and had no synthetic equivalents. At the time the pharmaceutical industry began
+ promoting estrogen as the female hormone to prevent miscarriage, it was already well known that
+ it could produce abortion, as well as causing inflammation and cancer, and some of the most
+ famous estrogen researchers were warning of its multiple dangers in the 1930s.
+
+
+
+ Menopause is a major landmark of aging, and if its meaning is radically misunderstood, a coherent
+ understanding of aging is unlikely, and without an understanding of the loss of functions with
+ age, we won't really understand life. More specifically, the real causes of the many serious
+ problems occurring in association with the menopause will be ignored. Finding the causes of the
+ seemingly trivial hot flash will affect the way we understand aging and its diseases.
+
+
+
+ If a common occurrence is thought to have some importance in itself, or to relate closely to
+ something of importance, it will be described carefully, and its general features will become
+ part of the common understanding. It's clear that our medical culture hasn't considered the hot
+ flash to be important, because there are still physicians who believe that the hot flash
+ represents a rise of body temperature caused by a sudden increase of heat production, which they
+ sometimes explain as an upward fluctuation of thyroid gland activity. Measurement of body
+ temperature before and during hot flashes has shown clearly that the internal temperature is
+ lowered slightly by the hot flash, as heat is lost from the skin, as a result of vasodilation.
+ Physiologists have been studying the differences in temperature regulation between men and
+ women, and the effects of hormones on temperature regulation, for more than 70 years, but the
+ medical profession in the United States showed almost no interest in the subject for about 50
+ years.
+
+
+
+ August Weismann's doctrine of "mortal soma, immortal germ line," led people to postulate that
+ "primordial germ" cells migrated into the ovary (consisting of "somatic" cells) during embryonic
+ development, and that the baby was born with a supply of germ cells that was used up during the
+ reproductive lifetime, accounting for the decline of fertility with aging. The fact that
+ menstrual cycles ended around the time that fertility ended was explained by the idea that
+ ovulation caused the release of estrogen, and that the absence of eggs caused a failure to
+ produce estrogen, and that the absence of estrogen led to the failure of the cyclical uterine
+ changes. It was all deduced from a mistaken ideology about the nature of life.
+
+
+
+ Cancer of the endometrium (lining) of the uterus and breast cancer were known to be the first and
+ second cancers, respectively, produced by uninterrupted exposure to estrogen (for example,
+ Lipshutz, 1950). Investigation of the causes of endometrial cancer showed that women with
+ anovulatory cycles, that failed to produce progesterone, or who had a reduced production of
+ progesterone, developed overgrowth of the endometrium, and that these were the women who were
+ later most likely to develop cancer of the endometrium. The peak incidence of endometrial cancer
+ is in the postmenopausal years, resulting from prolonged exposure to estrogen, unopposed by
+ progesterone. The medical belief* that "ovulation produces estrogen," and that the absence of
+ menstruation means an absence of estrogen, has been very harmful to women's health.
+
+
+
+ Several laboratories, from the 1950s through the 1980s, investigated the causes of age-related
+ infertility. A.L. Soderwall, among others, demonstrated that an excess of estrogen makes it
+ impossible for the uterus to maintain a pregnancy.
+
+
+ Subsequently, his lab showed that neither changes in the eggs nor changes in the uterus could
+ explain age related infertility. Altered pituitary hormone cycles, resulting from changes in the
+ brain, could account for the major changes in the ovaries and uterus.
+
+
+
+ Other experimenters, including P.M. Wise, V.M. Sopelak and R.L. Butcher (1982), P. Ascheim (1983),
+ and D.C. Desjardins (1995) have clarified the interactions between the ovaries and the brain.
+ For example, when the ovaries of an old animal are transplanted into a young animal, they are
+ able to function in response to the new environment, but when the ovaries of a young animal are
+ transplanted into an old animal, they fail to cycle. However, if the ovaries are removed from an
+ animal when it's young, so that it lives to the normal age of infertility without being
+ regularly exposed to surges of estrogen, it will then be able to support normal cycles when
+ young ovaries are transplanted into it. But if it received estrogen supplements throughout its
+ life, transplanted young ovaries will fail to cycle.
+
+
+
+ The work of Desjardins and others has demonstrated that free radicals generated by interactions of
+ estrogen and iron with unsaturated fatty acids are responsible for damage to brain cells
+ (Desjardins, et al., 1992). The damaged inhibitory nerve cells allow the pituitary to remain in
+ a chronically active state; in old rats, this can produce a state of constant estrus. Several
+ groups (Powers, et al., 2006; Everitt, et al., 1980; Telford, et al., 1986) have shown that
+ removal of the pituitary gland can greatly extend lifespan, if thyroid hormone is
+ supplemented.
+
+
+
+ One of the animal "models" used to study hot flashes is morphine withdrawal. The model seems
+ relevant to human hot flashes, because estrogen can stop the morphine withdrawal flushing, and
+ estrogen's acute and chronic effects on the brain-pituitary-ovary system involve the endorphins
+ and the opioidergic nerves (Merchenthaler, et al., 1998; Holinka, et al., 2008).
+
+
+ In young rats, sudden morphine withdrawal caused by injecting the anti-opiate naloxone, causes the
+ tail skin to flush, with a temperature increase of a few degrees, and causes the core body
+ temperature to fall slightly. However, old animals respond to the withdrawal in two different
+ ways. One group responded to the naloxone with an exaggerated flushing and decrease of core
+ temperature. The other group of old rats, which already had a lower body temperature, didn't
+ flush at all (Simpkins, 1994). I think this provides an insight into the reason that menopausal
+ treatment with estrogen can relieve some hot flashes--estrogen treatment might create a flush
+ resistant state similar to that of the cooler old animals in Simpkins' experiment.
+
+
+ It has been known for a long time, from studies in animals and people, that estrogen lowers body
+ temperature, and that this involves a tendency to increase blood flow to the skin in response to
+ a given environmental temperature, that is, the temperature "set-point" is lowered by estrogen.
+ Besides increasing heat loss, estrogen decreases heat production. These physiological effects of
+ estrogen can be seen in the normal menstrual cycle, with progesterone having the opposite effect
+ of estrogen on metabolic rate, skin circulation, body temperature, and heat loss. This causes
+ the familiar rise in temperature when ovulation occurs. Occasionally, young women will
+ experience hot flashes during the luteal phase of their menstrual cycle because of insufficient
+ progesterone production, or at menstruation, when the corpus luteus stops producing
+ progesterone.
+
+
+
+ Estrogen increases the free fatty acids circulating in the blood, and this shifts metabolism away
+ from oxidation of glucose to oxidation of fat, and it also reduces oxidative metabolism, for
+ example by lowering thyroid function (Vandorpe and Kühn, 1989). These changes are analogous to
+ those of fasting, in which metabolism shifts to the oxidation of fatty acids for energy, causes
+ decreased body temperature, and in some animals leads to a state of torpor or hibernation.
+
+
+
+ Despite decreasing oxidative metabolism, estrogen stimulates the adrenal cortex, both directly and
+ indirectly through the brain and pituitary, increasing the production of cortisol. Cortisol, by
+ increasing protein turnover, can increase heat production, but this effect isn't necessarily
+ sufficient to maintain a normal body temperature. It increases blood glucose, mainly by blocking
+ its use for energy production, but the glucose is derived from the breakdown of muscle protein.
+ It allows some glucose to be stored as fat. Sudden increases in the amount of glucose can lower
+ adrenaline, and chronically excessive cortisol tends to suppress adrenaline. Cushing's syndrome
+ (produced by excessive cortisol) commonly involves flushing and depression, both of which are
+ likely to be related to the decreased action of adrenaline.
+
+
+
+ While the biological changes occurring at menopause and during hot flashes are very similar to some
+ of the direct actions of estrogen, and although the menopause itself is the result of prolonged
+ exposure to estrogen, very large doses of estrogen can, in many women (as well as in morphine
+ addicted rats), stop the flushing. In some of the published animal experiments, effective doses
+ of estrogen were about 2000 times normal, and in some human studies, the dose was 30 times
+ normal. By blocking the production of heat, the estrogen treatments might be creating conditions
+ similar to those in Simpkin's cooler old rats, which failed to flush during morphine withdrawal.
+ Menopausal estrogen treatment is known to lower temperature (Brooks, et al., 1994).
+
+
+
+ Since the Women's Health Initiative publicized the dangers of estrogen, there has been some
+ interest in alternative treatments for hot flashes. Since a reduced production of progesterone
+ has been associated with hot flushes for several decades, it isn't surprising that it is now
+ being tested as an alternative to estrogen. Recently, 300 mg of oral progesterone was found to
+ be effective for decreasing hot flashes, and a month after discontinuing it, the hot flushes
+ were still less frequent than before using it (Prior and Hitchcock, 2012). Previously,
+ transdermal progesterone was found to be effective (Leonetti, et al., 1999).
+
+
+
+ One of the things progesterone does is to stabilize blood sugar. In one experiment, hot flashes
+ were found to be increased by lowering blood sugar, and decreased by moderately increasing blood
+ sugar (Dormire and Reame, 2003).
+
+
+ Hypoglycemia increases the brain hormone, corticotropin release hormone, CRH (Widmaier, et al.,
+ 1988), which increases ACTH and cortisol. CRH causes vasodilation (Clifton, et al., 2005), and
+ is more active in the presence of estrogen. Menopausal women are more responsive to its effects,
+ and those with the most severe hot flushes are the most responsive (Yakubo, et al., 1990).
+
+
+
+ The first reaction to a decrease of blood glucose, at least in healthy individuals, is to increase
+ the activity of the sympathetic nervous system, with an increase of adrenaline, which causes the
+ liver to release glucose from its glycogen stores. The effect of adrenaline on the liver is very
+ quick, but adrenaline also acts on the brain, stimulating CRH, which causes the pituitary to
+ secrete ACTH, which stimulates the adrenal cortex to release cortisol, which by various means
+ causes blood sugar to increase, consequently causing the sympathetic nervous activity to
+ decrease. Even when the liver's glycogen stores are adequate, the system cycles rhythmically,
+ usually repeating about every 90 minutes throughout the day.
+
+
+
+ Sympathetic nervous activity typically causes vasoconstriction in the skin and extremities,
+ reducing heat loss, but the small cycles in the system normally aren't noticed, except as small
+ changes in alertness or appetite. With advancing age, most tissues become less sensitive to
+ adrenaline and the sympathetic nervous stimulation, and the body relies increasingly on the
+ production of cortisol to maintain blood glucose. Many of the changes occurring around the
+ menopause, such as the rise of free fatty acids and decrease of glucose availability, increase
+ the sensitivity of the CRH nerves, causing the fluctuations of the adrenergic system to cause
+ larger increases of ACTH and cortisol. Estrogen is another factor that increases the sensitivity
+ of the CRH nerves, and unsaturated fatty acids (Widmaier, et al. 1995) and serotonin
+ (Buckingham, et al., 1982) are other factors stimulating it. Serotonin, like noradrenalin, rises
+ with hypoglycemia (Vahabzadeh, et al., 1995), and estrogen contributes to hypoglycemia, by
+ impairing the counterregulatory system (Cheng and Mobbs, 2009).
+
+
+
+ With the reduced vasoconstrictive effects of the sympathetic nerves, and the increased activity of
+ CRH, cyclic vasodilation under the influence of cortisol will become more noticeable. With the
+ onset of menopause, and in proportion to the number and intensity of symptoms (on the Greene
+ Climacteric Scale), the daily secretion of cortisol was increased (Cagnacci, et al.,
+ 2011).
+
+
+
+ Once the ideologically based doctrine of menopause as estrogen deficiency is discarded, it's
+ possible to see its features as clues to the ways in which "stress" contributes to the
+ age-related degeneration of the various systems of the body--not just the reproductive system,
+ but also the immune system, the nutritive, growth, and repair processes, and the motivational,
+ emotional, and cognitive processes of the nervous systems. The changes around menopause aren't
+ the same for all women, but the ways in which they vary can be understood in terms of the basic
+ biological principles of energy and adaptation that are universal.
+
+
+
+ Each type of cell and organ is subject to injury, and in some cases these injuries are
+ cumulative. In the healthy liver, which stores glycogen, toxins can be inactivated, for
+ example by combining with glucuronic acid, derived from the stored glucose. With injury,
+ such as alcoholism combined with a diet containing polyunsaturated fats, the liver's
+ detoxifying ability is reduced. Even at an early stage, before there is a significant
+ amount of fibrosis, the reduced activity of the liver causes estrogen to accumulate in
+ the body. Estrogen's valuable actions are, in health, exerted briefly, and then the
+ synthesis of estrogen is stopped, and its excretion reduces its activity, but when the
+ liver's function is impaired, estrogen's activity continues, causing further
+ deterioration of liver function, as well as injury of nerves such as Desjardins
+ described, and the systemic energy shifts and stress activations mentioned above.
+
+
+
+ Besides lowering the liver's detoxifying ability, stress, hypoglycemia, malnutrition,
+ hypothyroidism, and aging can cause estrogen to be synthesized inappropriately and continuously.
+ With aging, estrogen begins to be produced throughout the body--in fat, muscles, skin, bones,
+ brain, liver, breast, uterus, etc. Polyunsaturated fats are a major factor in the induction and
+ activation of the aromatase enzyme, which synthesizes estrogen.
+
+
+
+ Increased synthesis of estrogen, with aromatase, and decreased excretion of it, by the liver and
+ kidneys, are only two of the processes that affect the influence of estrogen during aging.
+ Cellular stress (chemical, mechanical, hypoxemic, hypoglycemic [Clere, et al., 2012; Aguirre, et
+ al., 2007, Zaman, et al., 2006, Saxon, et al., 2007; Tamir, et al., 2002; Briski, et al., 2010])
+ increases estrogen receptors (which activate CRH and the stress response). The presence of
+ estrogen receptors means that estrogen will be bound inside cells, where it acts to modify those
+ cells. Before estrogen can reach the liver to be inactivated, it must be released from cells.
+ Ordinarily, the cyclic production of progesterone has that function, by destroying the
+ estrogen-binding proteins. Progesterone also inhibits the aromatase which synthesizes estrogen,
+ and shifts the activities of other enzymes, including sulfatases and dehydrogenates, in a
+ comprehensive process of eliminating the presence and activity of estrogen. At menopause, when
+ the ovary fails to produce the cyclic progesterone, all of these processes of estrogen
+ inactivation fail. In the absence of progesterone, cortisol becomes more active, increasing
+ aromatase activity, which now becomes chronic and progressive. The decrease of progesterone
+ causes many other changes, including the increased conversion of polyunsaturated fatty acids to
+ prostaglandins, and the formation of nitric oxide, all of which contribute to the tendency to
+ flush.
+
+
+
+
+
+ *The limits of the belief system or consciousness of US medicine are nicely defined by the topics
+ included in the Index Medicus, which was published from 1879 to 2004, by the Surgeon General's
+ Office of the U.S. Army, the American Medical Association, and the National Library of Medicine,
+ at different times. If you look up any important topic in physiology or biochemistry in an index
+ of scientific publications such as Biological Abstracts or Chemical Abstracts, and then look for
+ the same subject in the Index Medicus, you will find some startling differences--long delays and
+ antagonistic attitudes. At first the discrepancies seem ludicrous and hard to account for, but I
+ think they can be explained by recognizing that the editors of medical journals consider science
+ to be their enemy.
+
+
+
+
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+
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+ Sakata T, Yoshimatsu H.
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+ vasodilation during postmenopausal hot flash episodes. Hubing KA, Wingo JE, Brothers RM, Del
+ Coso J, Low DA, Crandall CG.
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+ Cancer Epidemiol Biomarkers Prev. 2008 Mar;17(3):680-7. Nonsteroidal anti-inflammatory drug
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+ Maturitas. 1998 Nov 16;30(3):307-16. The effect of estrogens and antiestrogens in a rat model for
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+ Menopause. 2005 Mar;12(2):210-5. Adipose aromatase gene expression is greater in older women and is
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+ concentration in healthy subjects. Watanabe T, Akishita M, Toba K, Kozaki K, Eto M, Sugimoto N,
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+
+
+
+ © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com
+
+
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+
+ How do you know? Students, patients, and discovery
+
+
+ How do you know? Students, patients, and discovery
+
+
+
+
+ "For the real world has inexhaustible splendour, the real life is full of meaning and abundance, where we
+ grasp it, it is full of miracles and glory."
+ N. Hartmann
+
+
+ "I am myself plus my circumstances"
+ Jose Ortega y Gasset
+
+
+ Knowledge should be useful and provisional.
+
+
+ I think comparing the doctor-patient relationship with the teacher-student relationship can be useful, and
+ it might suggest ways that both of them could be made more productive, with implications for the nature of
+ learning and knowing.
+
+
+ 40 or 50 years ago, advocates of student-centered education were encouraged by the popularity of
+ psychologist Carl Rogers' client centered therapy. Rogers was interested in what made some therapists
+ successful, and he found that their personality and attitude, not their theories or techniques, accounted
+ for their success. Successful therapists had three essential traits. They offered their clients acceptance
+ or "unconditional positive regard" and empathic understanding, and they themselves were congruent, not
+ presenting a facade of authority or esoteric knowledge. According to Rogers, "accurate diagnosis" and
+ "specific treatment" didn't have anything to do with helping the client.
+
+
+
+ Some therapists thought Rogers' approach was impractical, others were sure it was foolish. Medically
+ oriented psychiatrists saw Roger's prestige among psychologists as evidence that psychology wasn't suited
+ for dealing with the "mentally ill," who needed authoritative diagnosis and treatment--such as drugs,
+ convulsive shock, or surgery. Scientifically, however, Rogers' ideas were supported by evidence, and medical
+ psychiatry had no evidence to support many of its diagnostic concepts or their therapeutic usefulness.
+
+
+ Most university professors felt that Rogers' ideas were irrelevant to their educational work, and some
+ clearly saw their own function as being a sort of Malthusian selection of the fittest, and deliberately
+ designed their classes as barriers that only a few could surmount.
+
+
+ When I taught English composition, instructors were told that they must grade according to a standard
+ scoring system for errors of grammar, punctuation, spelling, and diction. Our success was seen in terms of
+ the number of freshmen who had dropped out by the end of the year, as evidence that the department had "high
+ standards." Knowing that system, most students chose to write in the style of the first grade "See Spot run"
+ readers, hoping that they could handle the mechanics of writing if they reduced the complexity and content
+ of their essays. It didn't work, and they didn't improve during the weeks when their mistakes were being
+ brought painfully to their attention. Since I hated reading their meaningless efforts, I told them that I
+ was going to grade them on content, rather than punctuation and spelling, and that they should try to write
+ about something that was important to them. Only their success in communicating something would be graded.
+ Their papers became more readable, and the interesting thing was that the mechanical things improved
+ immediately. (The intention to communicate something is the real source of structure in language.) I had
+ another teacher score some of their compositions, and he confirmed that they had improved according to the
+ department's system. The attempt to steer a person can make it hard for them to move, because it inactivates
+ their own guidance system.
+
+
+
+ A physics professor would notice that writing classes have a lot in common with psychotherapy, and would
+ dismiss the possibility that such an approach could be used in serious education.
+
+
+ Professors of medicine see themselves as models of the authority that their students will need to apply in
+ dealing with patients, and the physicians trained in the authoritarian style are likely to see their
+ patients as recipients of their medical knowledge, rather than as occasions for listening and learning
+ something new.
+
+
+ Students entering these disciplines must expect to be disciplined. This means that they learn not to ask
+ silly questions about the fundamental assumptions of their profession. Their common sense of meaning, their
+ original guidance system, must be inactivated to keep them from asking questions such as "is that a disease
+ or a theory?" Some patients find that their physician has little patience for their questions, but most
+ patients don't want to ask questions, because they have been taught to respect the authorities.
+
+
+ Our nervous systems are made up of physiology and culture.
+
+
+ That can be a philosophical problem, because our experience is governed by our composition. In people like
+ Heraclitus, physiology was in the foreground, and in people like Plato, culture was in the foreground.
+ (Heraclitus understood that things are always becoming, Plato believed that change wasn't real.) To change
+ someone's mind, it's necessary to change the way they experience themselves and the world, and that requires
+ changing their substance.
+
+
+
+ In the 1950s a group called "Synectics" was formed to study the creative process. They found that having an
+ expert in the group could be useful, but it could also often stifle the group's ability to find a good
+ solution to a problem. W.J.J. Gordon described their method as "trusting things that are alien, and
+ alienating things that are trusted." They used metaphorical thinking to help them to see the complexity and
+ potentiality of a situation, and to go beyond the existing understanding.
+
+
+ Professors and physicians too often present themselves as having "definitive knowledge" about a subject. For
+ people who already have "definitive knowledge" about something, anomalous facts (if they are perceived at
+ all) will simply remain anomalous and will be quickly forgotten. The things they produce will be extensions
+ of what already exists. For others, things that aren't easily explained have special interest, and cause
+ them to ask new questions. New perspectives can lead to new possibilities and new realities.
+
+
+ Once during a lecture, Alfred Korzybski offered his students some cookies, which they seemed to enjoy, then
+ he showed them a label on the bag, "dog cookies," and some of them felt sick. "I have just demonstrated that
+ people don't just eat food, but also words, and that the taste of the former is often outdone by the taste
+ of the latter." Hypnotists have often demonstrated that words can have physiological effects.
+
+
+
+ Many of our institutions use language as a system for preserving culture, that is, for preventing change.
+ Korzybski wanted to correct the cultural habit of making abstractions seem like objects or "elements," by
+ making people aware of the degree of abstraction in their words. This can be useful, but his book has been
+ used to promote an extreme linguistic relativism in the theory of knowledge and science, placing "meaning"
+ entirely within the nervous system.
+
+
+ This approach evades the fact that patterns exist objectively, and that they can be perceived as they unfold
+ through time. Although Korzybski thought he was teaching people to overcome the limitations of thinking in
+ the style of Aristotle or Plato, he was supporting an attitude that would make it impossible to perceive in
+ the style of Heraclitus.
+
+
+ If Heraclitus said it's impossible to step in the same river twice, his comment was directed to those who
+ ignore the rich complexity of experience because of stereotyped "elemental" thinking. He was pointing to the
+ abundance of the world, but elemental-concept thinkers have felt that he simply negated their objective
+ meanings.
+
+
+ To perceive another person accurately requires the ability to perceive the person as a pattern unfolding
+ coherently through time, as a potential realizing itself. Carl Rogers' insight was that one's awareness of
+ being perceived in this way encourages the unfolding of potentials.
+
+
+ The refusal of institutions or individuals to perceive others in this way is an imposition of their way of
+ understanding, and is itself a form of oppression. People who think in terms of "professional training"
+ often describe learning in terms of "conditioned reflexes," producing a desired response to each stimulus.
+
+
+
+ The terms "conditioned reflex" and "conditioning" were introduced into psychology by the behaviorist J. B.
+ Watson, who mistranslated and misrepresented Pavlov's ideas, and who insisted that the ideas of
+ consciousness, volition, and self should be eliminated from the science of psychology.
+
+
+ The orienting reflex, the alertness provoked by something new, was described by Sechenov in 1863, and
+ explored by Pavlov (who also called it the "what is that? reflex" and the "exploration reflex") who
+ considered it to be our most basic and most powerful reflex. The fact that novelty powerfully arouses our
+ exploratory systems means that we have a mental image of our familiar environment, and that a change in that
+ environment requires us to investigate the properties of the new thing, to see whether it can be explained
+ by the things we already know, or whether it requires us to change our basic ideas about our place in our
+ surroundings. For Pavlov, the study of psychology or physiology without consciousness was simply crazy.
+
+
+ Pavlov said that he studied nutrition to understand consciousness and the nervous system, because eating is
+ our closest interaction with the world. Our brain is part of our digestive system. But eating has become
+ highly institutionalized and influenced by our cultural beliefs. If people begin to think about the meanings
+ of eating, they are beginning a process of cultural and philosophical criticism.
+
+
+ Helping people with physical problems (such as obesity, headaches or joint or nerve pain, or named diseases)
+ and helping people who want to understand something about the world beyond themselves, are structurally
+ similar, but in the issues of health the questions and the potential answers are more clearly present and
+ immediate.
+
+
+ The Synectics group began with the study of artistic creation, but they found that it was easier to evaluate
+ their progress when they concentrated on technical invention. They found, as Pavlov had, that consciousness
+ and meaning could best be studied in concrete situations. The process of goal-seeking was to be studied in
+ action.
+
+
+
+ I see the therapeutic or educational or productive situation as a goal-directed biological and social
+ interaction, and the goal can be either the creation of something new and better, or simply the preservation
+ and application of something already existing.
+
+
+ Until just about a generation ago, "teleology" (especially in biological explanation) was considered to be
+ metaphysical and inappropriate for science. Norbert Wiener, who coined the word "cybernetics" (from Greek
+ for "proficient pilot" or "good steersman") helped to change attitudes toward the word when he used the
+ phrase "teleological mechanism" to describe cybernetic control systems.
+
+
+ A goal-directed system is one that senses its actions and makes adaptations so that its actions can be
+ refined to achieve a purpose. Between 1932 and 1935, a student and colleague of Pavlov's, P.K. Anokhin,
+ developed this idea of self-regulating systems, and originated the concept of feedback, in describing the
+ ways organisms guide themselves and their adaptations. Building on Pavlov's work, and investigating the
+ origins of innate reflexes, he found principles that would explain the origin of organs and their functions,
+ and that would also apply to the interactions between individuals. The functional system on any level, in
+ embryology, psychology, or society, is a sequence of interactions with a useful result. Movement towards a
+ goal is adaptive, and the system is shaped by the adaptations it makes in moving toward the goal. Resources
+ are mobilized to meet needs, changing the system as it moves towards its goal.
+
+
+ Since there is always novelty in the real world as contexts change, the exploratory function is causing us
+ to continually revise our understanding. Every question forms a functional system, and our brain adapts as
+ we find answers.
+
+
+ This kind of systems theory and self-regulation theory developed along with the field theories in
+ embryology, psychology, chemistry, and some branches of physics. Pattern and analogy were central to their
+ approach. The functional systems are processes that occupy time and space.
+
+
+
+ The "field" idea in biology (wholes shaping themselves) can be understood by considering its opposite, the
+ belief that cells are guided by their genes (producing a mosaic of parts). That idea, in its extreme form,
+ claimed that cells contained an internal map and an internal clock telling them when and where to move and
+ how to change their form and function as they matured and aged. In reality, cells communicate with
+ surrounding cells and with the material between cells. The existence of long-range ordering processes
+ between atoms, molecules, and cells threatened some of the central dogmas of the sciences.
+
+
+ Although Norbert Wiener popularized some aspects of the "teleological" approach to regulatory systems in the
+ 1950s, and saw analogies between the teleological machines and the way the brain functions in Parkinson's
+ disease, by 1950 the digital approach to information processing, storage, and transmission was displacing
+ analog devices in computation and engineering, and was compatible with theories of intelligence, such as
+ neo-Kantianism, that believed that human intelligence can be defined precisely, in terms of discrete rules
+ and operations. Field thinking in embryology, cancer theory, psychology, and other sciences effectively
+ disappeared--or "was disappeared," for ideological reasons.
+
+
+ Wiener's goal-directed machines, like Anokhin's functional systems, worked in space and time, and the idea
+ of steering or guidance assumes a context of time and space in which the adjustments or adaptations are
+ made. Analog computers and control systems in various ways involved formal parallels with reality. The
+ components of the system, like reality, occupied space and time.
+
+
+ Digital computers, with their different history and functions, for example their use for creating or
+ breaking military codes, didn't intrinsically model reality in any way. Information had to be encoded and
+ processed by systems of definitions. A sequence of binary digits has meaning only in terms of someone's
+ arbitrary definitions.
+
+
+
+ Parallel with the development of electronic digital computing machines, binary digital theories of brain
+ function were being developed, by people who subscribed to views of knowledge very different from those of
+ Anokhin and Wiener. (Anokhin argued against the idea that nerves use a simple binary code.) These computer
+ models of intelligence justify educational practices based on authoritative knowledge and conditioned
+ (arbitrary) reflexes. Neo-Kantianism has been the dominant academic philosophy in the U.S., turning
+ philosophy into epistemology to exclude ontology. "Operationism" and logical positivism share with
+ neo-Kantianism its elimination of ontology (concern with being itself).
+
+
+ In the 1960s, Ludwig von Bertalanffy developed a theory of systems, defining a system as an "arrayed
+ multitude of inter-linked elements." Although it was intended as a description of biological systems, it
+ reduced the teleological factors, needs and goals, to a kind of mechanical inner program, such as
+ "regulatory genes." "Following old modes of thought, some called this orderliness of life 'purposiveness'
+ and sought for the 'purpose' of an organ or function. However, in the concept of a 'purpose' a desiring or
+ intending of the goal always appeared to be involved--the type of idea to which the natural scientist is
+ justly unsympathetic" (von Bertalanffy).
+
+
+
+ His system theory was highly compatible with programmed digital computers, that could define the
+ interactions of "elements," but unlike Anokhin's definition of functional systems, it lacked a
+ pattern-forming mechanism. In Anokhin's view, the system is formed by seeking its goal, and perceiving its
+ progress toward the goal.
+
+
+ Carl Rogers' approach to person-centered processes recognized that the interacting therapist and client or
+ teacher and student were a formative system, rather than just an occasion for one to inform the other.
+
+
+ In the Synectics group, they learned to identify the types of deeply involved interaction that would lead to
+ the best inventions. As in Anokhin's functional systems, resources are mobilized or generated as they are
+ needed. Like Anokhin, they showed that the process of creating something new can be understood and
+ controlled.
+
+
+ Every meaningful interaction involves formative systems.
+
+
+
+ Stimulation of sensory nerves can cause cells to move into the stimulated area, causing the organ to grow.
+ Environmental enrichment causes brains to become larger, and to metabolize at a higher rate. All of these
+ processes, from the level of energy production to the birth of new cells and the creation of new patterns in
+ the brain, are called up in the formation of a functional system.
+
+
+ The studies of organismic coherence by Mae-Wan Ho and Fritz Popp appear to support the idea that even the
+ alignment of molecules in cells is responsive to the state of the entire organism.
+
+
+ The reason this seems implausible to most biologists is that cells are commonly still seen as analogous to
+ little test-tubes in which chemical processes occur as the result of random collisions between molecules
+ floating in water. But Sidney Bernhard's study of glycolysis showed that the reactive sugar molecules are
+ passed individually from one enzyme to the next, in an orderly manner.
+
+
+ In this system, the flow of energy, a series of oxidations and reductions changing glucose into other
+ substances, effectively "pulls" the molecules through the system, contributing to order on a molecular
+ level. Function creates structure, which supports function.
+
+
+ Self-regulating systems are self-ordering systems. When a person is allowed to function freely as a
+ goal-directed, questioning system, the formation of patterns in the brain will be spontaneous and
+ appropriate, and orderly. Knowing is the ability to hold patterns in awareness. Knowledge, rather than being
+ stored like money in the bank, is something that is regenerated, or generated, as we need it.
+
+
+ When our own steering system is commandeered by the authorities, our patterns of knowledge will be
+ compartmented, and arranged in a fixed pattern. This kind of knowledge either deteriorates, or it seeks more
+ of its own kind.
+
+
+
+ While self-regulation and the generation of knowledge are pleasurable, having knowledge imposed isn't.
+
+
+ Korzybski was right in warning about the dangers of letting names become "elements." This perception led
+ Paolo Freire to emphasize the educational importance of critically giving things their appropriate names,
+ rather than just "banking" the names given by an authority. "To exist, humanly, is to name the world, to
+ change it. Once named, the world in its turn reappears to the namers as a problem and requires of
+ them a new naming. Human beings are not built in silence, but in word, in work, in
+ action-reflection." ". . . to speak a true word is to transform the world." "'Problem-posing' education,
+ responding to the essence of consciousness--intentionality--rejects communiques and embodies communication"
+ (Freire, 1993).
+
+
+ Having the power to assign names is a source of power and wealth. The pharmaceutical industry has been
+ accused of inventing new diseases to sell new drugs for treating them. Old definitions of cancer are hard to
+ change, when the medical profession has invested so much in treatments--radiation and cytotoxic
+ chemotherapy--which conflict with newer biological understanding of cancer.
+
+
+
+ The person who is learning is critically interacting with both nature and culture, with practical issues and
+ theories.
+
+
+ Applying this to practical problems of health and nutrition, a first step is to begin to think about which
+ things are theories or deductions from theories, which are habits, and which things are felt needs or
+ appetites, and to get in the habit of watching processes or things--such as "signs" and "symptoms"--develop
+ through time.
+
+
+ With practice, people can begin to see themselves as functional systems in their main activities, such as
+ eating, and to watch how their needs influence their actions, and what effects different ways of eating have
+ on their other functions, such as sleeping and working. Do appetites govern the timing of meals and the
+ choice of foods? How does the time of day or time of month affect appetites? People often watch for effects
+ of foods, but usually only for a few minutes or hours after eating. Some foods can produce symptoms days
+ after they were eaten, and the activation of the digestive system by a recent meal can cause a reaction to
+ something eaten previously.
+
+
+ Our traditional cultures, and advertising and schools give us definitions and expectations relating to foods
+ and symptoms and physiology, and they teach us to think of our bodies in terms of an "immune system,"
+ "endocrine system," "digestive system," "nervous system," and "circulatory system," which are mainly
+ anatomical concepts that are more useful to the drug companies than to the consumer of culture. Both
+ conventional and alternative approaches to medicine and health are likely to let those arbitrary ideas of
+ systems cause them to overlook real, but unnamed, processes.
+
+
+ When the organism is seen as a mosaic of parts, rather than as a system of developing fields, medical
+ treatments for one part, such as the "circulatory system," are likely to cause problems in other "systems,"
+ because the "parts" being treated don't exist as such in the real organism, with the result that the
+ treatments are seldom biologically reasonable.
+
+
+ Besides learning to perceive one's own physiology and becoming aware of the processes of perceiving and
+ knowing so that they can be improved, it's important to seek information to expand the interpretive
+ framework, and to look for new contexts and implications.
+
+
+
+ Reading with a critical imagination is as important for science as it is for literature or advertising. Good
+ literature often opens expansive new ways of seeing the world, and good science writing can do that too, but
+ too often scientific publications have ulterior motives, and should be read the way advertising propaganda
+ is read.
+
+
+ Some publications now require authors to state their conflicts of interest (such as receiving money from a
+ drug company while testing a drug), but editors and publishers, who choose which studies will be published,
+ seldom reveal their conflicts of interest. As Marcia Angell showed, editorial choices can turn statistical
+ randomness into statistical significance. Private ownership of science journals permits control of their
+ content.
+
+
+ Besides being aware of the conflicts of interest and the frequent insignificance of "statistical
+ significance," it's possible to recognize some features of the style of argument which is often used in
+ science propaganda. A deductive style, rather than a descriptive and inductive style is extremely common in
+ technical writing, and it should always lead the reader to question the principle from which deductions are
+ made.
+
+
+ "Membranes are made from Essential Fatty Acids, therefore those fatty acids are nutritionally essential."
+ But cells can multiply in a culture medium that provides no fats. In biology, the most popular "principles"
+ are simply dogmatic beliefs about genes and membranes.
+
+
+ In physics, where testable inferences can be drawn from arbitrary assumptions or doctrines, predictions that
+ may be made based on different assumptions are often ignored for ideological reasons. This ideological
+ quality of physics can permeate the other sciences when they use reductionist explanations.
+
+
+ Korzybski felt he was helping humanity to escape "word magic" and to advance to a mathematical view of the
+ world. But the same processes that caused people to "confuse words with things" can cause people to confuse
+ mathematical descriptions with reality.
+
+
+
+ "Chaos theory," which was a faddish excitement about the ability to generate unpredictable output from a
+ simple rule (which could be endlessly repeated by a computer), has been suggested to explain many things in
+ biology, including heart rate variability. It doesn't. Instead, it has probably had a slightly harmful
+ effect, by distracting attention from real biological pattern- forming processes.
+
+
+ Real substance can sometimes be modeled by descriptions of randomness, but substances at all levels have
+ intrinsic pattern-forming tendencies, and context-dependent histories. Water, for example, has structure and
+ structural memory that can affect even simple chemical reactions, and even gases have internal complexities
+ that are often ignored. Real observations shouldn't be displaced by theories. The ideal and identical atoms
+ of the reductionists are a crude fantasy, invented, more or less consciously, to serve their ideological
+ purposes. One purpose has been to justify their abstract models of reality. A particularly noxious way of
+ modeling reality has been based on the assumption of randomness, justifying a statistical view of all
+ things.
+
+
+ The neo-Kantian philosophy that has dominated US universities for more than a century argues that our senses
+ (even when extended instrumentally) are limited, so our knowledge must be limited--we can only speak of
+ theories or interpretations, not of being. The world we see is, according to them, only an artifact of our
+ senses. A popular example is that the flower a bee sees is different from the flower a human sees, because
+ the bee's eye is sensitive to ultraviolet light. (The triviality of the example is shown by the fact that
+ when a person's lens is removed because of a cataract, ultraviolet light becomes visible, because it is no
+ longer blocked by the tissue that is many times thicker than a bee's lens.) There is a straw-man quality to
+ their arguments against philosophical realism and empirical science:
+ No one claims that our senses deliver complete knowledge all at once. What the realists claim is that
+ interacting with the world is an endless source of valid knowledge.
+
+
+
+ When reading science articles, or listening to lectures, and even while privately thinking about
+ experiences, it can be useful to watch for the improper use of assumptions. Our understanding has been
+ shaped by the assumptions of our culture, and these assumptions present an attitude toward the nature of the
+ world, in some cases even about the ontology that our philosophers have said is beyond our reach. "Evolution
+ is shaped by random mutations," "nuclear decay is random," "the universe is expanding," "entropy only
+ increases," "DNA controls inheritance," "membrane pumps keep cells alive," and all of the negative
+ assumptions that have for so long denied the systematic generation of order.
+
+
+ Every communicative interaction is an opportunity for the discovery of new meanings and potentials.
+
+
+
+ Aristotelian motto: If the knower and the known form a functional system they are substantially
+ the same.
+
+
+ REFERENCES
+
+
+ P.K. Anokhin: 1975, The essays on physiology of functional systems.
+
+
+ 1978, Philosophical aspects of the theory of functional systems.
+
+
+ 1998, Cybernetics of functional systems: Selected works, Moscow, Medicine, 400 p., (in
+ Russian).
+
+
+ Pedagogy of the Oppressed,
+ by Paulo Freire. New York: Continuum Books, 1993.
+
+
+ Synectics,
+ W.J.J. Gordon, Harper & Row, 1961.
+
+
+ Crystals, Fabrics, and Fields : Metaphors of Organicism in Twentieth-Century Developmental
+ Biology, Donna Jeanne Haraway, 1976.
+
+
+ We Make the Road by Walking: Conversations on Education and Social Change,
+ Myles Horton, Paolo Freire, 1990.
+
+ Science and Sanity, Alfred Korzybski, 1933.
+
+ Alfred Korzybski, "The Role of Language in the Perceptual Processes," in Perception: An Approach to
+ Personality, edited by Robert R. Blake and Glenn V. Ramsey. 1951, The Ronald Press Company, New
+ York.
+
+
+
+ Marshall McLuhan: "...the devil is in the media," quoted by Derrick DeKerkhove, Director of the
+ McLuhan Program in Culture and Technology at the University of Toronto.
+
+
+ Biochemistry and Morphogenesis, by Joseph Needham. Cambridge University Press, 1942.
+
+
+ Cybernetics--or Control and Communication in the Animal and the Machine,
+
+ Norbert Wiener 1948
+
+
+
+ The Human Use of Human Beings, The Riverside Press (Houghton Mifflin Co.), 1950.
+
+
+
+ "...the rules of the war game never catch up with the facts of the real situation." "The future offers
+ very little hope for those who expect that our new mechanical slaves will offer us a world in which we
+ may rest from thinking. Help us they may, but at the cost of supreme demands upon our honesty and our
+ intelligence.
+ "
+ Norbert Weiner, God and Golem, Inc., 1964.
+
+
+ Digital thinking sees the organism as a mosaic of parts, making rigid and specific naming essential;
+ analog thinking sees the organism as fields in development, making flexibility in naming essential.
+
+
+ PS: When defense lawyers collaborate (collude) with prosecutors, it's considered a crime. What if
+ physicians, instead of covering up for each other, used the adversary system that is supposed to produce
+ the best knowledge in law and science, to evaluate their patient's diagnoses and treatments?
+
+
+ J Intern Med. 1999 Jan;245(1):57-61. Decreased heart rate variability in patients with type 1
+ diabetes mellitus is related to arterial wall stiffness. Jensen-Urstad K, Reichard P,
+ Jensen-Urstad M.
+
+
+
+ Eur J Appl Physiol. 2010 Apr 23. Heart period sensitivity to forced oscillations in ventilatory
+ pressure. Quint SR, Vaughn BV.
+
+
+ Copyright 2007. Raymond Peat, P.O. Box 5764, Eugene OR 97405. All Rights Reserved. www.RayPeat.comNot for
+ republication without written permission.
+
+
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+
+
+
+ TSH, temperature, pulse rate, and other indicators in hypothyroidism
+
+
+
+
+ TSH, temperature, pulse rate, and other indicators in hypothyroidism
+
+
+
+ Each of the indicators of thyroid function can be useful, but has to be interpreted in relation to
+ the physiological state.
+
+
+ Increasingly, TSH (the pituitary thyroid stimulating hormone) has been treated as if it meant
+ something independently; however, it can be brought down into the normal range, or lower, by substances
+ other than the thyroid hormones.
+
+
+ "Basal" body temperature is influenced by many things besides thyroid. The resting heart rate helps
+ to interpret the temperature. In a cool environment, the temperature of the extremities is sometimes a
+ better indicator than the oral or eardrum temperature.
+
+
+ The "basal" metabolic rate, especially if the rate of carbon dioxide production is measured, is very
+ useful. The amount of water and calories disposed of in a day can give a rough idea of the metabolic
+ rate.
+
+
+
+ The T wave on the electrocardiogram, and the relaxation rate on the Achilles reflex test are
+ useful.
+
+
+ Blood tests for cholesterol, albumin, glucose, sodium, lactate, total thyroxine and total T3 are
+ useful to know, because they help to evaluate the present thyroid status, and sometimes they can suggest
+ ways to correct the problem.
+
+
+ Less common blood or urine tests (adrenaline, cortisol, ammonium, free fatty acids), if they are
+ available, can help to understand compensatory reactions to hypothyroidism.
+
+
+ A book such as McGavack's The Thyroid, that provides traditional medical knowledge about
+ thyroid physiology, can help to dispel some of the current dogmas about the thyroid.
+
+
+ Using more physiologically relevant methods to diagnose hypothyroidism will contribute to
+ understanding its role in many problems now considered to be unrelated to the thyroid.
+
+
+
+
+
+
+
+ I have spoken to several people who told me that their doctors had diagnosed them as "both hypothyroid and
+ hyperthyroid." Although physicists can believe in things which are simultaneously both particles and not
+ particles, I think biology (and medicine, as far as it is biologically based) should occupy a world in which
+ things are not simultaneously themselves and their opposites. Those illogical, impossible diagnoses make it
+ clear that the rules for interpreting test results have in some situations lost touch with reality.
+
+
+ Until the 1940s, hypothyroidism was diagnosed on the basis of signs and symptoms, and sometimes the
+ measurement of oxygen consumption ("basal metabolic rate") was used for confirmation. Besides the
+ introduction of supposedly "scientific" blood tests, such as the measurement of protein-bound iodine (PBI)
+ in the blood, there were other motives for becoming parsimonious with the diagnosis of hypothyroidism. With
+ the introduction of synthetic thyroxine, one of the arguments for increasing its sale was that natural
+ Armour thyroid (which was precisely standardized by biological tests) wasn't properly standardized, and that
+ an overdose could be fatal. A few articles in prestigious journals created a myth of the danger of thyroid,
+ and the synthetic thyroxine was (falsely) said to be precisely standardized, and to be without the dangers
+ of the complete glandular extract.
+
+
+ Between 1940 and about 1950, the estimated percentage of hypothyroid Americans went from 30% or 40% to 5%,
+ on the basis of the PBI test, and it has stayed close to that lower number (many publications claim it to be
+ only 1% or 2%). By the time that the measurement of PBI was shown to be only vaguely related to thyroid
+ hormonal function, it had been in use long enough for a new generation of physicians to be taught to
+ disregard the older ideas about diagnosing and treating hypothyroidism. They were taught to inform their
+ patients that the traditional symptoms that were identified as hypothyroidism before 1950 were the result of
+ the patients' own behavior (sloth and gluttony, for example, which produced fatigue, obesity, and heart
+ disease), or that the problems were imaginary (women's hormonal and neurological problems, especially), or
+ that they were simply mysterious diseases and defects (recurring infections, arthritis, and cancer, for
+ example).
+
+
+
+ As the newer, more direct tests became available, their meaning was defined in terms of the statistical
+ expectation of hypothyroidism that had become an integral part of medical culture. To make the new TSH
+ measurements fit the medical doctrine, an 8- or 10-fold variation in the hormone was defined as "normal."
+ With any other biological measurement, such as erythrocyte count, blood pressure, body weight, or serum
+ sodium, calcium, chloride, or glucose, a variation of ten or 20 percent from the mean is considered to be
+ meaningful. If the doctrine regarding the 5% prevalence of hypothyroidism hadn't been so firmly established,
+ there would have been more interest in establishing the meaning of these great variations in TSH.
+
+
+ In recent years the "normal range" for TSH has been decreasing. In 2003, the American Association of
+ Clinical Endocrinologists changed their guidelines for the normal range to 0.3 to 3.0 microIU/ml. But even
+ though this lower range is less arbitrary than the older standards, it still isn't based on an understanding
+ of the physiological meaning of TSH.
+
+
+ Over a period of several years, I never saw a person whose TSH was over 2 microIU/ml who was comfortably
+ healthy, and I formed the impression that the normal, or healthy, quantity was probably something less than
+ 1.0.
+
+
+ If a pathologically high TSH is defined as normal, its role in major diseases, such as breast cancer,
+ mastalgia, MS, fibrotic diseases, and epilepsy, will simply be ignored. Even if the possibility is
+ considered, the use of an irrational norm, instead of a proper comparison, such as the statistical
+ difference between the mean TSH levels of cases and controls, leads to denial of an association between
+ hypothyroidism and important diseases, despite evidence that indicates an association.
+
+
+ Some critics have said that most physicians are "treating the TSH," rather than the patient. If TSH is
+ itself pathogenic, because of its pro-inflammatory actions, then that approach isn't entirely useless, even
+ when they "treat the TSH" with only thyroxine, which often isn't well converted into the active
+ triiodothyronine, T3. But the relief of a few symptoms in a small percentage of the population is serving to
+ blind the medical world to the real possibilities of thyroid therapy.
+
+
+
+ TSH has direct actions on many cell types other than the thyroid, and probably contributes directly to edema
+ (Wheatley and Edwards, 1983), fibrosis, and mastocytosis. If people are concerned about the effects of a TSH
+ "deficiency," then I think they have to explain the remarkable longevity of the animals lacking pituitaries
+ in W.D. Denckla's experiments, or of the naturally pituitary deficient dwarf mice that lack TSH, prolactin,
+ and growth hormone, but live about a year longer than normal mice (Heiman, et al., 2003). Until there is
+ evidence that very low TSH is somehow harmful, there is no basis for setting a lower limit to the normal
+ range.
+
+
+ Some types of thyroid cancer can usually be controlled by keeping TSH completely suppressed. Since TSH
+ produces reactions in cells as different as fibroblasts and fat cells, pigment cells in the skin, mast cells
+ and bone marrow cells (Whetsell, et al., 1999), it won't be surprising if it turns out to have a role in the
+ development of a variety of cancers, including melanoma.
+
+
+ Many things, including the liver and the senses, regulate the function of the thyroid system, and the
+ pituitary is just one of the factors affecting the synthesis and secretion of the thyroid hormones.
+
+
+ A few people who had extremely low levels of pituitary hormones, and were told that they must take several
+ hormone supplements for the rest of their life, began producing normal amounts of those hormones within a
+ few days of eating more protein and fruit. Their endocrinologist described them as, effectively, having no
+ pituitary gland. Extreme malnutrition in Africa has been described as creating ". . . a condition resembling
+ hypophysectomy," (Ingenbleek and Beckers, 1975) but the people I talked to in Oregon were just following
+ what they thought were healthful nutritional policies, avoiding eggs and sugars, and eating soy products.
+
+
+ Occasionally, a small supplement of thyroid in addition to a good diet is needed to quickly escape from the
+ stress-induced "hypophysectomized" condition.
+
+
+
+ Aging, infection, trauma, prolonged cortisol excess, somatostatin, dopamine or L-dopa, adrenaline
+ (sometimes; Mannisto, et al., 1979), amphetamine, caffeine and fever can lower TSH, apart from the effect of
+ feedback by the thyroid hormones, creating a situation in which TSH can appear normal or low, at the same
+ time that there is a real hypothyroidism.
+
+
+ A disease or its treatment can obscure the presence of hypothyroidism. Parkinson's disease is a clear
+ example of this. (Garcia-Moreno and Chacon, 2002: "... in the same way hypothyroidism can simulate
+ Parkinson's disease, the latter can also conceal hypothyroidism.")
+
+
+ The stress-induced suppression of TSH and other pituitary hormones is reminiscent of the protective
+ inhibition that occurs in individual nerve fibers during dangerously intense stress, and might involve such
+ a "parabiotic" process in the nerves of the hypothalamus or other brain region. The relative disappearance
+ of the pituitary hormones when the organism is in very good condition (for example, the suppression of ACTH
+ and cortisol by sugar or pregnenolone) is parallel to the high energy quiescence of individual nerve fibers.
+
+
+ These associations between energy state and cellular activity can be used for evaluating the thyroid state,
+ as in measuring nerve and muscle reaction times and relaxation rates. For example, relaxation which is
+ retarded, because of slow restoration of the energy needed for cellular "repolarization," is the basis for
+ the traditional use of the Achilles tendon reflex relaxation test for diagnosing hypothyroidism. The speed
+ of relaxation of the heart muscle also indicates thyroid status (Mohr-Kahaly, et al., 1996).
+
+
+ Stress, besides suppressing the TSH, acts in other ways to suppress the real thyroid function. Cortisol, for
+ example, inhibits the conversion of T4 to T3, which is responsible for the respiratory production of energy
+ and carbon dioxide. Adrenaline, besides leading to increased production of cortisol, is lipolytic, releasing
+ the fatty acids which, if they are polyunsaturated, inhibit the production and transport of thyroid hormone,
+ and also interfere directly with the respiratory functions of the mitochondria. Adrenaline decreases the
+ conversion to T4 to T3, and increases the formation of the antagonistic reverse T3 (Nauman, et al., 1980,
+ 1984).
+
+
+
+ During the night, at the time adrenaline and free fatty acids are at their highest, TSH usually reaches its
+ peak. TSH itself can produce lipolysis, raising the level of circulating free fatty acids.
+ This suggests that a high level of TSH could sometimes contribute to functional hypothyroidism, because of
+ the antimetabolic effects of the unsaturated fatty acids.
+
+
+ These are the basic reasons for thinking that the TSH tests should be given only moderate weight in
+ interpreting thyroid function.
+
+
+ The metabolic rate is very closely related to thyroid hormone function, but defining it and measuring it
+ have to be done with awareness of its complexity.
+
+
+ The basal metabolic rate that was commonly used in the 1930s for diagnosing thyroid disorders was usually a
+ measurement of the rate of oxygen consumption, made while lying quietly early in the morning without having
+ eaten anything for several hours. When carbon dioxide production can be measured at the same time as oxygen
+ consumption, it's possible to estimate the proportion of energy that is being derived from glucose, rather
+ than fat or protein, since oxidation of glucose produces more carbon dioxide than oxidation of fat does.
+ Glucose oxidation is efficient, and suggests a state of low stress.
+
+
+ The very high adrenaline that sometimes occurs in hypothyroidism will increase the metabolic rate in several
+ ways, but it tends to increase the oxidation of fat. If the production of carbon dioxide is measured, the
+ adrenaline/stress component of metabolism will be minimized in the measurement. When polyunsaturated fats
+ are mobilized, their spontaneous peroxidation consumes some oxygen, without producing any usable energy or
+ carbon dioxide, so this is another reason that the production of carbon dioxide is a very good indicator of
+ thyroid hormone activity. The measurement of oxygen consumption was usually done for two minutes, and carbon
+ dioxide production could be accurately measured in a similarly short time. Even a measurement of the
+ percentage of carbon dioxide at the end of a single breath can give an indication of the stress-free,
+ thyroid hormone stimulated rate of metabolism (it should approach five or six percent of the expired air).
+
+
+
+ Increasingly in the last several years, people who have many of the standard symptoms of hypothyroidism have
+ told me that they are hyperthyroid, and that they have to decide whether to have surgery or radiation to
+ destroy their thyroid gland. They have told me that their symptoms of "hyperthyroidism," according to their
+ physicians, were fatigue, weakness, irritability, poor memory, and insomnia.
+
+
+ They didn't eat very much. They didn't sweat noticeably, and they drank a moderate amount of fluids. Their
+ pulse rates and body temperature were normal, or a little low.
+
+
+ Simply on the basis of some laboratory tests, they were going to have their thyroid gland destroyed. But on
+ the basis of all of the traditional ways of judging thyroid function, they were hypothyroid.
+
+
+ Broda Barnes, who worked mostly in Fort Collins, Colorado, argued that the body temperature, measured before
+ getting out of bed in the morning, was the best basis for diagnosing thyroid function.
+
+
+ Fort Collins, at a high altitude, has a cool climate most of the year. The altitude itself helps the thyroid
+ to function normally. For example, one study (Savourey, et al., 1998) showed an 18% increase in T3 at a high
+ altitude, and mitochondria become more numerous and are more efficient at preventing lactic acid production,
+ capillary leakiness, etc.
+
+
+
+ In Eugene during a hot and humid summer, I saw several obviously hypothyroid people whose temperature seemed
+ perfectly normal, euthyroid by Barnes' standards. But I noticed that their pulse rates were, in several
+ cases, very low. It takes very little metabolic energy to keep the body at 98.6 degrees when the air
+ temperature is in the nineties. In cooler weather, I began asking people whether they used electric
+ blankets, and ignored their temperature measurements if they did.
+
+
+ The combination of pulse rate and temperature is much better than either one alone. I happened to see two
+ people whose resting pulse rates were chronically extremely high, despite their hypothyroid symptoms. When
+ they took a thyroid supplement, their pulse rates came down to normal. (Healthy and intelligent groups of
+ people have been found to have an average resting pulse rate of 85/minute, while less healthy groups average
+ close to 70/minute.)
+
+
+ The speed of the pulse is partly determined by adrenaline, and many hypothyroid people compensate with very
+ high adrenaline production. Knowing that hypothyroid people are susceptible to hypoglycemia, and that
+ hypoglycemia increases adrenaline, I found that many people had normal (and sometimes faster than average)
+ pulse rates when they woke up in the morning, and when they got hungry. Salt, which helps to maintain blood
+ sugar, also tends to lower adrenalin, and hypothyroid people often lose salt too easily in their urine and
+ sweat. Measuring the pulse rate before and after breakfast, and in the afternoon, can give a good impression
+ of the variations in adrenalin. (The blood pressure, too, will show the effects of adrenaline in hypothyroid
+ people. Hypothyroidism is a major cause of hypertension.)
+
+
+ But hypoglycemia also tends to decrease the conversion of T4 to T3, so heat production often decreases when
+ a person is hungry. First, their fingers, toes, and nose will get cold, because adrenalin, or adrenergic
+ sympathetic nervous activity, will increase to keep the brain and heart at a normal temperature, by reducing
+ circulation to the skin and extremities. Despite the temperature-regulating effect of adrenalin, the reduced
+ heat production resulting from decreased T3 will make a person susceptible to hypothermia if the environment
+ is cool.
+
+
+ Since food, especially carbohydrate and protein, will increase blood sugar and T3 production, eating is
+ "thermogenic," and the oral (or eardrum) temperature is likely to rise after eating.
+
+
+
+ Blood sugar falls at night, and the body relies on the glucose stored in the liver as glycogen for energy,
+ and hypothyroid people store very little sugar. As a result, adrenalin and cortisol begin to rise almost as
+ soon as a person goes to bed, and in hypothyroid people, they rise very high, with the adrenalin usually
+ peaking around 1 or 2 A.M., and the cortisol peaking around dawn; the high cortisol raises blood sugar as
+ morning approaches, and allows adrenalin to decline. Some people wake up during the adrenalin peak with a
+ pounding heart, and have trouble getting back to sleep unless they eat something.
+
+
+ If the night-time stress is very high, the adrenalin will still be high until breakfast, increasing both
+ temperature and pulse rate. The cortisol stimulates the breakdown of muscle tissue and its conversion to
+ energy, so it is thermogenic, for some of the same reasons that food is thermogenic.
+
+
+ After eating breakfast, the cortisol (and adrenalin, if it stayed high despite the increased cortisol) will
+ start returning to a more normal, lower level, as the blood sugar is sustained by food, instead of by the
+ stress hormones. In some hypothyroid people, this is a good time to measure the temperature and pulse rate.
+ In a normal person, both temperature and pulse rate rise after breakfast, but in very hypothyroid people
+ either, or both, might fall.
+
+
+ Some hypothyroid people have a very slow pulse, apparently because they aren't compensating with a large
+ production of adrenalin. When they eat, the liver's increased production of T3 is likely to increase both
+ their temperature and their pulse rate.
+
+
+ By watching the temperature and pulse rate at different times of day, especially before and after meals,
+ it's possible to separate some of the effects of stress from the thyroid-dependent, relatively "basal"
+ metabolic rate. When beginning to take a thyroid supplement, it's important to keep a chart of these
+ measurements for at least two weeks, since that's roughly the half-life of thyroxine in the body. When the
+ body has accumulated a steady level of the hormones, and begun to function more fully, the factors such as
+ adrenaline that have been chronically distorted to compensate for hypothyroidism will have begun to
+ normalize, and the early effects of the supplementary thyroid will in many cases seem to disappear, with
+ heart rate and temperature declining. The daily dose of thyroid often has to be increased several times, as
+ the state of stress and the adrenaline and cortisol production decrease.
+
+
+
+ Counting calories achieves approximately the same thing as measuring oxygen consumption, and is something
+ that will allow people to evaluate the various thyroid tests they may be given by their doctor. Although
+ food intake and metabolic rate vary from day to day, an approximate calorie count for several days can often
+ make it clear that a diagnosis of hyperthyroidism is mistaken. If a person is eating only about 1800
+ calories per day, and has a steady and normal body weight, any "hyperthyroidism" is strictly metaphysical,
+ or as they say, "clinical."
+
+
+ When the humidity and temperature are normal, a person evaporates about a liter of water for every 1000
+ calories metabolized. Eating 2000 calories per day, a normal person will take in about four liters of
+ liquid, and form about two liters of urine. A hyperthyroid person will invisibly lose several quarts of
+ water in a day, and a hypothyroid person may evaporate a quart or less.
+
+
+ When cells, because of a low metabolic rate, don't easily return to their thoroughly energized state after
+ they have been stimulated, they tend to take up water, or, in the case of blood vessels, to become
+ excessively permeable. Fatigued muscles swell noticeably, and chronically fatigued nerves can swell enough
+ to cause them to be compressed by the surrounding connective tissues. The energy and hydration state of
+ cells can be detected in various ways, including magnetic resonance, and electrical impedance, but
+ functional tests are easy and practical.
+
+
+ With suitable measuring instruments, the effects of hypothyroidism can be seen as slowed conduction along
+ nerves, and slowed recovery and readiness for new responses. Slow reaction time is associated with slowed
+ memory, perception, and other mental processes. Some of these nervous deficits can be remedied slightly just
+ by raising the core temperature and providing suitable nutrients, but the active thyroid hormone, T3 is
+ mainly responsible for maintaining the temperature, the nutrients, and the intracellular respiratory energy
+ production.
+
+
+ In nerves, as in other cells, the ability to rest and repair themselves increases with the proper level of
+ thyroid hormone. In some cells, the energized stability produced by the thyroid hormones prevents
+ inflammation or an immunological hyperactivity. In the 1950s, shortly after it was identified as a distinct
+ substance, T3 was found to be anti-inflammatory, and both T4 and T3 have a variety of anti-inflammatory
+ actions, besides the suppression of the pro-inflammatory TSH.
+
+
+ Because the actions of T3 can be inhibited by many factors, including polyunsaturated fatty acids, reverse
+ T3, and excess thyroxine, the absolute level of T3 can't be used by itself for diagnosis. "Free T3" or "free
+ T4" is a laboratory concept, and the biological activity of T3 doesn't necessarily correspond to its
+ "freedom" in the test. T3 bound to its transport proteins can be demonstrated to enter cells, mitochondria,
+ and nuclei. Transthyretin, which carries both vitamin A and thyroid hormones, is sharply decreased by
+ stress, and should probably be regularly measured as part of the thyroid examination.
+
+
+
+ When T3 is metabolically active, lactic acid won't be produced unnecessarily, so the measurement of lactate
+ in the blood is a useful test for interpreting thyroid function. Cholesterol is used rapidly under the
+ influence of T3, and ever since the 1930s it has been clear that serum cholesterol rises in hypothyroidism,
+ and is very useful diagnostically. Sodium, magnesium, calcium, potassium, creatinine, albumin, glucose, and
+ other components of the serum are regulated by the thyroid hormones, and can be used along with the various
+ functional tests for evaluating thyroid function.
+
+
+ Stereotypes are important. When a very thin person with high blood pressure visits a doctor, hypothyroidism
+ isn't likely to be considered; even high TSH and very low T4 and T3 are likely to be ignored, because of the
+ stereotypes. (And if those tests were in the healthy range, the person would be at risk for the
+ "hyperthyroid" diagnosis.) But remembering some of the common adaptive reactions to a thyroid deficiency,
+ the catabolic effects of high cortisol and the circulatory disturbance caused by high adrenaline should lead
+ to doing some of the appropriate tests, instead of treating the person's hypertension and "under nourished"
+ condition.
+
+ REFERENCES
+
+ Clin Chem Lab Med. 2002 Dec;40(12):1344-8. Transthyretin: its response to malnutrition and stress
+ injury. Clinical usefulness and economic implications. Bernstein LH, Ingenbleek Y.
+
+
+
+ Endokrinologie. 1968;53(3):217-21.[Influence of hypophysectomy and pituitary hormones on dextran
+ edema in rats] German. Boeskor A, Gabbiani G.
+
+
+ J Clin Endocrinol Metab. 2001 Nov;86(11):5148-51. Sudden enlargement of local recurrent thyroid
+ tumor after recombinant human TSH administration.
+ Braga M, Ringel MD, Cooper DS.
+
+
+ J Investig Med. 2002 Sep;50(5):350-4; discussion 354-5. The nocturnal serum thyrotropin surge is
+ inhibited in patients with adrenal Incidentaloma.
+ Coiro V, Volpi R, Capretti L, Manfredi G, Magotti MG, Bianconcini M, Cataldo S, Chiodera P.
+
+
+
+ Rev Neurol (Paris). 1992;148(5):371-3.
+ [Hashimoto's encephalopathy: toxic or autoimmune mechanism?] [Article in French] Ghawche F,
+ Bordet R, Destee A. Service de Clinique Neurologique A, CHU, Lille. A 36-year-old woman presented with
+ partial complex status epilepticus. Magnetic resonance imaging with T2-weighted sequences showed a
+ high-intensity signal in the left posterior frontal area. Hashimoto's thyroiditis was then discovered. The
+ disappearance of the high-intensity signal after corticosteroid therapy was suggestive of an autoimmune
+ mechanism. However, improvement could be obtained only with a hormonal treatment, which supports the
+ hypothesis of a pathogenetic role of the Tyrosine-Releasing Hormone (TRH).
+
+
+ Am J Clin Nutr. 1986 Mar;43(3):406-13. Thyroid hormone and carrier protein interrelationships in
+ children recovering rom kwashiorkor.
+
+ Kalk WJ, Hofman KJ, Smit AM, van Drimmelen M, van der Walt LA, Moore RE. We have studied 15 infants with
+ severe protein energy malnutrition (PEM) as a model of nutritional nonthyroidal illness. Changes in
+ circulating thyroid hormones, binding proteins, and their interrelationships were assessed before and during
+ recovery. Serum concentrations of total thyroxine and triiodothyronine and of thyroxine-binding proteins
+ were extremely reduced, and increased progressively during 3 wk of refeeding. The T4:TBG molar ratio was
+ initially 0.180 +/- 0.020, and increased progressively, parallel to the increases in TT4, to 0.344 +/- 0.038
+ after 21 days (p less than 0.025). The changes in free T4 estimates varied according to the methods
+ used--FTI and analogue FT4 increased, dialysis FT4 fraction decreased. Serum TSH levels increased
+ transiently during recovery. It is concluded 1) there is reduced binding of T4 and T3 to TBG in untreated
+ PEM which takes 2-3 wk to recover; 2) there are methodological differences in evaluating free T4 levels in
+ PEM; 3) increased TSH secretion appears to be an integral part of the recovery from PEM.
+
+
+ Neuroendocrinology. 1982;35(2):139-47.
+ Neurotransmitter control of thyrotropin secretion.
+
+ Krulich L. "The central dopaminergic system seems to have an inhibitory influence on the secretion of
+ thyrotropin (TSH) both in humans and rats."
+
+
+ Endocrinology 1972 Mar;90(3):795-801. TSH-induced release of 5-hydroxytryptamine and histamine rat
+ thyroid mast cells. Ericson LE, Hakanson R, Melander A, Owman C, Sundler F.
+
+
+ Rev Neurol. 2002 Oct 16-31;35(8):741-2. [Hypothyroidism concealed by Parkinson's disease][in Spanish] Garcia-Moreno JM, Chacon J. Servicio de Neurologia, Hospital Universitario Virgen Macarena,
+ Sevilla, Espana.
+
+ Sinue@arrakis.es AIMS: Although it is commonly
+ recognised that diseases of the thyroids can simulate extrapyramidal disorders, a review of the causes of
+ Parkinsonism in the neurology literature shows that they are not usually mentioned or, if so, only very
+ briefly. The development of hypothyroidism in a patient with Parkinson s disease can go undetected, since
+ the course of both diseases can involve similar clinical features. Generally speaking there is always an
+ insistence on the need to conduct a thyroidal hormone study in any patient with symptoms of Parkinson, but
+ no emphasis is put on the need to continue to rule out dysthyroidism throughout the natural course of the
+ disease, in spite of the fact that the concurrence of both pathological conditions can be high and that, in
+ the same way hypothyroidism can simulate Parkinson s disease, the latter can also conceal hypothyroidism.
+ CASE REPORT: We report the case of a female patient who had been suffering from Parkinson s disease for 17
+ years and started to present on off fluctuations that did not respond to therapy. Hypothyroidism was
+ observed and the hormone replacement therapy used to resolve the problem allowed the Parkinsonian
+ fluctuations to be controlled. CONCLUSIONS: We believe that it is very wise to suspect hypothyroidism in
+ patients known to be suffering from Parkinson s disease, and especially so in cases where the clinical
+ condition worsens and symptoms no longer respond properly to antiparkinsonian treatment. These observations
+ stress the possible role played by thyroid hormones in dopaminergic metabolism and vice versa.
+
+
+ Endocrine. 2003 Feb-Mar;20(1-2):149-54.
+ Body composition of prolactin-, growth hormone, and thyrotropin-deficient Ames dwarf mice.
+ Heiman ML, Tinsley FC, Mattison JA, Hauck S, Bartke A. Lilly Research Labs, Corporate Center, Indianapolis,
+ IN, USA.
+ Ames dwarf mice have primary deficiency of prolactin (PRL), growth hormone (GH), and thyroid-stimulating
+ hormone (TSH), and live considerably longer than normal
+
+ animals from the same line.
+
+
+ (Lancet. 1975 Nov 1;2(7940):845-8.. Triiodothyronine and thyroid-stimulating hormone in
+ protein-calorie malnutrition in infants. Ingenbleek Y, Beckers C.)
+
+
+
+ Am J Med Sci. 1995 Nov;310(5):202-5. Case report: thyrotropin-releasing hormone-induced myoclonus
+ and tremor in a patient with Hashimoto's encephalopathy.
+ Ishii K, Hayashi A, Tamaoka A, Usuki S, Mizusawa H, Shoji S.
+
+
+ Rev Neurol (Paris). 1985;141(1):55-8. [Hashimoto's thyroiditis and myoclonic encephalopathy.
+ Pathogenic hypothesis] [Article in French] Latinville D, Bernardi O, Cougoule JP, Bioulac B,
+ Henry P, Loiseau P, Mauriac L. A 49 year old caucasian female with Hashimoto thyroiditis, developed during
+ two years a neurological disorder with tonic-clonic and myoclonic seizures and confusional states. Some
+ attacks were followed by a transient postictal aphasia.
+ Some parallelism was noted between the clinical state and TSH levels. Neurological events
+ disappeared with the normalisation of thyroid functions. This association of Hashimoto thyroiditis and
+ myoclonic encephalopathy has been rarely published. Pathogenesis could be double. Focal signs could be due
+ to an auto-immune mechanism, perhaps through a vasculitis. A non-endocrine central action could explain
+ diffuse signs: tonic-clonic seizures, myoclonus and confusional episodes.
+
+
+
+ J Clin Endocrinol Metab. 1992 Jun;74(6):1361-5. Fatty acid-induced increase in serum dialyzable free
+ thyroxine after physical exercise: implication for nonthyroidal illness. Liewendahl K, Helenius
+ T, Naveri H, Tikkanen H.
+
+
+ Adv Exp Med Biol. 1990;274:315-29. Role of monokines in control of anterior pituitary hormone
+ release. McCann SM, Rettori V, Milenkovic L, Jurcovicova J, Gonzalez MC.
+
+
+ Acta Endocrinol (Copenh). 1979 Feb;90(2):249-58. Dual action of adrenergic system on the regulation
+ of thyrotrophin secretion in the male rat.
+ Mannisto, Ranta T, Tuomisto J. "
+ ....noradrenaline (NA) (1 h), and L-Dopa (1 h) were also effective in decreasing serum TSH
+ levels...."
+
+
+
+ Endocrinology 1971 Aug;89(2):528-33. TSH-induced appearance and stimulation of amine-containing mast
+ cells in the mouse thyroid.
+
+ Melander A, Owman C, Sundler F.
+
+
+ Epilepsy Res. 1988 Mar-Apr;2(2):102-10. Evidence of hypothyroidism in the genetically epilepsy-prone
+ rat. Mills SA, Savage DD. Department of Pharmacology, University of New Mexico School of
+ Medicine, Albuquerque 87131. A number of neurochemical and behavioral similarities exist between the
+ genetically epilepsy-prone (GEPR) rat and rats made hypothyroid at birth. These similarities include lower
+ brain monoamine levels, audiogenic seizure susceptibility and lowered electroconvulsive shock seizure
+ threshold. Given these similarities, thyroid hormone status was examined in GEPR rats. Serum samples were
+ collected from GEPR-9 and non-epileptic control rats at 5, 9, 13, 16, 22, 31, 45, 60, 90, 150 and 350 days
+ of age. Serum thyroxine (T4) levels were significantly lower in GEPR-9 rats compared to control until day 22
+ of age.
+ GEPR-9 thyrotropin (TSH) levels were significantly elevated during the period of diminished serum T4.
+ GEPR-9 triiodothyronine (T3) levels were lower than control throughout the first year of life. The data
+ indicate that the GEPR-9 rat is hypothyroid from at least the second week of life up to 1 year of age.
+ The critical impact of neonatal hypothyroidism on brain function coupled with the development
+ of the audiogenic seizure susceptible trait by the GEPR-9 rat during
+ the third week after birth suggests that neonatal hypothyroidism could be one etiological factor in the
+ development of the seizure-prone state of GEPR-9 rats.
+
+
+
+ Przegl Lek. 1998;55(5):250-8. [Mastopathy and simple goiter--mutual relationships] [Article
+ in Polish] Mizia-Stec K, Zych F, Widala E. "Non-toxic goitre was found in 80% patients with
+ mastopathy, and the results of palpation examination of thyroid were confirmed by thyroid
+ ultrasonographic examination. Non-toxic goitre was significantly more often in patients with mastopathy
+ in comparison with healthy women,
+ and there was found significantly higher thyroid volume in these patients." Endocrinology. 1997
+ Apr;138(4):1434-9. Thyroxine administration prevents streptococcal cell wall-induced inflammatory
+ responses. Rittenhouse PA, Redei E.
+
+
+ Eur J Appl Physiol Occup Physiol. 1998;77(1-2):37-43. Pre-adaptation, adaptation and de-adaptation
+ to high altitude in humans: hormonal and biochemical changes at sea level.
+
+ Savourey G, Garcia N, Caravel JP, Gharib C, Pouzeratte N, Martin S, Bittel J.
+
+
+
+ Endocrinol Jpn. 1992 Oct;39(5):445-53. Plasma free fatty acids, inhibitor of extrathyroidal
+ conversion of T4 to T3 and thyroid hormone binding inhibitor in patients with various nonthyroidal
+ illnesses. Suzuki Y, Nanno M, Gemma R, Yoshimi T.
+
+
+ Natl Med J India. 1998 Mar-Apr;11(2):62-5. Neuropsychological impairment and altered thyroid hormone
+ levels in epilepsy. Thomas SV, Alexander A, Padmanabhan V, Sankara Sarma P. Department of
+ Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala,
+ India. BACKGROUND: Neuropsychological impairment is a common problem in epilepsy which interferes with the
+ quality of life of patients. Similarly, thyroid hormone levels have been observed to be abnormal in patients
+ with epilepsy on various treatments. This study aimed to ascertain any possible correlation between
+ neuropsychological performance and thyroid hormone levels among epilepsy patients. METHODS: Thyroid hormone
+ levels, indices of neuropsychological performance and social adaptation of 43 epilepsy patients were
+ compared with those of age- and sex-matched healthy control subjects. RESULTS: Epilepsy patients exhibited
+ significantly (p < 0.001) lower scores on attention, memory, constructional praxis, finger tapping time,
+ and verbal intelligence quotient (i.q.) when compared with controls. Their T3, T4 and Free T3 levels
+ were significantly lower;
+
+ and TSH and Free T4 levels were significantly higher than that of controls.
+ There was no statistically significant correlation between the indices of neuropsychological
+ performance and thyroid hormone levels. CONCLUSION: We did not observe any correlation between
+ neuropsychological impairment and thyroid hormone levels among patients with epilepsy.
+
+
+
+ Crit Care Med. 1994 Nov;22(11):1747-53. Dopamine suppresses pituitary function in infants and
+ children. Van den Berghe G, de Zegher F, Lauwers P.
+
+
+ Ned Tijdschr Geneeskd. 2000 Jan 1;144(1):5-8.
+ [Epilepsy, disturbances of behavior and consciousness in presence of normal thyroxine levels: still,
+ consider the thyroid gland]
+
+ [Article in Dutch] Vrancken AF, Braun KP, de Valk HW, Rinkel GJ. Afd. Neurologie, Universitair Medisch
+ Centrum Utrecht. Three patients, one man aged 51 years, and two women aged 49 and 52 years, had severe
+ fluctuating and progressive neurological and psychiatric symptoms. All three had normal thyroxine levels but
+ elevated thyroid stimulating hormone levels and positive thyroid antibodies. Based on clinical, laboratory,
+ MRI and EEG findings they were eventually diagnosed with Hashimoto's encephalopathy, associated with
+ Hashimoto thyroiditis. Treatment with prednisone in addition to thyroxine suppletion resulted
+ in a remarkable remission of their neuropsychiatric symptoms. The disease is probably under-recognized.
+
+
+
+ Cell Immunol. 1999 Mar 15;192(2):159-66. Neuroendocrine-induced synthesis of bone marrow-derived
+ cytokines with inflammatory immunomodulating properties.
+ Whetsell M, Bagriacik EU, Seetharamaiah GS, Prabhakar BS, Klein JR.
+
+
+ © Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Immunodeficiency, dioxins, stress, and the hormones
+
+
+ Immunodeficiency, dioxins, stress, and the hormones
+
+
+
+ CRITICAL POINTS:
+
+ *There are many toxins which modify hormonal responses, activating cells and altering the immune system
+ (including estrogens and dioxins.) When these act early in life, extremely small amounts can cause
+ life-long changes.
+
+
+
+
+ *When respiratory energy production is blocked in stimulated cells, the cells are likely to die.
+ (Cortisol, estrogen, polyunsaturated oils have this effect, especially on thymus cells.)
+
+
+
+
+ *Antibodies are involved in removing the debris of cells that have disintegrated. Intense cellular
+ damage causes many "autoantibodies" to be produced. People with AIDS have a high incidence of
+ "autoimmunity."
+
+
+
+
+ *Endogenous retroviruses are activated by toxins known to be associated with immunodeficiency. Everyone
+ has endogenous retroviruses. The antibodies which are used to diagnose "HIV" infection can, in the
+ demonstrated absence of that virus, be produced in connection with lupus, Sjogren's syndrome, and
+ arthritis. These autoimmune conditions are promoted by estrogen.
+
+
+
+
+ *Estrogen activates the production of cortisol, and damages the normal feedback control, causing both
+ cortisol and ACTH to be elevated.
+
+
+
+
+ *Estrogen causes chronically elevated free fatty acids, and synergizes with unsaturated fats.
+
+
+
+
+ *Estrogen inhibits thyroid function.
+
+
+
+
+ Hypercortisolism is typically associated with hypothyroidism, and both tend to cause the loss of lean
+ body mass.
+
+
+
+
+ *AIDS is often compared to Addison's disease, because of hyponatremia (loss of sodium) and fatigue.
+ Hypothyroidism causes hyponatremia and many other features seen in AIDS.
+
+
+
+
+ *Increased levels of cortisol, estrogen, and polyunsaturated fatty acids, and decreased levels of the
+ active thyroid hormone (T3) and (placental) progesterone have been found to occur in AIDS.
+
+
+
+
+ *Progesterone can contribute to the inhibition of HIV replication and transmission.
+
+
+
+
+ *Common environmental factors can produce hormonal changes leading to immunodeficiency.
+
+
+
+
+ One hospital in southern Vietnam admitted 437 septicemia patients between mid-1993 and 1994; 23%
+ of the adults died. In 8 months, 17,000 seals died of infections in Europe. In California, many seals die with
+ an unusual form of metastatic cancer. Seals are highly contaminated with industrial dioxins. In
+ Africa, aflatoxin is strongly associated with immunodeficiency. In animals, both dioxin and aflatoxin activate
+ the expression of viruses. Endometriosis is stimulated by dioxins. Environmental estrogens affect the immune
+ system.
+
+
+ It has been over ten years since I wrote about "AIDS" (e.g., "Repairing the Immune System," in Cofactors in
+ AIDS and HIV infection, edited by R.R. Watson, l989) and the official doctrine that it is caused by the
+ "HIV" virus still hasn't been supported by anything that resembles real science. Duesberg's arguments have never
+ been answered (except by bureaucratic thuggery). In 1989 I pointed out that septicemia, blood stream infection,
+ in young adults, which used to be a rare thing, and which indicates defective immunity, has been increasing in a
+ remarkably continuous way since the late 1940s, and I reviewed the many things in our environment that are known
+ to suppress immunity, and which
+
+ have become increasingly prevalent in our
+ environment--unsaturated vegetable oils, ferrous iron and carrageenan in our foods, lead in air, food,
+ and water, exposure to medical, military, and industrial ionizing radiation, vaccinations, pesticides,
+ chlorinated hydrocarbons, nitric oxide (smog and medications) and oral contraceptives and environmental
+ estrogens, in particular. Of these factors, only radiation and lead exposure have decreased in the
+ last several years, after several decades of rapid increase. The widespread use of diuretics in pregnancy, which
+ began in the 1950s and contributed to an epidemic of premature births, also declined after the late 1960s. Most
+ of these environmental factors damage the thymus gland, which regulates the immune system, and by acting on the
+ thymus their effects tend to be additive with other immunosuppressive factors, including cancer, traumatic
+ injury, inflammation, toxins in spoiled food (e.g., aflatoxins) and malnutrition. Cancer, AIDS, and extreme
+ hypothyroidism have several features in common--they cause tissue loss and organ damage, with immunodeficiency
+ and intense activation of the stress hormones, including cortisol. In cancer and AIDS, a good case has been made
+ for the primacy of stress-induced wasting as the main cause of death. Whatever one might believe to be the cause
+ of cancer and AIDS, it is always good for the patient to prevent tissue damage from the stress associated with
+ the sickness. Since the stress hormones primarily destroy tissues by the activation of specific proteases, the
+ use of protease inhibitors for treating AIDS could conceivably be affecting the stress response. However, the
+ body's normal protection against the cortisol-activated proteases is centered on the protective hormones,
+ progesterone, thyroid, and the androgens.
+
+
+ Environmental stress
+ One of the most broadly substantiated principles in biology is that a great variety of harmful causes
+ all lead to a few forms of biological harm--the concept of the stress reaction shows the powerful implications
+ of the principle. Stress, no matter what the specific cause, has a particularly destructive effect on three
+ organ systems:
+
+ The nervous system, the immune system, and the reproductive system. Inflammation, lipid peroxidation, tissue
+ atrophy, the "calcium catastrophe" (when almost anything goes wrong, calcium can transmit and amplify and extend
+ the problem, but isn't itself the source of the problem), mitochondrial decay, and similar events help to define
+ the stress reaction in greater detail. Hans Selye showed that the thymus shrinks very early in the stress
+ reaction. In his understanding of the process, when adaptation was followed by the "exhaustion phase," the
+ adrenal glands had simply become exhausted from overuse. F. Z. Meerson's work showed that cortisol, and the free
+ fatty acids mobilized by stress, have a toxic influence on the mitochondrial energy production system. Both
+ cortisol and the free fatty acids block the efficient use of glucose for producing energy, creating a
+ diabetes-like condition. The exhaustion problem caused by excessive stress is generalized, not just a matter of
+ adrenal insufficiency. Meerson's work created the basis for undersanding several degenerative processes,
+ especially the phenomenon of "excitotoxicity," in which the combination of excessive stimulation and deficient
+ energy supply damages or kills cells. Selye believed that some hormones are antagonistic to each other. A few of
+ the oppositions that he identified have been thoroughly researched, especially the catabolic/anabolic functions
+ of glucocorticoids and androgens, and the shock/antishock functions of estrogen and progesterone, respectively.
+ Puberty, because of hormonal changes, especially increased estrogen, can be seen as the first stage of a chronic
+ stress, resembling diabetes, since elevated free fatty acids cause "insulin resistance," with slightly impaired
+ oxidation of glucose. The thymus shrinks considerably at puberty, under the influence of the hormonal changes
+ and the increased free fatty acids (caused mainly by estrogen). The degenerative diseases can be seen as the
+ cumulative result of stress, in which tissue damage results from the diabetes-like impairment of energy
+ production. The thymus, and the thymus-dependent areas of the spleen, are required for full and subtle control
+ of immunity. In the absence of thymic control, the B cells are still able to produce antibodies, but they are
+ more likely to produce autoantibodies. Stress produces a variety of cellular changes, including the production
+ of the "shock proteins." These proteins can make up 20% of the cell's total protein content. In themselves, the
+ shock proteins are immunosuppressive. They can be recognized by the immune system as antigens, and so are a
+ factor in the appearance of "autoimmune" antibodies. The autoantibodies themselves are often blamed for the
+ diseases they are sometimes associated with, but since they can be present (for example, following removal of
+ the spleen) in people who have no symptoms, their function is probably to facilitate the removal of tissues
+ which are defective for some other reason. The shock proteins could be one of the signals that activate the
+ immune system to remove damaged tissue, and they might be involved in the removal of senescent cells, though I
+ don't think any experiments have been done to test this idea. Besides activating the cells to produce massive
+ amounts of the shock proteins, stress can also activate the so-called hormone receptors, such as estrogen
+ receptors, even in the absence of the hormones. Stress also activates the endonucleases, which cut sections out
+ of the DNA molecules, and activates mobile genetic elements, producing genetic instability. Like cortisol and
+ estrogen, stress itself activates integrated retroviruses. The "endogenous retroviruses" make up nearly 10% of
+ the human genome, and many of them locate themselves in regulatory sites in the chromosomes. Since stress lowers
+ the discriminatory ability of the immune system, and stimulates the expression of retroviruses, the antibodies
+ sometimes seen in association with immunodeficiency may be similar to the various autoantibodies that are also
+ produced by stress. People who have autoimmune diseases such as lupus and Sjogrens syndrome (which are promoted
+ by estrogen: Ahmed and Talal) have antibodies which sometimes react positively in the AIDS
+ test, and searches for the HIV virus in such people have found no evidence of it. (Nelson, et al., 1994; Deas, et al., 1998.) Treatments for roundworms and other parasites cause antibodies to retroviruses
+ to appear in animals that previously tested negative; this might account for the high rates of
+ positive tests for HIV in areas such as Africa in which treatment for filiariasis is common (Kitchen and Cotter,
+ 1988). Organisms are most sensitive to environmental damage early in life, especially prenatally. This is the
+ period in which normal hormone exposure masculinizes the brain, for example. The term "imprinting" refers to the
+ extreme responsiveness of the organism at this time, and it has been extended to include long lasting influences
+ which may result from abnormally high or low levels of natural substances, or from the presence of other,
+ abnormal substances during the sensitive period. The effects of early "imprinting" can cause permanently altered
+ sensitivities. In animal studies, L. C. Strong showed that prenatal influences determine the age at which
+ puberty and reproductive senescence occur. In humans, premature birth, a powerful stressor, is associated with
+ premature puberty. The thymus is damaged both by premature birth and by puberty. The effects of damage early in
+ life will increase vulnerability in subsequent decades. When babies are imprinted by the mother's disturbed
+ hormones, or by diuretics, by milk substitutes, or by industrial effluents, the worst effects are likely to be
+ seen decades later, or even generations later. A similar long-range effect can be produced by nutritional
+ deficiencies. Although more mature organisms are less sensitive to stress, both early imprinting, and the
+ cumulative effects of exposure, will cause some individuals to be much more sensitive than others, and aging
+ itself increases vulnerability. If the present epidemic of immunodeficiency is produced by environmental stress,
+ then we should expect to see a variety of other stress-related diseases increasing at roughly the same time.
+ When a stressor is acting through imprinting, then the harmful effects may not be seen until 20 or 30 years
+ later, but when the stressor has acute and immediate effects, the effects should rise and fall at roughly the
+ same time as the environmental cause. The rise of the Acquired Immunodeficiency Syndrome during the last 50
+ years hasn't been the only health problem that has grown rapidly during that time. The "flesh eating bacteria,"
+ causing necrotizing fasciitis and related conditions, should probably be classed along with
+ septicemia/bacteremia as the consequence of a weakened immune system, but there are many other diseases that
+ have followed a similar pattern, which might be caused by the same factors which are causing immunodeficiency.
+
+ Thyroid diseases (mostly in women), some autoimmune diseases including primary biliary cirrhosis (mostly
+ in women) and inflammatory bowel disease, liver cancer, diabetes (doubling in children since 1949),
+ prostate cancer, decreased sperm counts, premature births and birth defects, minimal brain
+ dysfunction-attention deficit-hyperactivity, cerebral palsy, premature puberty (which is associated with
+ premature birth), congestive heart failure, osteoporosis (independently of the changing age-structure of
+ the population), depression (most common in women, more than doubling among children in recent decades),
+ and multiple sclerosis have increased in prevalence during this period.
+
+ Some of these conditions are strongly associated with each other, for example, primary biliary cirrhosis,
+ breast cancer, and osteoporosis.
+ It is common knowledge, among people who study immunity, that radiation, polyunsaturated fatty acids,
+ estrogens, and dioxins are toxic to the thymus gland, and can produce immuno-deficiency. They mimic or
+ accelerate the thymic atrophy of aging, causing a deficient thymus-dependent immune response, usually without
+ harming the ability of B cells to produce antibodies. There are probably many examples of damage to immune
+ systems, besides immunodeficiency, caused by these agents. Slight damage to the immune system, such as can be
+ produced by hypoglycemia or other energy deficit--creates an exaggerated inflammatory response, and the release
+ of the mediators of inflammation, including histamine, serotonin, and prostaglandins, activates the stress
+ hormone system, leading to further biological damage. Liver disease and several other "autoimmune" diseases
+ involve abnormal immune responses, probably including thymic deficiency and an intensified inflammatory
+ response. The fact that livers transplanted from female donors to male recipients are less successful than are
+ livers from male donor transplanted into female recipients, is consistent with the idea that autoantibodies
+ (which are far more common in women than in men) are a relatively harmless response to changes in the organs
+ themselves. Are antiviral therapies working? Ivan Ilich, in Medical Nemesis,
+ showed that historically, many diseases have had characteristic incidence curves, rising to a maximum, and then
+ falling away to relative insignificance, independently of what people were doing as treatment or prevention. As
+ susceptible people are exposed to conditions that cause a disease, they will get sick, and then either die or
+ develop resistance. The conditions which at first caused increasing disease incidence, will eventually tend to
+ affect only children who haven't developed resistance. If AIDS mortality rose rapidly to a peak a few years ago,
+ and then began falling, we should ask whether this pattern fits that of other diseases discussed by Ilich.
+ Looking for causes other than the virus, we might find a parallel in the rise and fall of some other factor. In
+ the 1950s, new diuretics came on the market, and millions of pregnant women took them. It was predicted that
+ there would be an epidemic of brain damage as a result, and in fact the incidence of hyperactivity,
+ attention-deficit, and other "minimal" brain damage disorders did rise during those years. After about 15-20
+ years, experiences such as the Thalidomide episode caused physicians to temper their enthusiasm for the use of
+ drugs during pregnancy. The incidence of low birth-weight babies in the U.S. peaked around 1965, and 28
+ years later AIDS mortality in the US peaked.
+ The rising curve had followed both the increase in radioactive fallout from atmospheric testing of
+ large numbers of atomic bombs up to 1963, and the intense promotion of the new diuretics beginning in the early
+ 1950s. The peak in AIDS mortality in 1993 came ten or twelve years after the long decline in SAT scores had
+ stopped. (The most extreme declines in SAT scores had occurred among the brightest students, disproving the
+ contention that the average score fell simply because more students were taking the tests.) The same prenatal
+ damage which caused the extreme decline in SAT scores 18 years later (when the damaged babies reached that age)
+ would have left many of the same individuals with weakened immune systems, which would fail prematurely, but at
+ varying intervals, depending on the exposure to other factors. The use of unleaded gasoline increased into the
+ 1990s, and there was a corresponding decrease in tissue lead content, reflecting the smaller amount of lead
+ being put into the environment. According to some reports, medical and dental x-ray exposures were declining
+ during this period. Yet other factors, including dioxins and unsaturated dietary fats, were probably increasing.
+ Although the new protease inhibitors wouldn't be used until years after the AIDS mortality had begun falling,
+ the government and drug companies are claiming that it is the drugs which are decreasing the mortality.
+
+
+ A Synthesis
+ Many things in our environment are increasing the incidence of certain kinds of liver disease. The
+ liver processes things that are ingested or that enter the blood stream after being inhaled or absorbed through
+ the skin, so in a toxic environment it is susceptible to injury. If deprived of good nutrition or adequate
+ thyroid hormone it is especially sensitive to toxins. The body's own estrogen is a burden on the liver, causing
+ women's livers to be on average slower than men's in processing enviornmental chemicals. Almost any kind of
+ toxin causes the liver to be less efficient at excreting other substances, including hormones. In malnutrition,
+ sickness, and in aging, there is a tendency for higher levels of estrogen to remain circulating in the blood.
+ Natural estrogen, and environmental substances that act like estrogen, act as excitants in many types of cell,
+ and at the same time, reduce the efficiency of energy production. Both of these properties relate to its known
+ ability to activate the adrenal glands. A. L. Soderwall, who was my thesis adviser at the University of Oregon,
+ found that estrogen caused hamsters' adrenal glands to enlarge, and that larger doses overstimulated the glands
+ sufficiently to cause tissue damage. It is now known that estrogen acts directly on the adrenal cells to
+ stimulate cortisol production, and that it also stimulates the pituitary to produce more adrenocorticotropin
+ (ACTH), which also stimulates the adrenals;
+ estrogen's effect is to impair the negative feedback, in which cortisol normally shuts down ACTH production.
+ This impaired feedback is characteristic of aging. Estrogen directly causes the thymus gland to atrophy, and
+ several of its effects, such as increased adrenal activity and elevated free fatty acids, also contribute to the
+ shrinkage of the thymus and the inhibition of its functions. While this is happening, the B cells, which
+ normally are under the control of the thymus cells, are not killed by estrogen, and actually seem to be
+ stimulated by estrogen to produce certain types of antibodies. This combination of effects, weakening the thymus
+ and stimulating antibody production, is thought to contribute to the development of autoimmune diseases.
+ Estrogen also stimulates mast cells and similar cells to release histamine and other promoters of inflammation,
+ and these effects are probably closer to the actual problem in the autoimmune diseases. Several of the
+ substances formed under the influence of estrogen interfere with energy production and contribute to cellular
+ excitation, causing tissue injury. Cortisol also stimulates antibody production while suppressing thymic
+ immunity (Norbiato, et al., 1997). Estrogen and stress cause increased levels of free fatty acids to circulate.
+ The polyunsaturated fatty acids are immunosuppressive, antithyroid, diabetogenic, inhibit respiration, and
+ promote the actions of estrogen and cortisol. People suffering from AIDS have been found to have increased
+ estrogen, with high cortisol and ACTH, and very low T3. (Unfortunately, some researchers and the editors who
+ publish their ideas, conclude that the hormones don't cause the stress and wasting symtpoms, because they call
+ thyroid a "catabolic hormone," and because they describe the fatigue and sodium deficiency as evidence of
+ "deficiency of cortisol." Such is the state of the research establishment.) In animal experiments, and a few
+ human tests, the HIV and similar viruses have produced effects that could plausibly explain some of the
+ conditions seen in AIDS, such as damage to brain cells (C. Pert, R. Sapolsky), and altered steroid secretion.
+ But this is real science, that promises to link up with information about stress, aging, allergy, and biological
+ adaptability. For example, Sapolsky's group (Brooke, et al., 1998) found that the nerve toxicity caused by a
+ viral protein (called gp120) synergizes with glucocorticoid toxicity, lowering the ATP level and inhibiting
+ mitochondrial function, and that simply supplying the nerve with additional energy protects it from destruction.
+ In other words, the viral peptide just increases excitotoxicity. Another group (Amirhessami-Aghili and Spector,
+ 1991) found that the presence of the virus can decrease the production of progesterone. Since progesterone
+ blocks (Lee, et al., 1997) the expression (and transmission) of the virus, this suggests how the overgrowth of
+ the virus might be triggered by stress--once progesterone synthesis falls, a vicious circle could get started.
+ Lee, et al., found that progesterone can help to prevent transmission of the virus from an infected mother to
+ the fetus. But the most interesting study of the virus in pregnancy involved mice that were engineered to
+ contain extremely large quantities of the HIV provirus (De, et al., 1997). At birth, they seemed normal, but
+ within a few days their skin became diseased, and they quickly wasted away and died. The experimenters realized
+ that something present in the mother's body had permitted normal development up to the point of birth, and then
+ the wasting disease set in. The placental hormone, chorionic gonadotropin, is produced in large amounts during
+ pregnancy. The experimenters gave newborn infected mice regular doses of human chorionic gonadotropin (hCG), and
+ they developed normally. Rodents don't respond to gonadotropins or other ovarian stimulation exactly the way
+ pigs and primates and people do. For example, prolactin and melatonin usually inhibit progesterone synthesis in
+ people, but in rodents, they increase it. So it's necessary to see exactly what happens to the ovarian hormones
+ when a mouse is given hCG. In 1996, another group (H. Krzanowska and M. Szoltys) had done that, and found that
+ hCG greatly increases progesterone synthesis, but decreases estrogen.
+ Considering the progesterone-HIV experiments together, I am reminded of a science fiction movie, in
+ which a disease from another planet killed everyone in the lab that was studying it, except for one woman, who
+ turned out to be pregnant. The medical version of AIDS research, though, pushes aside all of the real science,
+ in favor of a simplistic idea that the virus kills the cells of the immune system, and uses false diagnostic
+ methods and deadly drugs to treat something which too often doesn't exist, while denying that there are other
+ real causes of immune deficiency and wasting-sickness, etc. Aging is characterized by loss of lean body mass,
+ immunodeficiency, and a variety of autoimmune reactions. My perennial argument has been that decreased thyroid
+ and progesterone, associated with increased estrogen and stress hormones, are largely responsible for those
+ changes. The huge investment in AIDS research has found that these occur in AIDS, but, because of the medical
+ pharmaceutical culture which has created myths about these hormones, no one is yet interpreting the hormone
+ imbalances in ways that would reveal their responsibility for the symptoms. While the institutionalized theory
+ claims that the HIV virus is responsible for the syndrome, the hormones are reduced to epiphenomena.
+
+ REFERENCES
+ Ann Med 1996 Apr;28(2):107-13.
+ Histamine-2 receptor antagonists as immunomodulators: new therapeutic views? Nielsen HJ.
+ Considerable evidence has emerged to suggest that histamine participates in the regulation of the inflammatory
+ response, immune reaction, coagulation cascade, and cardiovascular function.
+ The beneficial effect of histamine-2 receptor antagonists as adjuvant single drugs to reduce trauma-, blood
+ transfusion- and sepsis-induced immunosuppression has led to research in combined treatment regimens in
+ major surgery, particularly, of patients operated on for malignant diseases.
+ J Am Coll Nutr 1982;1(2):207-14. Auto-immune complications of D-penicillamine--a possible
+ result of zinc and magnesium depletion and of pyridoxine inactivation. Seelig MS. Pyridoxine is
+ necessary for cellular accumulation of zinc and magnesium, deficiencies of which have caused thymic and
+ other immunologic abnormalities.
+
+ J Am Vet Med Assoc 1999 Jan 1;214(1):67-70, 43-4.. Outbreak of fatal salmonellosis in cats following use
+ of a high-titer modified-live panleukopenia virus vaccine. Foley JE, Orgad U, Hirsh DC, Poland A,
+ Pedersen NC. J Immunol 1998 Nov 15;161(10):5313-20 Apoptotic death of CD8+ T lymphocytes after
+ immunization: induction of a suppressive population of Mac-1+/Gr-1+ cells. Bronte V, Wang M,
+ Overwijk WW, Surman DR, Pericle F, Rosenberg SA, Restifo NP. Infect Immun 1998 Sep;66(9):4018-24 Decreased resistance to primary intravenous Cryptococcus neoformans infection in aged mice despite adequate
+ resistance to intravenous rechallenge.
+
+ Aguirre KM, Gibson GW, Johnson LL. Pediatr Med Chir 1998 May-Jun;20(3):213-6
+ [The cell-mediated response after measles vaccination]. [Article in Italian] Pala S, Crimaldi G,
+ Consolini R, Macchia P. Natural measles virus infection is recognized for causing prolonged
+ abnormalities in immune responses, that contribute to the severe and complicated evolution of the
+ disease. Immunization with live measles virus vaccine could be considered a mild form of the measles infection.
+ The in vitro proliferative response to polyclonal mitogen was significantly reduced (p < 0.01). This study
+ confirms the presence of a mainly functional immunosuppression of cellular response in a cohort of children
+ belonging to a developed area. J Neuroimmunol 1998 Dec 1;92(1-2):133-8 An inhibitor of inducible nitric
+ oxide synthase ameliorates experimental autoimmune myocarditis in Lewis rats.
+ Shin T, Tanuma N, Kim S, Jin J, Moon C, Kim K, Kohyama K, Matsumoto Y, Hyun B. We studied the effect of
+ nitric oxide (NO) on experimental autoimmune myocarditis (EAC) in rats. These results suggest that iNOS
+ is upregulated in EAC lesions and increased NO production plays an important role in the development of EAC.
+ In addition, selective iNOS inhibitors may have a therapeutic role in treating certain autoimmune diseases
+ including EAC.
+ Langenbecks Arch Chir Suppl Kongressbd 1997;114:508-12 [Necrotizing fasciitis].
+ Billing A, Arendt RM, Arnoldt H, Schildberg FW Necrotizing fasciitis has changed considerably over time. Clin
+ Infect Dis 1998 Mar;26(3):584-9 Invasive group A streptococcal disease in Taiwan is not associated with
+ the presence of streptococcal pyrogenic exotoxin genes. Hsueh PR, Wu JJ, Tsai PJ, Liu JW, Chuang
+ YC, Luh KT. High-level protease activity and the M1 serotype of the isolates were significantly
+ associated with the clinical signs of STSS and with mortality. M1 serotype and protease activity, as well as
+ host immune status, might play significant roles in the pathogenesis of invasive GAS disease in
+ Taiwan. Can J Surg 1997 Feb;40(1):18-25 Group A Streptococcus invasive infections: a review.
+ Weiss KA, Laverdiere M. The incidence of group A Streptococcus (GAS) invasive infections has
+ been increasing worldwide,
+ and there is no obvious explanation for this phenomenon. Unfallchirurg 1993 Apr;96(4):181-91
+ [Necrotizing soft tissue infections].
+ [Article in German] Kach K, Kossmann T, Trentz O. Necrotizing soft tissue infections are a group of life- and
+ limb-threatening infections. They are caused by aerobic and anaerobic bacteria occasionally in a
+ synergistic polymicrobial combination. The literature describing necrotizing soft tissue infections is
+ controversial and often contradictory.
+ Ann Dermatol Venereol 1993;120(6-7):469-72 [Epidemiology and etiopathogeny of necrotizing fasciitis and
+ streptococcal shock syndrome]. Simonart T, Simonart JM, Schoutens C, Ledoux M, De Dobbeleer G. A
+ significant increase in the frequency of necrotizing fasciitis caused by streptococci of group A has
+ recently been noted. The disease usually appears in individuals without obvious risk factors.
+ The sensitivity of the host is linked to the genetic expression of the V. beta. elements on the surface
+ of lymphocytes.
+ J Infect 1989 May;18(3):231-48 Invasive streptococcal infections in the era before the acquired
+ immune deficiency syndrome: a 10 years' compilation of patients with streptococcal bacteraemia in North
+ Yorkshire.
+
+ Barnham M. Significant streptococcal (non-pneumococcal, non-enterococcal) bacteraemia was detected in 100
+ patients in two Health Districts of North Yorkshire in the decade 1978-1988. Transpl Immunol 1998 Jun;6(2):84-93
+ Stress protein-induced immunosuppression: inhibition of cellular immune effector functions following
+ overexpression of haem oxygenase (HSP 32). Woo J, Iyer S, Cornejo MC, Mori N, Gao L, Sipos I,
+ Maines M, Buelow R. The results indicate that overexpression of HO results in the inhibition of several
+ immune effector functions and thus provides an explanation for stress-induced immunosuppression.
+ Genome 1998 Oct;41(5):662-8. A single-primer PCR-based retroviral-related DNA polymorphism
+ shared by two distinct human populations. Deb P, Klempan TA, O'Reilly RL, Singh SM Department of
+ Zoology, University of Western Ontario, London, Canada. "Almost 10% of the human genome consists of DNA
+ sequences that share homology with retroviruses.
+ These sequences, which represent a stable component of the human genome
+ (although some may retain the ability to transpose), remain poorly understood." "Such novel
+ polymorphisms should provide useful markers and permit assessment of evolutionary mechanisms associated with
+ retroviral-related genomic evolution. " Gen Pharmacol 1998 May;30(5):685-7, Imprinting of thymic
+ glucocorticoid receptor and uterine estrogen receptor by a synthetic steroid hormone at different times
+ after birth. Csaba G, Inczefi-Gonda A. J Clin Endocrinol Metab 1998 Dec;83(12):4373-81.
+ Human immunodeficiency virus induction of corticotropin in lymphoid cells. Hashemi FB, Hughes TK,
+ Smith EM. Eur J Cancer Clin Oncol 1988 Jul;24(7):1179-83. Abnormal free fatty acids and cortisol
+ concentrations in the serum of AIDS patients.
+ Christeff N, Michon C, Goertz G, Hassid J, Matheron S, Girard PM, Coulaud JP, Nunez EA. The serum free fatty
+ acid (FFA), cortisol and urinary creatinine, 17-hydzoxycorticosteroid and 17-oxosteroid concentrations of
+ acquired immunedeficiency syndrome (AIDS-I: beginning and AIDS-II: end phase) and AIDS-related complex (ARC)
+ patients were determined. Both groups were compared to a control group (healthy men). ARC and AIDS-I patients.
+ The ratios of stearic (C18:0) to oleic (C18:1) acid were 75%, P less than 0.01 (ARC) and 45%, P less than 0.05
+ (AIDS-I) greater than normal, due to a decrease in the relative percentage of monounsaturated fatty acids by
+ 25%, P less than 0.001 (ARC) and 20%, P less than 0.01 (AIDS-I). In contrast, the relative percentage of
+ polyunsaturated fatty acids was 85% greater than normal (P less than 0.001) in ARC and 100% greater than
+ normal (P less than 0.001) in AIDS-I patients.
+ Total FFA levels did not differ from controls. Serum cortisol levels were 35% (P less than 0.01) above
+ normal in ARC and 60% (P less than 0.001) above normal in AIDS-I patients. Urinary 17-hydroxycorticosteroids and
+ 17-oxosteroids were very low (2-3-fold lower than normal values, P less than 0.001) in both groups of patients.
+ Urinary creatinine did not differ from controls. In AIDS-II patients the total FFA concentration was below
+ normal 35% (P less than 0.01) and the stearic/oleic acid ratio was 50% above normal (P less than 0.05). The
+ relative percentages of monounsaturated and polyunsaturated fatty acids in this group were similar to those of
+ controls. Serum cortisol concentrations were significantly higher, 50% (P less than 0.001), but the
+ urinary 17-hydroxycorticosteroids and 17-oxosteroids were 2-fold lower
+
+ (P less than 0.001) than those of controls. Urinary creatinine did not differ from controls. J Clin Endocrinol
+ Metab 1992 May;74(5):1045-52. Lipids, lipoproteins, triglyceride clearance, and cytokines in human
+ immunodeficiency virus infection and the acquired immunodeficiency syndrome. Grunfeld C, Pang M,
+ Doerrler W, Shigenaga JK, Jensen P, Feingold KR. Infection causes disturbances in lipid metabolism that may be
+ mediated by cytokines. Therefore we studied plasma lipids, lipoproteins, triglyceride (TG) metabolism, and serum
+ cytokines in three groups: patients with the acquired immunodeficiency syndrome (AIDS) without active
+ secondary infection,
+ patients with evidence of human immunodeficiency virus infection but without clinical AIDS (HIV+), and controls.
+ Plasma TGs and FFA were increased in AIDS, while plasma cholesterol, high density lipoprotein
+ (HDL) cholesterol, apolipoprotein-A-1 (Apo-A-1), low density lipoprotein (LDL) cholesterol, and Apo-B-100 levels
+ were decreased. J Virol 1991 May;65(5):2231-6.
+ Human immunodeficiency virus type 1 infection of human placenta: potential route for fetal
+ infection.
+ Amirhessami-Aghili N, Spector SA. AIDS Res Hum Retroviruses 1997 Sep 20;13(14):1235-42. Interaction of
+ pregnancy steroid hormones and zidovudine in inhibition of HIV type 1 replication in monocytoid and
+ placental Hofbauer cells: implications for the prevention of maternal-fetal transmission of HIV.
+ Lee AW, Mitra D, Laurence J. Folia Biol (Krakow) 1996;44(3-4):111-6. Preovulatory dynamics of ovarian
+ steroid hormones in two mouse strains differing in the rate of meiotic maturation. Krzanowska H,
+ Szoltys M. J Clin Invest 1997 Apr 1;99(7):1484-91.
+ Human chorionic gonadotropin hormone prevents wasting syndrome and death in HIV-1 transgenic mice.
+
+ De SK, Wohlenberg CR, Marinos NJ, Doodnauth D, Bryant JL, Notkins AL., Metabolism 1993 Oct;42(10):1270-6.
+ Indices of function and weight loss in human immunodeficiency virus infection and the acquired immunodeficiency
+ syndrome. Grunfeld C, Pang M, Doerrler W, Jensen P, Shimizu L, Feingold KR, Cavalieri RR. Int J Health Serv
+ 1994;24(2):311-35 Nuclear fallout, low birthweight, and immune deficiency. Gould JM, Sternglass
+ EJ Radiation and Public Health Project, New York, NY 10024. An investigation of the mortality rates
+ of young adults born in the postwar period of large-scale atmospheric nuclear testing (1945-1965) in the United
+ States and other western industrial nations reveals an increasingly anomalous rise in mortality from its
+ previous secular decline. Beginning in the late 1970s and particularly since 1983, the deterioration in
+ the health of the 25-44 age group is related to in utero exposure to fission products in the milk and diet,
+ associated with an unprecedented rise in underweight births and neonatal mortality known to be accompanied
+ by loss of immune resistance.
+
+ The 1945-1965 rise
+ in the percentage of live births below 2500 grams is highly correlated with the amount of strontium-90 in
+ human bone, both peaking in the mid-1960s. In the 1980s, for the baby boom generation (those
+ born
+ between 1945 and 1965), cancer incidence and mortality due to infectious diseases associated with a
+ rising degree of immune deficiency, such as pneumonia, septicemia, and AIDS, increased sharply. This process of
+ increasing immune deficiency appears to have been exacerbated by continuing secondary exposures to accidental
+ reactor releases and by an acceleration of radiation-induced mutation of pathogenic microorganisms increasingly
+ resistant to drugs. Biokhimiia 1987 Sep;52(9):1501-11 [Activation of lipolysis and ketogenesis in
+ tumor-bearing animals as a reflection of chronic stress states].
+ Chekulaev VA, Shelepov VP, Pasha-zade GR, Shapot VS. Arkh Patol 1987;49(6):10-8 [Combination of
+ immunodepression and disorders in nucleic acid metabolism of lymphoid tissue as a manifestation of a
+ paraneoplastic syndrome]. [Article in Russian] Potapova GI, Shapot VS Several physiological,
+ biochemical, and molecular biological approaches to the study of factors determining immunodepression in
+ tumor-bearing animals are considered. Cancer cells release substances of nucleic and peptide nature that
+ suppress the functional activity of macrophages and lymphocytes and stimulate cell proliferation in organs and
+ tissues of the host. Suppressor T cells capable of inhibiting the function of helper T cells and impairing the
+ differentiation of killer T cells are activated. The suppression
+ of T- and B-cell-mediated immunity in the tumor host involves disturbances of nucleic acid metabolism in
+ those cells as well as hypersecretion of glucocorticoids.
+
+ The impairments of lymphocyte proliferation and differentiation that result in reduced immune responsiveness are
+ attributable to drastic alterations in the metabolism of purine and pyrimidine nucleotides and to the damage
+ sustained by the lymphocyte's DNA. Eksp Onkol 1987;9(6):62-7 [Relation between disorders of glucose
+ metabolism, secretion of somatotropic hormone, thyroxine, thyrotropin and hematocrit indices in rats with
+ transplanted hepatomas]. Shelepov VP, Pasha-zade GR, Chekulaev VA, Shapot VS. Am J Pathol 1987
+ Jan;126(1):103-13 Dietary fatty acid effects on T-cell-mediated immunity in mice
+ infected with mycoplasma pulmonis or given carcinogens by injection. Bennett M, Uauy R, Grundy
+ SM. To test whether or not diets enriched in w-6 polyunsaturated fatty acids are significantly immunosuppressive
+ . . . mice were fed diets enriched for fatty acids: linoleic (POLY), oleic (MONO), palmitic (SAT), or
+ eicosapentanoic (FISH). . . . only mice on the
+ POLY diet were significantly immunosuppressed, and only T-cell-mediated cutaneous sensitivity reactions were
+ affected.
+ After instillation, mice on the POLY and MONO diets were suppressed for T-cell cutaneous responses. Deliberate
+ infection with Mycoplasma pulmonis resulted in suppressed cutaneous T-cell responses in the POLY group of C3B6F1
+ mice, and aspirin partially reversed the immunosuppression. Mice on the FISH diet were resistant to
+ immunosuppression. It is tentatively concluded that diets rich in w-6 polyunsaturated diets, while not
+ directly immunosuppressive, do predispose animals to suppression of certain T-cell-mediated immune
+ responses. This immunosuppression can be "triggered" by infection and/or by exposure to carcinogens.
+ Tumour Biol 1988;9(5):225-32 Modulation of cell-mediated immune response by steroids and free
+ fatty acids in AIDS patients: a critical survey. Nunez EA. The overall data presented in this
+ review show that cortisol and free fatty acids, in particular long-chain polyunsaturated fatty acids, each have
+ immunoinhibitory properties on lymphoblastic transformation of
+ certain T lymphocytes. This effect is enhanced when the two factors are associated. These data could explain
+ in part the immunosuppression observed in acquired immunodeficiency syndrome (AIDS) patients where enhanced
+ concentrations of cortisol and polyunsaturated fatty acids have been observed.
+ Basic Life Sci 1988;49:615-20 Vitamin E and immune functions. Bendich A.
+ Supplementation of these diets with higher than nutritionally adequate
+ levels of vitamin E enhances immune responses. High levels of PUFA are immunosuppressive, and vitamin E can
+ partially overcome this immunosuppression. High levels of vitamin C can protect tissue levels of
+ vitamin E and may indirectly contribute to the immunoenhancement by vitamin E. Severe selenium deficiency is
+ immunosuppressive. Vitamin E can protect some aspects of immune responses from the adverse effects of selenium
+ deficiency. These data clearly indicate that nutrients that affect the overall antioxidant status have important
+ effects on immune functions. In addition, antioxidant nutrient interactions can synergize to overcome the
+ adverse effects of polyunsaturated fatty acids on immune functions. Transplantation 1989 Jul;48(1):98-102
+ Enhancement of immunosuppression by substitution of fish oil for olive oil as a vehicle for
+ cyclosporine.
+ Kelley VE, Kirkman RL, Bastos M, Barrett LV, Strom TB. J Am Coll Nutr 1992 Oct;11(5):512-8 Role of
+ nutrition in the management of malnutrition and immune dysfunction of trauma.
+
+ Cerra FB Dept. of Clinical Nutrition, University of Minnesota, Minneapolis. Current nutrition support improves
+ patient outcome in trauma patients. It appears to do so by limiting the adverse effects of specific nutrient or
+ generalized nutrient deficiencies. Immunosuppression, however, continues as a significant clinical problem. This
+ immunosuppression appears to be part of the inflammatory response that accompanies trauma, and in part,
+ to represent the need for conditional nutrients in this setting. Three nutrients that are being
+ evaluated include arginine, uracil as ribonucleic acid and omega-3 polyunsaturated fatty acids. Animal studies
+ report improved immune function. Early clinical trials are reporting improved immune function and patient
+ outcomes. J Nutr 1996 Mar;126(3):681-92 Dietary butter protects against ultraviolet radiation-induced
+ suppression of contact hypersensitivity in Skh:HR-1 hairless mice. Cope RB, Bosnic M, Boehm-Wilcox
+ C, Mohr D, Reeve VE. Dietary fats modulate a wide variety of T cell functions in mice and humans. This study
+ examined the effects of four different dietary fats, predominantly polyunsaturated sunflower oil, margarine, and
+ predominantly saturated butter, clarified butter, on the T cell-mediated, systemic suppression of contact
+ hypersensitivity by ultraviolet radiation. There was a linear relationship (r > 0.9) between protection
+ against
+ photoimmunosuppression and the proportion of clarified butter in mice fed a series of 200 g/kg mixed
+ fat diets that provided varying proportions of clarified butter and sunflower oil. The dietary fats
+ did not modulate the contact hypersensitivity reaction in unirradiated animals. The observed phenomena were not
+ primary due to the carotene, tocopherol, cholecalciferol, retinol, lipid hydroperoxide or the nonfat solid
+ content of the dietary fats used and appeared to be a result of the different fatty acid composition of the
+ fats. Cancer Lett 1996 Nov 29;108(2):271-9 Dependence of photocarcinogenesis and photoimmunosuppression
+ in the hairless mouse on dietary polyunsaturated fat. Reeve VE, Bosnic M, Boehm-Wilcox C. The
+ photocarcinogenic response was of increasing severity as the polyunsaturated content of the mixed dietary fat
+ was increased, whether measured as tumour incidence, tumour multiplicity, progression of benign tumours to
+ squamous cell carcinoma, or reduced survival. When mice were exposed acutely to UV radiation (UVR), a diet of 20% saturated fat provided almost complete protection from the suppression of CHS, whereas feeding 20%
+ polyunsaturated fat resulted in 57% suppression; the CHS of unirradiated mice was unaffected by the
+ nature of the dietary fat. These results suggest that the enhancement of photocarcinogenesis by the dietary
+ polyunsaturated fat component is mediated by an induced predisposition to persistent immunosuppression
+
+
+ caused by the chronic UV irradiation, and supports the evidence for an immunological role in dietary fat
+ modulation of photocarcinogenesis in mice. Ann Acad Med Singapore 1991 Jan;20(1):84-90.
+ Clinical implications of food contaminated by aflatoxins. Hendrickse RG. Arch Toxicol
+ 1996;70(10):661-71. Host resistance to rat cytomegalovirus (RCMV) and immune function in adult PVG rats
+ fed herring from the contaminated Baltic Sea. Ross PS, Van Loveren H, de Swart RL, van der Vliet H,
+ de Klerk A, Timmerman HH, van Binnendijk R, Brouwer A, Vos JG, Osterhaus AD. In a semi-field study, we
+ previously showed that harbour seals (Phoca vitulina) fed herring from the contaminated Baltic Sea had
+ lower natural killer cell activity, T-lymphocyte functionality and delayed-type hypersensitivity
+ responses than seals fed herring from the relatively uncontaminated Atlantic Ocean. A novel model
+ was established to assess the specific T-cell response to rat cytomegalovirus (RCMV). When applied to the
+ feeding study, no differences between the Atlantic and Baltic groups in the RCMV-induced proliferative
+ T-lymphocyte responses could be detected, but virus titres in salivary glands of infected rats of the Baltic Sea
+ group were higher. These elevated RCMV titres and changes in thymus cellularity suggest that
+ the dietary exposure to low levels of contaminants may have been immunotoxic at a level which our immune
+ function test could not otherwise detect. While the herring diet per se appeared to have
+ an effect on several immune function parameters, lower plasma thyroid hormone levels in the Baltic Sea group
+ of rats confirmed that exposure to the environmental mixture of contaminants led to adverse PHAH-related
+ health effects.
+ Environ Health Perspect 1995 Apr;103(4):366-71 Dioxin activates HIV-1 gene expression by an
+ oxidative stress pathway requiring a functional cytochrome P450 CYP1A1 enzyme. Yao Y, Hoffer A,
+ Chang CY, Puga A.
+ Aflatoxin B1, 2,3,7,8-tetrachlorodibenzo-p-dioxin
+
+ (TCDD; dioxin) and benzo[a]pyrene cause a significant increases in CAT expression in mouse hepatoma Hepa-1
+ cells. We conclude that induction of a functional CYP1A1 monooxygenase by TCDD stimulates a pathway that
+ generates thiol-sensitive reactive oxygen intermediates which, in turn, are responsible for the TCDD-dependent
+ activation of genes linked to the LTR. These data might provide an explanation for findings that TCDD increases
+ infectious HIV-1 titers in experimental systems and for
+ epidemiologic reports suggesting that exposure to aromatic hydrocarbons, such as found in cigarette smoke,
+ is associated with an acceleration in AIDS progression.
+ Ann Trop Med Parasitol 1997 Oct;91(7):787-93 Of sick turkeys, kwashiorkor, malaria, perinatal
+ mortality, heroin addicts and food poisoning: research on the influence of aflatoxins on child health in the
+ tropics.
+
+
+
+ Ann N Y Acad Sci 1986;475:320-8. Hormonal approaches to immunotherapy of autoimmune disease.
+ Talal N, Ahmed SA, Dauphinee M. Cell Immunol 1998 Nov 1;189(2):125-34.
+ Estrogen increases the number of plasma cells and enhances their autoantibody production in nonautoimmune
+ C57BL/6 mice. Verthelyi DI, Ahmed SA. J Rheumatol 1987 Jun;14 Suppl 13:21-5. Interleukin 2,
+ T cell receptor and sex hormone studies in autoimmune mice. Talal N, Dang H, Ahmed SA, Kraig E,
+ Fischbach M. The administration of estrogen to pregnant mice late in gestation results in offspring with
+ a permanently altered immune system. These mice develop features of autoimmunity similar to those that occur
+ spontaneously in genetically susceptible autoimmune mice. This phenomenon may have etiopathological
+ significance for familial SLE. Endocrinology 1994 Dec;135(6):2615-22. 17 beta-estradiol, but not 5
+ alpha-dihydrotestosterone, augments antibodies to double-stranded deoxyribonucleic acid in nonautoimmune
+ C57BL/6J mice. Verthelyi D, Ahmed SA. J Autoimmun 1993 Jun;6(3):265-79 Antibodies to
+ cardiolipin in normal C57BL/6J mice: induction by estrogen but not dihydrotestosterone.
+ Ahmed SA, Verthelyi D. J Autoimmun 1989 Aug;2(4):543-52.
+ Estrogen induces the development of autoantibodies and promotes salivary gland lymphoid infiltrates in
+ normal mice. Ahmed SA, Aufdemorte TB, Chen JR, Montoya AI, Olive D, Talal N. . . . normal mice were
+ prenatally exposed to estrogens.
+ . . . mice prenatally exposed to estrogens had accelerated development of autoimmune salivary gland lesions
+ indistinguishable from Sjogren's syndrome (SS) in humans. Further experiments are warranted to confirm these
+ findings. The prenatal effects of estrogen may have relevance for familial and neonatal autoimmune syndromes.
+ Isr J Med Sci 1988 Dec;24(12):725-8.
+ Sex hormones, CD5+ (Lyl+) B-cells, and autoimmune diseases. Talal N, Ahmed SA. Ann N Y Acad Sci
+ 1986;475:320-8 Hormonal approaches to immunotherapy of autoimmune disease. Talal N, Ahmed SA,
+ Dauphinee M. Life Sci 1998;63(20):1815-22. Exacerbated immune stress response during experimental
+ magnesium deficiency results from abnormal cell calcium homeostasis. Malpuech-Brugere C, Rock E,
+ Astier C, Nowacki W, Mazur A, Rayssiguier Y. These studies first showed that an abnormal calcium
+ handling induced by extracellular magnesium depression in vivo may be at the origin of exacerbated
+ inflammatory response.
+ Magnes Res 1998 Sep;11(3):161-9. Early morphological and immunological alterations in the
+ spleen during magnesium deficiency in the rat.
+
+ Malpuech-Brugere C, Kuryszko J, Nowacki W, Rock E, Rayssiguier Y, Mazur A. Dietary magnesium deficiency in
+ rodents, and especially in rats, causes inflammation and leads to alterations in the immune response. Ann Rheum
+ Dis 1994 Nov;53(11):749-54
+ Polymerase chain reaction fails to incriminate exogenous retroviruses HTLV-I and HIV-1 in rheumatological
+ diseases although a minority of sera cross react with retroviral antigens. Nelson PN, Lever AM,
+ Bruckner FE, Isenberg DA, Kessaris N, Hay FC. Clin Diagn Lab Immunol 1998, Mar;5(2):181-5. Reactivity of
+ sera from systemic lupus erythematosus and Sjogren's syndrome patients with peptides derived from human
+ immunodeficiency virus p24 capsid antigen. Deas, JE, et al. We have previously
+ demonstrated that about one-third of patients with either Sjogren's syndrome (SS) or systemic lupus
+ erythematosus (SLE) react to human immunodeficiency virus (HIV) p24 core protein antigen without
+ any evidence of exposure to, or infection with, HIV itself. J Clin Lab Immunol 1988 Feb;25(2):101-3. Effect of diethylcarbamazine on serum antibody to feline oncornavirus-associated cell membrane antigen in
+ feline leukemia virus cats. Kitchen LW, Cotter SM. Department of Cancer Biology, Harvard School of
+ Public Health, Boston. Diethylcarbamazine (N,N-diethyl-4-methyl-1- piperazine carboxamide; DEC) is a drug
+ frequently used for prevention and treatment of the filariases. An opsonic action of DEC may generate increased
+ immune responses to microfilariae. We tested the hypothesis that DEC treatment could result in higher antibody
+ levels to other infectious agents. A retroviral animal model was studied,
+ in light of the consideration that use of DEC as an antifilarial agent could conceivably alter
+ seroepidemiologic surveys as well as serologic outcomes of vaccine trials in Africa regarding human
+ immunodeficiency virus (HIV).
+ The effect of DEC treatment on serum antibody to feline oncornavirus-associated cell membrane antigen
+ (FOCMA) in domestic cats exposed to feline leukemia virus (FeLV) was examined. Nine cats that
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
+
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+
+ Estrogen, memory and heredity: Imprinting and the stress response
+
+
+ Estrogen, memory and heredity: Imprinting and the stress response
+
+
+
+
+
+ IN OUTLINE: Stresses, including estrogen excess, activate the Heat Shock Proteins (HSP), the
+ stress-proteins, a primitive defense system. Heat Shock Proteins and "hormone receptors" are closely related
+ and interdependent. Stress (at least partly via HSP) activates viral expression, ordinary gene expression,
+ and destabilizes the genome, activating the "endonucleases," enzymes which break up DNA chains. Stress
+ increases genetic variability. DNA chains can be chemically modified (e.g., methylated) in a way that limits
+ enzymes' accesss, probably as protection, and to regulate gene expression. Genes, and subsequent growth and
+ development, are modified by the prenatal hormonal environment, that of the newborn, and even that of the
+ parents before conception.
+
+ Genomic imprinting makes maternal genes behave differently from paternal genes.
+ Hormonal imprinting early in life sets the pattern of expression of genes. "Crossing-over"
+ intermixes the genes on the chromosomes as cells multiply. Stresses and regulatory substances can change the
+ patterns of gene expression that define cell types. "Stem cells" are those capable of renewing tissues, and
+ may be "pluripotent," able to become glial cells and neurons in the brain, or, in the bone marrow, to become
+ red blood cells or white blood cells, depending on regulatory influences. "Cloning" animals from body cells
+ strongly suggests that any cell is potentially totipotent, able to differentiate into any other type of
+ cell. We are "imprinted" by our mothers' hormonal and nutritional conditions, but we can intervene to
+ correct these "inherited" conditions, by maintaining optimal hormonal and nutritional balances.
+
+
+
+ Recent work in several areas of biology is showing that heredity is not rigidly deterministic, in the way
+ implied by traditional genetics, and it is opening the way for the development of therapies for incurable,
+ chronic, or congenital problems, in natural and holistic ways that don't involve the mechanistic
+ interventions of "gene therapy" or "genetic engineering."
+ For example, nontoxic treatments for cancer that were demonstrated decades ago, were discarded because
+ they didn't seem consistent with "genetics." Many problems that are classified as congenital or genetic,
+ turn out to be physiological, and correctable. Even the brain and the heart, which until recently were
+ considered to be incapable of regenerative repair, are now seen to be capable of great anatomical
+ flexibility.
+
+
+ There are still great authoritarian forces opposed to recognizing, and supporting, the organism's full
+ potential. The most useful therapies will remain in obscurity until many people see that those
+ therapies have a firmer scientific foundation than orthodox (antiquated) medical genetics has.
+ Over 100 years ago, Samuel Butler had an argument with Charles Darwin, and concluded that Darwin
+ was philosophically muddled, and dishonest. Butler was annoyed that Darwin had belittled the work of his
+ predecessors, including his grandfather, Erasmus Darwin. Butler was defending the idea of biological
+ intelligence, the incorporation of experience into physiology and heredity.
+
+
+ My parents had an old copy of one of Darwin's books, and I was impressed by the fact that in his
+ introduction, Darwin was careful to point out that his ideas were already being misrepresented, and that
+ he did not hold "natural selection" to be the only mechanism of evolution,
+
+ but that several factors were important, including sexual selection and the inheritance of acquired traits.
+ I suppose those remarks might have been motivated partly by knowing that Butler didn't approve of the way he
+ was behaving, but they didn't seem to have much influence on the way history has characterized Darwin's
+ work. All of my biology professors would have been happier if Darwin had never made those remarks. I suspect
+ that Darwin's problem was that any theory of evolution
+ was under such heavy attack that he couldn't devote much time to the relatively minor issue of how evolution
+ works. After Darwin's death, the study of heredity made some strange concessions to the culture of
+ anti-evolutionism. As people began thinking about "particles that carry heredity," the "genes," ideas from
+ the anti-evolutionist culture formed much of the context for understanding these "particles."
+
+
+
+ Darwin had suggested that the mature organism reconstitutes itself in the germ cells, by sending gemmules or
+ pangens (buds or sprouts or derivatives) from its various parts, so that the parent's traits would be
+ incorporated into the reproductive cells. This was called pangenesis, meaning that the whole organism was
+ the source for the new offspring. This theory opened the possibility for newly acquired traits to be passed
+ on. It grew out of the experience of animal breeders and horticulturists, who were dedicated to improving
+ their breeds and strains, by selecting the best individuals grown under the best conditions.
+ It was known that the miniature ponies, Shetlands for example, would grow larger each
+ generation when bred under favorable conditions of domestication, rather than under the harsh conditions
+ of their native island.
+ It apparently never occurred to most plant and animal breeders that they might be able to improve a breed by subjecting it to harmful conditions. Around the end of the 19th century, August
+ Weismann began a systematic attack on the ideas of Darwin. As part of his campaign, he invented the doctrine
+ that the reproductive cells are absolutely isolated from the rest of the organism, and that they are
+ immortal. The rest of the organism is built up by the deletion of genetic information. This
+ doctrine was very convenient for those who maintained that all organisms had been created in a single
+ moment, and that the appearance
+
+ of evolution resulted from the extinction of some species, but not the new appearance of some species. Some
+ people, reasoning from Weismannism, suggested that evolution might have resulted without any change in the
+ immortal genetic material, except deletion, in a manner analogous to Weismann's theory of the developing
+ individual. Bacteria, in that view, would contain all the genes needed to make a tree or a person, and the
+ more complex forms would have evolved through the differential loss of that primeval genetic information.
+
+
+ The changes produced by subtraction were compatible with the notion of fallen man in a corrupt
+ world, while the addition of heritable traits through experience would connote a sharing in the
+ process of creation. The hereditary particles making up Weismann's "immortal isolated germ line" connoted a
+ single original creation.
+
+
+
+ As mutations in the genes came to be seen as a reality, experiments with X-rays suggested to some that all
+ mutations were harmful, and this attitude blended into the stream of doctrine which insisted that no
+ improvement could be inherited. Although many experiments showed what seemed to be meaningfully directed mutations, the doctrine held its ground, as its advocates taught that mutations were always
+ random. (The doctrine of random change, like the idea that entropy only increases, excluded acts of creation
+ from the fallen material world.) If a new trait appeared under new conditions, it was said to be only
+ because an old trait was being revealed by the induced loss of another trait.
+
+
+ I think anyone who reads the "landmark publications" in genetics will see that genetics had very little to
+ do with scientific method, as commonly conceived, and that it had all the traits of a cult. Analysis of the
+ language of genetics reveals that terms have more often been used to cover up empty speculation than to
+ clarify situations of fact.
+
+
+
+ Parallel to the way Darwin infuriated Samuel Butler by misrepresenting the origins of his theory, the
+ neodarwinists who debate the creationists over school textbooks are ignoring the ways in which the culture
+ of antievolutionism shaped their own view of genetics. The discovery of enzymes that produce DNA modeled on
+ RNA, "reverse transcriptases," began undermining traditional genetics, because it showed that new
+ information can enter our genome. The discovery that bacteria can pass "genes" from one individual to
+ another, conferring antibiotic resistance upon previously sensitive strains, was a major nuisance to people
+ working in infectious disease, since it complicates the treating of disease, but it indicated that
+ "evolution," or genetic change, was capable of happening in non-random ways. Early in the study of viral
+ genetics, many people realized that "organisms" which can't reproduce without their relatively complex
+ hosts, presented a problem for evolutionary theory. If the virus requires a cell in order to exist, it is
+ hardly a separate organism. A few people suggested that viruses were, or were based on, functional normal
+ parts of higher organisms. Some researchers have suggested that virus-like particles serve to carry
+ information from one part of an organism to other parts of that organism. Mobile genetic elements are now
+ well recognized, operating within cells, and it is common laboratory practice to use viral particles to
+ transfer genetic material from one cell to another.
+
+
+ Cellular systems which cut and splice nucleic acids, creating sequences of information which don't exist in
+ the inherited chromosomes, are now accepted parts of cell biology. Hormonal and environmental influences on
+ the stability of messenger RNA, and on mobile genetic elements, and on genomic stability in general, are
+ recognized. The center of gravity in the study of the nucleic acids has now shifted from
+ heredity to development.
+ Almost nothing remains of Weismannism, which was the foundation of neodarwinism. The "isolation of
+ the germline" doctrine persists in a few places, such as explaining why "the ovary runs out of eggs,"
+ despite some examples of egg-cell renewal.
+
+
+
+
+ But when the identity of "germline cells" is found to depend on signals from the environment, the last
+ vestige of Weismannian germ-line doctrine disappears. The only meaning of "germline" is that
+ some cells are destined to be germ cells, and the meaning disappears when such cells differentiate to form
+ body parts. (see Donovan, 1998, Labosky, et al., 1994.)
+
+
+ The difference between primordial germ cells and embryonic cells is a matter of "imprinting," the process in
+ which a hormone or "growth factor" or other "signal" directs a cell down a certain course of
+ differentiation. "Imprinting" is where genetics and physiology, phylogeny and ontoneny, come together, and
+ the new facts that are being discovered are removing the last vestige of scientific content from
+ Weismannism/neodarwinism. The argument between Peter Duesberg and the virus establishment, in which Duesberg
+ argues that acquired immunodeficiency is produced by a variety of causes, including drug use, and the
+ establishment argues that the HIV retrovirus is the only cause, becomes a little clearer when we consider it
+ in the context of the larger debate between the genetic determinists and the Darwinian adaptationists. I
+ will talk about that in more detail in a newsletter on immunodeficiency.
+
+
+ The issues of cancer, aging, and "hormone receptors," are also illuminated by seeing the organism as capable
+ of adaptive modification of its genes.
+
+
+
+ These newer molecular approaches to the study of biology are vindicating some of the practical observations
+ of plant and animal breeders, and terms such as telegony, heterosis, and xenia might come
+ into common use again, along with genomic imprinting.
+ Here, I want to give examples of "hormonal imprinting" amd "genetic imprinting," and to show how the
+ idea of the "retrovirus" or "mobile genetic elements" relates to practical health issues and therapies. The
+ developing egg cell is constructed and modified in many ways during its growth. The nurse cells which
+ surround it in the ovarian follicle inject massive quantities of material, especially RNA, into the
+ expanding egg cell. Regulatory substances and energy production modify enzyme activities and structural
+ proteins, which will influence the way it develops after fertilization. During the entire lifetime of the
+ individual person, the developing egg cells are open to influences from the organism as a whole. Because of
+ the Weismannian scientific culture, it's important to start with a few of the clearest interaction between
+ the environment and the reproductive cell, but many other types of interaction are starting to be explored.
+ It has been suggested that environmental stress is responsible for viral epidemics, by activating viruses in
+ their animal hosts, and causing them to spread to humans. Whether that's true or not, it is well recognized
+ that stress causes increased susceptibility to the development of viral infections. It also causes increased
+ genetic variability, which is logical in the evolutionary sense, that a species should become more variable
+ when its environmental niche has changed. The mobile genetic elements that were first recognized by Barbara
+ McClintock are now considered to be the most important means by which stress increases genetic variability.
+ In bacteria (J. Cairns; Salyers & Shoemaker, 1996), genetic changes are known to occur
+ in response to specific substances, which lead to adaptation to that substance. The mobile elements which
+ are responsible for the defensive adaptive response to antibiotics are similar to viruses. In these
+ instances, the genetic dogma which has been taught very recently in the universities couldn't have been
+ more clearly disproved. So far, the tendency in the United States is to concentrate on the details
+ because of their technological potential (for genetic engineering of lucrative products) and to ignore
+ the larger biological meaning of this interaction of stress with genetics.
+
+
+
+
+ Resistance to antibiotics is transmitted to other bacteria by "injecting," during conjugation of a resistant
+ bacterium with a sensitive one, a small virus-like granule containing the DNA required for detoxifying the
+ antibiotic, along with some adjoining genes. The antibiotic itself, producing stress, stimulates the
+ formation of this genetic package. (Whole university courses used to be devoted to showing why such things
+ couldn't happen.)
+
+
+ The enzymes which cut out sections of DNA are the "restrictases," which are famous for their use in
+ identifying samples of DNA. These "endonucleases" are activated by stress. In "excitotoxicity," which kills
+ nerve cells through a combination of intense activation with deficient energy stores (i.e., stress), these
+ enzymes are activated. In apoptosis, or "programmed cell death," these enzymes are activated, along with
+ enzymes which repair the broken genes, and the resulting energy drain from an impossible repair job causes
+ the cell's sudden dissolution. Between excitotoxicity and apoptosis, there are intermediate states, in which
+ the dissolution is retarded or reversed.
+
+
+ When the stress is more generalized, so that the cells survive, the more sensitive sections of DNA are
+ rearranged within the cell. Some of them may escape as infective particles.
+
+
+ Barbara McClintock wrote about the effects of stress causing genetic rearrangement, and traced the movements
+ of the mobile genetic elements. At the same time, without knowing about her work, Leonell Strong was working
+ with mice, exploring the role of "genetic instability" in causing cancer, and identifying estrogen and "milk
+ particle," or "milk factor," a virus-like particle that interacted with estrogen, as causes of breast
+ cancer. With only the elements of stress, the endonucleases, and the mobile packets of
+ genes, adaptively increased variability, and the spreading of genes among a population can be
+ explained. However, there is a subtler level at which the adaptations acquired by an indiviual can be passed
+ on to offspring. This is "imprinting."
+
+
+
+ "Genetic imprinting" is being studied mainly in terms of the covering of regions of DNA with methyl groups.
+ This is thought to have evolved as a way to keep the endonucleases from attacking the DNA. Sections of DNA
+ that have been methylated can be passed on to offspring in that form, and they can be traced as a pattern of
+ gene activity or inactivity. The maternal genes function in a manner identifiably different from the
+ paternal genes. Having passed through the mother's body, the genes have been modified.
+
+
+ "Hormonal imprinting" refers to the great changes in sensitivity to hormones (and related substances) that
+ persist after exposure to that substance early in life. When the mother's hormones are imbalanced during
+ pregnancy or nursing, the baby is "imprinted" with an altered sensitivity to hormones. Leonell Strong showed
+ that these effects could be exaggerated generation after generation. But--strangely, considering that he was
+ a student of T. H. Morgan, who is considered to be the founder of classical genetics--
+ Strong
+ found that a single treatment, or a series of treatments, with an extract of liver, or with certain
+ nucleosides (the units for constructing DNA), could reverse the course of generations of breeding, and
+ eliminate the susceptibility to cancer.
+
+
+
+ In modern terms, he was probably working with a combination of genetic imprinting and
+ hormonal imprinting. His "milk factor" very probably was one of the "endogenous retroviruses," or mobile
+ genetic elements. (However, Gaal, et al., 1998, found that imprinting factors can be transmitted in the
+ milk.)
+
+
+ Movable genetic elements appear to regulate normal developmental processes (Long, et al., 1998) and the
+ introduction of new particles can "improve fitness." This is an aspect of the HIV controversy that has been
+ completely ignored, as far as I can tell. Peter Duesberg argues that the presence of antibodies to the HIV
+ indicates that the immune system is active, and that there is no evidence showing the virus to be harmful.
+ My suggestion would be that the virus is probably present quietly in many people who have no antibodies to
+ it, and that environmental toxins and other stressors cause it to be adaptively expressed, creating the
+ possibility for an antibody response. The "viral particle" itself might be biologically useful, though this
+ wouldn't exclude the possibility that an abnormal immunological response to it could have harmful
+ repercussions.
+
+
+ The importance of the retroviruses in the human genome hasn't been widely appreciated. ("almost 10%
+ . . . homology with the retroviruses," Deb, et al, 1998.)
+
+
+ Environmental pollution with estrogens and immunosuppressive substances, when it persists throughout the
+ developmental period, and across generations, will be dangerous at levels much below those that show an
+ immediate hormonal or immunosuppressive effect. Tests that determine the "mutagenicity" or "carcinogenicity"
+ of a substance are performed within a context of a theoretical genetics which is demonstrably false;
+ until the complexities of imprinting and transgenerational effects are taken into account, it would be wrong
+ to accept the claim that there are "safe levels," or "thresholds of harmful effects."
+
+
+ When babies are imprinted by the mother's diuretics, by milk substitutes, and by industrial effluents, the
+ worst effects are likely to be seen decades later, or even generations later. There is a simple image that I
+ think makes it possible to grasp as a whole the unity of things which have been described as existing on
+ different "levels," the genetic, the metabolic, and the ecological. This is the image of an interaction
+ between water and large molecules, such as proteins and nucleic acids, with the system--the way the large
+ molecule is folded, and the way the water molecules are ordered--having more than one arrangement, or
+ physical state, each state differing slightly in the amount of potential energy it contains. Then, the
+ differences between respiratory energy (producing carbon dioxide and consuming electron-equivalents), and
+ relatively anaerobic conditions, determine the probability that the system will return to its higher energy
+ state after it has been perturbed.
+
+
+ A brief perturbation amounts to simple perception and response, reflecting the basic "irritability" of life,
+ to use Lamarck's term. But with more intense disturbances, the structures are altered at deeper levels, and
+ structures will be restored with different degrees of completeness, and the organism will have adapted,
+ according to its resources, either toward increased "fitness" and sensitivity, or toward decreased
+ sensitivity.
+
+
+
+ On the level of an individual, the movement away from fitness and sensitivity would resemble the development
+ of aging and degenerative disease;
+ on the level of a species, it would amount to "reverse evolution," a mammal would become more reptilian, a
+ primate would become more rodent-like.
+
+
+ Protective interventions, and therapies, will consist of things which protect the structures (preserving
+ sensitivity, while blocking excessive stimulation), and which increase the energy resources. A great variety
+ of physiological indicators show that substances such as progesterone, thyroid and carbon dioxide are acting
+ "universally" as protectants, in ways that make sense only with some perspective such as this, of the
+ systematic changes in the physical state of the living substance.
+
+
REFERENCES
+
+ Taruscio D, et al.,
+ Human endogenous retroviruses and environmental endocrine disrupters: a connection worth exploring?
+ Teratology. 1998 Aug;58(2):27-8.
+
+
+ Taruscio D, et al., Human endogenous retroviral sequences: possible roles in reproductive
+ physiopathology.
+ Biol Reprod. 1998 Oct;59(4):713-24
+
+
+
+ Genome 1998 Oct;41(5):662-8. A single-primer PCR-based retroviral-related DNA polymorphism shared by
+ two distinct human populations. Deb P, Klempan TA, O'Reilly RL, Singh SM Department of Zoology,
+ University of Western Ontario, London, Canada. "Almost 10% of the human genome consists of DNA
+ sequences that share homology with retroviruses.
+ These sequences, which represent a stable component of the human genome
+ (although some may retain the ability to transpose), remain poorly understood." "Such novel
+ polymorphisms should provide useful markers and permit assessment of evolutionary mechanisms associated with
+ retroviral-related genomic evolution. "
+
+
+
+ Chromosoma 1991 Dec;101(3):141-56 Integration site preferences of endogenous retroviruses.
+ Taruscio D, Manuelidis L. Yale Medical School, New Haven, CT 06510. "Retroviruses have the ability to
+ integrate into the genome of their host, in many cases with little apparent sequence or site specificity.".
+ "Retroviral elements in Alu-rich domains would be expected to be actively transcribed in all cells.
+ Surprisingly, hybridization to blots of brain RNA showed an approximately 25 fold lower level of
+ transcripts from these Alu associated elements than from retroviral sequences restricted to later
+ replicating, heterochromatic domains." "Each host genome may utilize these elements for contrary, and
+ possibly beneficial functions."
+
+
+
+ APMIS Suppl 1998;84:37-42 The potential of integrons and connected programmed
+ rearrangements for mediating horizontal gene transfer.. Sundstrom L. "Site-specific
+ recombination of integrons, mediates transfer of single genes in small genomes and plasmids. Recent data
+ suggest that new genes are recruited to the cassettes--the units moved by integrons. Integrons are resident
+ in a class of transposons with pronounced target selectivity for resolution loci in
+ broad host range plasmids. A resulting network of programmed transfer routes, with potential offshoots
+ reaching into eukaryotic cells, may channel genes to unexpectedly remote organisms."
+ "It seems very clear that integrons and associated programmed transfer mechanisms have high
+ significance for the dissemination of antibiotic resistance genes in bacteria whereas further studies are
+ needed to assess their importance for spreading of arbitrary genes in a wider range of host
+ systems."
+
+
+
+ Clin Infect Dis 1996 Dec;23 Suppl 1:S36-43. Resistance gene transfer in anaerobes: new insights, new
+ problems. Salyers AA, Shoemaker NB. "Integrated gene transfer elements, called
+ conjugative transposons, appear to be responsible for much of the transfer of resistance genes among
+ Bacteroides species. Conjugative transposons not only transfer themselves but also mobilize
+ coresident plasmids and excise and mobilize unlinked integrated elements." "An unusual feature of the
+ Bacteroides conjugative transposons is that transfer of many of them is stimulated considerably by
+ low concentrations of antibiotics. Thus, antibiotics not only select for resistant strains but also can
+ stimulate transfer of the resistance gene in the first place."
+
+
+ Genetics 1991 Aug;128(4):695-701 Adaptive reversion of a frameshift mutation in Escherichia
+ coli. Cairns J, Foster PL Department of Cancer Biology, Harvard School of Public Health,
+ Boston, Massachusetts 02115. Mutation rates are generally thought not to be influenced by selective forces.
+ This doctrine rests on the results of certain classical studies of the mutations that make bacteria
+ resistant to phages and antibiotics. We have studied a strain of Escherichia coli which
+ constitutively expresses a lacI-lacZ fusion containing a frameshift mutation that renders it Lac-. Reversion
+ to Lac+ is a rare event during exponential growth but occurs in stationary cultures when lactose is
+ the only source of energy. No revertants accumulate in the absence of lactose, or in the presence of
+ lactose if there is another, unfulfilled requirement for growth. The mechanism for such
+ mutation in stationary phase is not known, but it requires some function of RecA which is apparently not
+ required for mutation during exponential growth.
+
+
+ Science 1993 Oct 15;262(5132):317-319. Whither directed mutation?
+ Foster, P.L.
+
+
+
+ Science 1995, 268(5209):418-420. Adaptive mutation in Escherichia coli: a role for
+ conjugation. Radicella JP, Park PU, Fox, M.S. Nature 1998 Mar 12;392(6672):141-2
+ Are retrotransposons long-term hitchhikers? Burke WD, Malik HS, Lathe WC 3rd, Eickbush TH.
+
+
+ J Biomol Struct Dyn 1998 Feb;15(4):717-21 Mammalian retroposons integrate at kinkable DNA
+ sites. Jurka J, Klonowski P, Trifonov EN "This suggests that during interaction with the
+ endonucleolytic enzyme, or enzymes, DNA undergoes bending at the integration sites and kinks are formed, as
+ initial steps in generating the nicks. Nicking at kinkable sites, particularly at TA steps, may also play a
+ role in integration of other insertion elements."
+
+
+
+ J. Mol Evol 1997 Dec;45(6):599-609 The evolution of MHC diversity by segmental duplication and
+ transposition of retroelements. Kulski JK, Gaudieri S, Bellgard M, Balmer L, Giles K, Inoko H,
+ Dawkins RL.
+
+
+ Biochemistry (Mosc) 1997 Nov;62(11):1202-5. Telomerase is a true reverse transcriptase. A
+ review. Cech TR, Nakamura TM, Lingner J Department of Chemistry and Biochemistry, Howard Hughes
+ Medical Institute, University of Colorado,Boulder. "We find it remarkable that the same type of
+ protein structure required for retroviral replication is now seen to be essential for normal chromosome
+ telomere replication in diverse eukaryotes."
+
+
+
+ Gene 1997 Dec 31;205(1-2):177-82 Mobile elements inserted in the distant past have taken on
+ important functions. Britten RJ.
+
+
+ Genetika 1994 Jun;30(6):725-30 ["Adaptive transposition" of retrotransposons in the Drosophila
+ melanogaster genome accompanying the increase in features of adaptability].
+ Beliaeva ES, Pasiukova EG, Gvozdev V.A. . "The transpositions were accompanied by a
+ dramatic increase in individual fitness (competitive success)."
+
+
+
+ Genetika 1997 Aug;33(8):1083-93 [Stress induction of retrotransposon transposition in Drosophila:
+ reality of the phenomenon, characteristic features, possible role in rapid evolution].
+ Vasil'eva LA, Ratner VA, Bubenshchikova EV "This stress response involved mobilization of retrotransposons."
+ "In all these cases, stress induction of retrotransposon transpositions was mediated by molecular
+ mechanisms of the heat shock system-the general system of cell resistance to external and physiological
+ stress factors. From the viewpoint of evolution, stress induction of transpositions is a powerful factor
+ generating new genetic variation in populations under stressful environmental conditions.
+ Passing through a "bottleneck," a population can rapidly and significantly alter its population norm and
+ become the founder of new, normal forms."
+
+
+
+ Mol Biol (Mosk) 1995 May-Jun;29(3):522-8 [Conserved regions of potential ORF1 protein products of
+ mobile elements and retroviral proteins, encoded by the gag gene].
+ Kanapin AA, Ivanov VA, Il'in IuV.
+
+
+ Radiats Biol Radioecol 1995 May-Jun;35(3):356-63 [DNA analysis of retroposon-like genetic LINE
+ elements in blood plasma of rats exposed to radio-diapason electromagnetic waves]. [Article in
+ Russian] Belokhvostov AS, Osipovich VK, Veselova OM, Kolodiazhnaia VA
+ The elevation of LINE-elements' DNA level was revealed in blood plasma of rats exposed to
+ electromagnetic waves. The amount of full-size 5'-containing LINE-elements copies was
+ increased
+ especially. Connection of this effect with retrotransposon activation and genetic instability condition
+ of organism development is supposed.
+
+
+
+
+ Dokl Akad Nauk 1995 Jan;340(1):138-40 [Induction of virus-like particles Tu1 by
+ the mini-Tu1 element in the SPT3 mutant strain of Saccharomyces cerevisiae].
+ Reznik NL, Zolotova LI, Shuppe NG.
+
+
+ Dokl Akad Nauk 1994 Dec;339(6):838-41 [Extracellular virus-like particles retrotransposon Gypsy (MDG
+ 4) as an infectivity factor]. Semin BV, Il'in IuV.
+
+
+ Mol Biol (Mosk) 1994 Jul-Aug;28(4):813-21.
+ [Expression of the third open reading frame of the drosophila MDG4 retrotransposon similar to the
+ retroviral env-genes, occurring through splicing].
+ Avedisov SN, Il'in IuV "The presence of a third long open reading frame (ORF3) is the common
+ feature of a number of Drosophila retrotransposons, including MDG4 (gypsy). Thus, these elements
+ have a strong structural resemblance to the integrated forms of vertebrate retroviruses."
+ "The regulation at the level of splicing is supposed to be one of the most important factors controlling the
+ transposition frequency of MDG4."
+
+
+ Genetika 1994 Jun;30(6):743-8 [Introduction of a single transpositionally-active copy of MDG4 into
+ the genome of a stable line of Drosophila melanogaster causes genetic instability].
+ Liubomirskaia NV, Shostak NG, Kuzin AB, Khudaibergenova BM, Il'in IuV, Kim AI. "A previously described
+ system of a Drosophila melanogaster mutative strain (MS), which originates from a stable strain (SS), is
+ characterized by genetic instability caused by transposition of the retrotransposon gypsy. New unstable
+ strains were obtained by microinjections of the gypsy transposable copy into SS embryos." "Genetic
+ instability in the MS system is apparently induced by a combination of two factors: the presence of a gypsy
+ transposable copy and mutation(s) in the gene(s) regulating its transpositions."
+
+
+
+ Genetika 1991 Mar;27(3):404-10 [Maintenance of the copy number of retrotransposon MDG3 in the
+ Drosophila melanogaster genome]. Glushkova IV, Beliaeva ESp, Gvozdev VA The genomes of
+ laboratory stocks and natural population of Drosophila melanogaster contain 8-12 copies of retrotransposon
+ MDG3 detected by in situ hybridization. Construction of genotypes with decreased MDG3 copy number using
+ X-chromosome and chromosome 3 free of MDG3 copies results in appearance of hybrid genomes carrying
+ up to 7-10 copies, instead of 2-4 copies expected. New MDG3 copies are detected in different
+ genome regions, including the 42B hot spot of their location. The chromosomes, where new clusters of MDG3
+ were observed, carry conserved "parental pattern" of MDG1 arrangement.
+ The data obtained suggest the existence of genomic mechanism for maintenance of retrotransposon copy
+ number on a definite level.
+
+
+ Biull Eksp Biol Med 1998 Jul;126(7):4-14 [The role of retroposition in the
+ self-regulation of genome processes (do genes program the body and retroposons program genome]?
+ Bebikhov DV, Postnov AIu, Nikonenko TA.
+
+
+ Genetika 1996 Jul;32(7):902-13 [Analysis of motifs of functional MDG2 sites in assuring its possible
+ molecular functions]. Ratner VA, Amikishiev VG "Enhancers of mobile genetic elements are
+ assumed to determine modification of adjacent genes and polygenes. Excisions and transpositions of
+ mobile elements seem to be induced by external stress factors or physiological factors through a
+ heat-shock system."
+
+
+
+ Genomics 1998 Dec 15;54(3):542-55 A long terminal repeat of the human endogenous
+ retrovirus ERV-9 is located in the 5' boundary area of the human beta-globin locus control
+ region. Long Q, Bengra C, Li C, Kutlar F, Tuan D. "Transcription of the human beta-like
+ globin genes in erythroid cells is regulated by the far-upstream locus control region (LCR). In
+ an attempt to define the 5' border of the LCR, we have cloned and sequenced 5 kb of new upstream DNA. We
+ found an LTR retrotransposon belonging to the ERV-9 family of human endogenous retroviruses
+ in the apparent 5' boundary area of the LCR." "This LTR is conserved in human and gorilla, indicating its
+ evolutionary stability in the genomes of the higher primates. In both recombinant constructs and the
+ endogenous human genome, the LTR enhancer and promoter activate the transcription of cis-linked DNA
+ preferentially in erythroid cells. Our findings suggest the possibility that this LTR
+ retrotransposon may serve a relevant host function in regulating the transcription of the
+ beta-globin LCR." Copyright 1998 Academic Press.
+
+
+ Genetika 1995 Dec;31(12):1605-13 [Heterologous induction of the retrotransposon Ty1: reverse
+ transcriptase plays a key role in initiating the retrotransposition cycle].
+ Reznik NL, Kidgotko OV, Zolotova LI, Shuppe NG A new method was developed to study the mechanism
+ of initiation of the retrotransposition cycle: retrotransposons of Drosophila melanogaster, gypsy, copia,
+ and 17.6 were expressed in yeast under the control of potent yeast promoters.
+ Expression of retrotransposons induced formation of viruslike particles (VLPs) associated with
+ full-length Ty1 RNA and DNA sequences. This phenomenon was termed heterologous induction.
+ When the gene for reverse transcriptase of human immunodeficiency virus (HIV) was expressed in
+ yeast, the same results were obtained. These data allowed us to assume the excess of active reverse
+ transcriptase to play the central role in induction of transposition. Possible mechanisms of
+ induction of Ty1 transposition by homologous and heterologous elements are discussed. Hum Exp Toxicol 1998
+ Oct;17(10):560-3 Effect of retinoid (vitamin A or retinoic acid) treatment (hormonal imprinting)
+ through breastmilk on the glucocorticoid receptor and estrogen receptor binding capacity of the adult
+ rat offspring. Gaal A, Csaba G. "Hormonal imprinting occurs perinatally when the developing
+ receptor and the appropriate hormone meet each other. The presence of related molecules in this critical
+ period causes misimprinting. Ligands bound
+ to a member of the steroid-thyroid receptor superfamily can disturb the normal maturation of other
+ members of the family, which is manifested in altered binding capacity of the receptor and
+ decreased or increased response of the receptor-bearing cell for life. Excess or absence of the hormone also
+ can cause misimprinting."
+ "The results of the experiment call attention to the transmission of imprinter molecules by breastmilk
+ to the progenies, which can cause lifelong alterations at receptorial level and points to the human
+ health aspect. Possible reasons for the differences between retinol and retinoic acid effects and in the
+ sensitivity of receptors are discussed."
+
+
+
+ Life Sci 1998;63(6):PL 101-5 Neonatal vitamin E treatment induces long term
+ glucocorticoid receptor changes: an unusual hormonal imprinting effect. Csaba G, Inczefi-Gonda
+ A. "Thousandfold tocopherol did not compete with labeled dexamethasone for their receptors,
+ suggesting
+ that neonatal vitamin E imprinting effect was not done at direct receptorial level."
+
+
+ J Hypertens 1998 Jun;16(6):823-8 Female Wistar-Kyoto and SHR/y rats have the same
+ genotype but different patterns of expression of renin and angiotensinogen genes. Milsted A,
+ Marcelo MC, Turner ME, Ely DL "Female SHR/y rats have the parental Wistar-Kyoto rat autosomes and X
+ chromosomes and have no chromosomes of spontaneously hypertensive rat origin; thus they are genetically
+ equivalent to female Wistar-Kyoto rats." "The combination of removing estrogen early in development and
+ supplementing the ovariectomized females with testosterone revealed strain differences in response of blood
+ pressure." "Differences in regulation of renin-angiotensin system genes between strains may result from
+ epigenetic mechanisms such as genome imprinting of these genes or of another gene that
+ functions as a common regulator of renin and angiotensinogen."
+
+
+
+ Gen Pharmacol 1998 May;30(5):685-7 Imprinting of thymic glucocorticoid receptor and uterine estrogen
+ receptor by a synthetic steroid hormone at different times after birth. Csaba G, Inczefi-Gonda
+ A. 1. "Single allylestrenol treatment (hormonal imprinting) of 3-day old rats reduced the density of thymus
+ glucocorticoid receptors and increased the density of uterus estrogen receptors at adult age." "4. The
+ experiments demonstrate that hormonal imprinting can be provoked by allylestrenol not only pre- or
+ neonatally, as was done in previous experiments, but also a few days later. The imprintability was lost
+ between the 4th and 8th day of life."
+
+
+ Gen Pharmacol 1998 May;30(5):647-9 Fetal digoxin treatment enhances the binding capacity of thymic
+ glucocorticoid receptors in adult female rats. Csaba G, Inczefi-Gonda A. 1. Hormonal imprinting
+ is provoked in the perinatal critical period in the presence of the appropriate hormone or molecules similar
+ to it. As a consequence of hormonal imprinting, the developing receptor finishes its maturation normally (in
+ the presence of the adequate hormone) or abnormally (under the effect of foreign molecules that are able to
+ bind to the receptor). 2. Digoxin--which has a steroid character--caused faulty imprinting by treatments at
+ the 15th, 17th and 20th days of pregnancy. In the adult (3-month-old) animals, the density of thymic
+ glucocorticoid receptors was significantly elevated, whereas the density of uterine estrogen receptors was
+ not, without any change in receptor affinity. 3. The experiments call attention to the steroid receptor
+ imprinting effect of fetal digoxin treatment that must be considered in regard to this treatment at this
+ period and later in regard steroid treatments.
+
+
+
+ Hum Exp Toxicol 1998 Feb;17(2):88-92 Transgenerational effect of a single neonatal benzpyrene
+ treatment on the glucocorticoid receptor of the rat thymus. Csaba G, Inczefi-Gonda A. Hormonal
+ imprinting is provoked perinatally by the appropriate hormone on its receptor,
+ causing a life-long adjustment of the connection between the two participants. Faulty imprinting is caused
+ by the presence of molecules similar to the hormone in this critical period, which results in a persistent
+ alteration of the receptor. In the present experiment the transgenerational imprinting effect of a
+ steroid-like environmental pollutant, benzpyrene, on the receptor binding capacity of filial thymic
+ dexamethasone and uterine estrogen receptors was studied. The receptor density (Bmax) of the thymic
+ glucocorticoid receptors of the males was reduced up to the third (F2) generation.
+ In females this reduction was observed only in the F1 generation of treated animals. There was no
+ change in receptor affinity (Kd). Uterine estrogen receptors were not subjected to transgenerational
+ imprinting. The experiments demonstrate (1) the possibility of the
+ transgenerational transmission of imprinting effect, (2) the differences of steroid receptors
+ in different organs, and (3) the differences of male's and female's reactions from this aspect. The results
+ call attention to the dangers of perinatal aromatic hydrocarbon exposition to the progeny generations.
+
+
+
+ Genetika 1994 Apr;30(4):437-44 [Tv1--a new family of Drosophila virilis retrotransposons]. Andrianov BV,
+ Shuppe NG."The method is based on the hypothesis about the universal character of retrotransposition
+ through reverse transcription."
+
+
+ Genetika 1990 Mar;26(3):399-411 [Transpositional bursts and chromosome
+ rearrangements in unstable lines of Drosophila].
+ Gerasimova TI, Ladvishchenko AB, Mogila VA, Georgieva SG, Kiselev SL, Maksymiv DV "The phenomenon
+ of transpositional bursts--massive simultaneous transpositions of mobile elements belonging to different
+ structural classes and accompanied by multiple mutagenesis were earlier described. Although the mechanisms
+ of this phenomenon are still unclear, it is obvious now that
+ it embraces total genome and includes not only transpositions of different mobile elements but also
+ recombination processes--homologous recombination
+ for LTR's and gene conversion."
+
+
+
+ Eksp Onkol 1986;8(2):29-32
+ [Nature of the endogenous retrovirus-like particles of the rat liver].
+
+ Korokhov NP, Pyrinova GB, Kurtsman MIa, Tomsons VP, Salganik RI.
+
+
+ © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Intelligence and metabolism
+
+
+ Intelligence and metabolism
+
+
+
+
+
+
+
+
+ Appropriate stimulation is an essential part of the developmental process. Inappropriate stimulation
+ is a stress that deforms the process of growth. Mediators of stress, such as serotonin, can cause
+ persistent distortions of physiology and behavior.
+
+
+ Education can either activate or suppress mental energy. If it is mainly obedience training, it
+ suppresses energy. If it creates social dislocations, it disturbs mental and emotional energy.
+
+
+ Stress early in life can impair learning, cause aggressive or compulsive behavior, learned
+ helplessness, shyness, alcoholism, and other problems.
+
+
+ Serotonin activates the glucocorticoid system, which can produce brain atrophy. Antiserotonin agents
+ protect against brain atrophy and many other effects of stress. The brain-protecting neurosteroids,
+ including pregnenolone and progesterone, which are increased by some kinds of stimulation, are decreased
+ by isolation stress, and in their absence, serotonin and the glucocorticoids are relatively unopposed.
+
+
+
+ Since excess serotonin can cause thrombosis and vasospasms, and the excess cortisol resulting from
+ hyperserotonemia can weaken blood vessels and the immune system, a person's longevity is likely to be
+ shortened if something doesn't intervene to alter the patterns induced by stress early in life.
+
+
+
+
+
+
+
+ Baroness Blatch: "My Lords, the levels of achievement are well above the national average of our own
+ state schools."
+
+
+
+ "This is a school which attained 75 per cent A to C passes in 1998, and 63.9 per cent in 1999. Those
+ figures are well above national averages. There is no truancy; and there is the highest possible level
+ of parental satisfaction with the school. When those parents are paying their money and know what they
+ are paying for, who are we to take a different view about the philosophy of education in a private
+ school?"
+
+
+ Comment during debate in House of Lords, June 30, 1999, on Chief Inspector of Schools Woodhead's
+ threat to close Summerhill, a democratic school which had been started in 1921.
+
+
+
+ In 1927, the government inspectors had recommended that 'all educationalists' should come to
+ Summerhill to see its 'invaluable' research, which demonstrated that students' development is better
+ when they regulate themselves and are not required to attend lessons.
+
+
+
+
+
+
+
+ Having written about animal intelligence, and the ways in which it is similar to human intelligence, now I
+ want those ideas to serve as a context for thinking about human intelligence without many of the usual
+ preconceptions.
+
+
+ Intelligence is an interface between physiology and the environment, so it's necessary to think about each
+ aspect in relation to the other. Things, both biochemical and social, that enhance intelligence enhance life
+ itself, and vice versa.
+
+
+ Psychologists have tried to give their own definitions to words like idiot, imbecile, moron, and genius, but
+ they have just been refining the clich"s of the culture, in which "dummy" is one of the first words that
+ kids in the U.S. learn. Many psychologists have tried to create "culture-free" tests of intelligence, making
+ it clear that they believe in something like innate animal intelligence, though they usually call it
+ "genetic" intelligence. Other psychometrists have transcended not only biology but even rationality, and
+ have catalogued the preferences
+
+ of people that they define as intelligent, and designed "I.Q. tests" based on the selection of things that
+ were preferred by "intelligent people." This behavior is remarkably similar to the "psychometry" of the
+ general culture, in which "smart" people are those who do things the "right" way.
+
+
+ About thirty years ago, someone found that the speed with which the iris contracts in response to a flash of
+ light corresponds very closely to the I.Q. measured by a psychologist using a standard intelligence test.
+ The devices used to measure reaction time in drivers' education courses also give a good indication of a
+ person's intelligence, but so does measuring their heart rate, or taking their temperature. Colleges would
+ probably be embarrassed to admit students on the basis of their temperature (though they commonly award
+ scholarships on the basis of the ability to throw a ball). Colleges, to the extent that they are serious
+ about the business of education, are interested in the student's ability to master the culture.
+
+
+ The way a person has learned during childhood can shape that person's manner of grasping the culture. To
+ simply accelerate the learning of a standard curriculum will increase that person's "I.Q." on a conventional
+ test, but the important issue is whether it is really intelligent to learn and to value the things taught in
+ those curricula. Some educators say that their purpose is to socialize and indoctrinate the students into
+ their discipline, others believe their purpose is to help their students to develop their minds. Both of
+ these approaches may operate within the idea that "the culture" is something like a museum, and that
+ students should become curators of the collection, or of some part of it. If we see the culture
+ metaphorically as a mixture of madhouse, prison, factory, and theater, the idea of "developing the student's
+ mind" will suggest very different methods and different attitudes toward "the curriculum"
+
+
+ Even sophisticated people can fall into stereotyped thinking when they write about issues of intelligence.
+ For example, no one considers it a sign of genius when a slum kid is fluent in both Spanish and English, but
+ when some of history's brightest people are discussed, the fact that they learned classical Greek at an
+ early age is always mentioned. No one mentions whether they were competent in idiomatic Spanish.
+
+
+
+ One of the old cultural stereotypes is that child prodigies always "burn out," as if they were consuming a
+ fixed amount of mental energy at an accelerated rate. (This idea of burn-out is isomorphic with the other
+ cultural stereotypes relating aging to the "rate of living," for example that people with slow heart beats
+ will live longer.) Some of the men who have been considered as the world's brightest have, in fact, gone
+ through a crisis of depression, and Terman's long-term study of bright people found that "maladjustment" did
+ increase with I.Q., especially among women. But the facts don't support the concept of "burn-out" at all. I
+ think the facts reveal instead a deep flaw in our ideas of education and professional knowledge.
+
+
+ In a world run by corporation executives, university presidents ("football is central to the university's
+ mission"), congressmen, bankers, oilmen, and agency bureaucrats, people with the intelligence of an ant (a
+ warm ant) might seem outlandishly intelligent. This is because the benighted self-interest of the
+ self-appointed ruling class recognizes that objective reality is always a threat to their interests. If
+ people, for example, realized that estrogen therapy and serotonin-active drugs and x-rays and nuclear power
+ and atomic bomb tests were beneficial only to those whose wealth and power derive from them, the whole
+ system would lose stability. Feigned stupidity becomes real stupidity.
+
+
+ But apart from ideologically institutionalized stupidity, there are real variations in the ability to learn,
+ to remember and to apply knowledge, and to solve problems. These variations are generally metabolic
+ differences, and so will change according to circumstances that affect metabolism. Everyday social
+ experiences affect metabolism, stimulating and supporting some kinds of brain activity, suppressing and
+ punishing others. All of the activities in the child's environment are educational, in one way or another.
+
+
+ Some of the famous prodigies of history illustrate the importance of ideology in the development of
+ intellect. Family ideology, passing on the philosophical orientations of parents and their friends, shapes
+ the way the children are educated.
+
+
+ Some of these family traditions can be traced by considering who the child's godfather was. Jeremy Bentham
+ was John Stuart Mill's godfather, Mill was Bertrand Russell's; Ralph Waldo Emerson was William James'
+ godfather, James was W. J. Sidis's. Willy Sidis was educated by his parents to demonstrate their theory of
+ education, which grew out of the philosophies of Emerson and James. His father, Boris Sidis, was a pioneer
+ in the study of hypnosis, and he believed that suggestion could mobilize the mind's "reserve energy." Willy
+ learned several languages and advanced mathematics at an early age. After he graduated from Harvard at the
+ age of 16, he tried teaching math at Rice Institute, but he was displeased by the attitudes of his students
+ and of the newspaper and magazine writers who made a profession of mocking him. He attended law school at
+ Harvard, and would have been imprisoned as a conscientious objector if the war hadn't ended.
+
+
+ Antisemitism probably played a role in his sense of isolation when he was at Harvard and Rice. In 1912 Henry
+ Goddard, a pioneer in intelligence testing (and author of The Kallikak Family: A Study in the
+ Heredity of Feeble- Mindedness), administered intelligence tests to immigrants and
+ determined that 83 percent of Jews and 87 percent of Russians were "feeble-minded." By the standards of the
+ time, it was highly inappropriate for the child of extremely poor Jewish immigrants from eastern Europe to
+ be so bright.
+
+
+ Sidis hid from the press, and worked as a bookkeeper and clerk, while he studied and wrote. During his years
+ of obscurity, he wrote books on philosophy and American history. Eventually, the journalists discovered him
+ again, and after prolonged lawsuits against the magazines for invasion of privacy and slander, he died of a
+ stroke at the age of 46.
+
+
+ Sidis is probably the culture's favorite example of the child prodigy who burns out, but people (Robert
+ Persig, Buckminster Fuller) who have read his books have said favorable things about them. The journalists'
+ emphasis on the fact that Sidis never held a prestigious job nicely illustrates their clich" mentality: "If
+ you're so smart, why aren't you rich?" But throughout history, intelligent nonconformists have supported
+ themselves as craft-workers or technicians--Socrates as a stone mason, Spinoza as a lens grinder, Blake as
+ an engraver, Einstein as a patent examiner, for example.
+
+
+
+ In conventional schools (as in conventional society) 10,000 questions go unanswered, not only because a
+ teacher with many students has no time to answer them, but also because most teachers wouldn't know most of
+ the answers.
+
+
+ The parents of W. J. Sidis and J. S. Mill were remarkably well educated people who, because they dissented
+ from society's ideology, chose to spend much of their time educating their children. Whenever a question
+ about Euclidean geometry or Greek grammar occurred to the child, it could be answered immediately. It was
+ only natural that progress would be fast, but there were more important differences.
+
+
+ When questions are answered, curiosity is rewarded, and the person is enlivened. In school, when following
+ instructions and conforming to a routine is the main business, many questions must go unanswered, and
+ curiosity is punished by the dulling emptiness of the routine.
+
+
+ Some schools are worse than others. For example, slum children were given I.Q. tests when they started
+ school, and each subsequent year, and their I.Q.s dropped with each year of school. In a stimulating
+ environment, the reverse can happen, the I.Q. can rise each year. Since the tests aren't "culture free,"
+ their scores reflected the material that they were being taught, but they undoubtedly also reflected the
+ increasing boredom and despair of the children in a bad school, or the increasing liveliness of the children
+ in the stimulating environment.
+
+
+ I have spoken with people in recent years who still held the idea of a fixed genetic mental potential, who
+ believe that poor children fall behind because they are reaching their "genetic limit." For them, the I.Q.
+ represents an index of intrinsic quality, and is as important as distinguishing between caviar and frogs'
+ eggs. The rat research of Marion Diamond and others at the University of California, however, showed that
+ the structure, weight, and biochemistry of a rat's brain changes, according to the amount of environmental
+ stimulation and opportunity for exploration. This improvement of brain structure and function is passed on
+ to the next generation, giving it a head-start. It isn't likely that rats are more disposed than humans to
+ benefit from mental activity, and in the years since Diamond's research there have been many discoveries
+ showing that brains of all sorts complexify structurally and functionally in response to stimulation.
+
+
+
+ Rats isolated in little boxes, generation after generation--the normal laboratory rats--were the standard,
+ but now it's known that isolation is a stress that alters brain chemistry and function.
+
+
+ Willy Sidis and John Stuart Mill were being stimulated and allowed to develop in one direction, but they
+ were being isolated from interaction with their peers. When Mill was twenty he went into a depression, and
+ later he wrote that it was because he discovered that he was unable to feel. He
+ had developed only part of his personality.
+
+
+ Bertrand Russell (1872-1970), orphaned at the age of four, went to live with his grandmother, who chose not
+ to send him to school, but provided tutors. He didn't experience a sense of academic pressure, and was able
+ to read whatever he wanted in his late grandfather's library. He didn't realize that he was unusually bright
+ until he went to Cambridge. The unusual freedom of his childhood must have contributed to his willingness to
+ hold unpopular opinions. In 1916 he was fined, and in 1918 imprisoned for 6 months, for opposing the war.
+
+
+
+ In 1927, Russell and his wife, Dora Black, started a school. He later wrote that, although the average
+ student at the school was very bright, an exceptionally bright student was likely to be ostracized by the
+ less bright students. He commented on the harm done to the brightest students by their social isolation,
+ probably thinking about his own education in relative isolation. A psychologist (Leta Hollingworth, 1942)
+ has made similar observations about the isolation that can be produced by a large difference of I.Q. She did
+ a series of studies of very bright children, beginning in 1916, including working with some of them in a
+ program she designed in a New York public school. Her empathy allowed her to discover things that weren't
+ apparent to her contemporaries.
+
+
+ During this time Lewis Terman was studying bright children, and wanted to disprove some of the popular
+ stereotypes about intelligent people, and to support his ideology of white racial superiority. In 1922 he
+ got a large grant, and sorted out about 1500 of the brightest children from a group of 250,000 in
+ California. He and his associates then monitored them for the rest of their lives (described in Genetic Studies of Genius). His work contradicted the stereotype of bright people as
+ being sickly or frail, but, contrary to his expectation, there was an association between maladjustment and
+ higher I.Q.; the incidence of neurotic fatigue, anxiety, and depression increased along with the I.Q. The
+ least bright of his group were more successful in many ways than the most bright. He didn't really confront
+ the implications of this, though it seriously challenged his belief in a simple genetic racial superiority
+ of physique, intellect, and character.
+
+
+ I.Q. testing originated in a historical setting in which its purpose was often to establish a claim of
+ racial superiority, or to justify sterilization or "euthanasia," or to exclude immigrants. More recently,
+ the tests have been used to assign students to certain career paths. Because of their use by people in power
+ to control others, the I.Q. tests have helped to create misunderstanding of the nature of intelligence. A
+ person's "I.Q." now has very strong associations with the ideology of schooling as a road to financial
+ success, rather than to enrichment of a shared mental life.
+
+
+ If a bad school resembles, on the intellectual level, a confining rat box, the educational isolation of
+ Mill, Russell, and Sidis was emotionally limiting, almost like solitary confinement. Once when Willy Sidis
+ was arrested for marching in a May Day parade, his father was able to keep him from going to prison, but
+ Willy apparently would have preferred the real prison to life with his parents.
+
+
+
+ None of these three famous intellects was known for youthful playfulness, though playfulness is a quality
+ that's closely associated with intelligence in mammals and birds. (Russell, however, in middle age developed
+ many new interests, such as writing short stories, and had many new loves even in old age.) Stress early in
+ life, such as isolation, reduces the playfulness of experimental animals. Playfulness is contagious, but so
+ is the inability to play.
+
+
+ In schools like Summerhill, which was founded in 1921 by A. S. Neill, students aren't required to attend
+ classes when they would rather do something else, but at graduation they usually do better on their
+ standardized national examinations than students who have dutifully attended classes for years. For
+ students, as for rats, freedom and variety are good for the brain, and tedious conformity is harmful. When a
+ school is very good, it can spread a contagion of playfulness along with an interest in learning.
+
+
+ An environment that fosters optimal intelligence will necessarily promote the development of emotional
+ health, and will almost certainly foster good physical health and longevity, because no part of the
+ physiological system can thrive at the expense of another part. And within the boundaries of life-enriching
+ environments, there are infinite possibilities for variety.
+
+
+ There is a common belief in the rigidity of the adult nervous system, in analogy with feral cats or dogs,
+ that supposedly can't be tamed if they have grown up without knowing humans. But people who have had the
+ inclination to understand wild animals have found that, even when the animals have been captured as adults,
+ they can become as sociable as if they had grown up in domestication. The "horse whisperer" demonstrated
+ this sort of empathetic approach to animals. Sometimes, these people have a similar ability to communicate
+ with people who are retarded, or autistic, or demented, but the professionalization of society has made it
+ increasingly unlikely that people with the need for intuitive help will encounter someone who is able to
+ give it. The closest psychology has come to professionally recognizing the importance of empathy was in Carl
+ Rogers' work, e.g.,
+ Client-Centered Therapy.
+
+
+ Rogers showed that a sense of solidarity must exist between therapist and client for the therapy to be
+ helpful. A similar solidarity has to exist between teacher and student, for education to be successful. If
+ ordinary family and social contacts could occur within such an atmosphere of mutual respect, psychopathology
+ (including learning difficulties) would be much less common.
+
+
+ Although three individuals don't prove an argument, I think the lives and situations of Sidis, Mill, and
+ Russell are usefully symbolic. Sidis, who grew up under intense pressure and social isolation and in extreme
+ poverty, died at the age of 46. Mill, who was educated mainly by his father, in secure financial
+ circumstances, experienced social isolation and moderate pressure, and lived about 20 years longer than
+ Sidis did. Russell, who grew up in the highest circles of the ruling class, experienced no pressure, and
+ only the mild kind of social isolation that wasn't exceptional for his class. He lived to be 97.
+
+
+ The psychopathology of social isolation has been studied in a variety of animals, and many features are
+ similar across species, including humans. Aggression, helplessness, and reduced ability to learn are
+ typically produced in animals by social isolation, and it's clear that certain kinds of family environment
+ produce the same conditions in children. Schools seldom help, and often hinder, recovery from such early
+ experiences.
+
+
+ "Vital exhaustion," decreased slow wave sleep, and anger, which are associated with the "type A personality"
+ and with circulatory and heart disease, appear to have their origin in childhood experiences. Low income and
+ financial insecurity are strongly associated with anger, sleep disturbances, and circulatory disease. In
+ animals stressed by social isolation, similar features emerge, under the influence of decreased
+ neurosteroids, and increased serotonin and activity of the glucocorticoid system.
+
+
+ The "smart drug" culture has generally been thinking pharmaceutically rather than biologically. Behind that
+ pharmaceutical orientation there is sometimes the idea that the individual just isn't trying hard enough, or
+ doesn't have quite the right genes to excel mentally.
+
+
+ Many stimulants--amphetamine and estrogen, for example--can increase alertness temporarily, but at the
+ expense of long range damage. The first principle of stimulation should be to avoid a harmful activation of
+ the catabolic stress hormones. Light, play, environmental variety and exploratory conversations stimulate
+ the whole organism in an integral way, stimulating repair processes and developmental processes.
+
+
+ Any chemical support for intelligence should take into account the mind-damaging stresses that our culture
+ can impose, and provide defense against those. In darkness and isolation, for example, the stress hormones
+ increase, and the brain-protective steroids decrease. The memory improvement that results from taking
+ pregnenolone or thyroid (which is needed for synthesizing pregnenolone from cholesterol) is the result of
+ turning off the dulling and brain-dissolving stress hormones, allowing normal responsiveness to be restored.
+
+
+ If we know that rats nurtured in freedom, in an interesting environment, grow more intelligent, then it
+ would seem obvious that we should experiment with similar approaches for children--if we are really
+ interested in fostering intelligence. And since violence and mental dullness are created by the same social
+ stresses, even the desire to reduce school violence might force the society to make some improvements that
+ will, as a side effect, foster intelligence.
+
+
+ REFERENCES
+
+ B. Russell: "If you wish to know what men will do, you must know not only or principally their material
+ circumstances, but rather the whole system of their desires with their relative strengths."
+
+
+ John Holt, from an interview in Mother Earth News, July/August, 1980:
+ "I suggested that we simply provide young people with schools where there are a lot of interesting things to
+ look at and work with . . . but that we let the chidlren learn in their own wqys. If they have questions,
+ answer the questions. If they want to know where to look for something, show them where to look."
+
+
+ John Holt, from the introduction to his book, Teach Your Own, (New York: Dell, 1981): "The children in the classroom, despite their rich backgrounds and high I.Q.'s, were with few
+ exceptions frightened, timid, evasive, and self-protecting. The infants at home were bold adventurers."
+
+
+
+ "It soon became clear to me that children are by nature and from birth very curious about the world around
+ them, and very energetic, resourceful, and competent in exploring it, finding out about it, and mastering.
+ In short, much more eager to learn, and much better at learning, than most adults. Babies are not blobs, but
+ true scientists. Why not then make schools into places in which children would be allowed, encouraged, and
+ (if and when they asked) helped to explore and make sense of the world around them (in time and space) in
+ ways that most interested them?"
+
+
+ Psychosom Med 1984 Nov-Dec;46(6):546-8. Rapid communication: whole blood serotonin and the type A
+ behavior pattern. Madsen D, McGuire MT.
+ In 72 young males, whole blood serotonin is shown to have a pronounced relationship with the Type A
+ behavior pattern. The relationship is explored with multivariate statistical techniques.
+
+
+ J Neurochem. 2000 Aug;75(2):732-40. Serra M, Pisu MG, Littera M, Papi G, Sanna E, Tuveri F, Usala L, Purdy
+ RH, Biggio G.
+ Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor
+ function in rat brain.
+
+
+
+ Ann Med 2000 Apr;32(3):210-21. Role of serotonin in memory impairment. Buhot MC, Martin S,
+ Segu L.
+
+
+ Ivan Illich and Etienne Verne, Imprisoned in the global classroom.
+ London, Writers and Readers Publishing Cooperative, 1976.
+
+
+ Ivan Illich, Deschooling society. Harmondsworth: Penguin, 1976 (1971).
+
+
+
+ ----Tools for Conviviality (1973).
+
+ ----Toward a history of needs. New York, Pantheon Books, c1978.
+
+ ----Limits to medicine. medical nemesis : the expropriation of health. Harmondsworth New York, Penguin,
+ 1977.
+
+
+ ----Celebration of awareness: a call for institutional revolution. Harmondsworth,
+ Penguin Education, 1976. Pelican books Originally published: Garden City [N.Y.]: Doubleday, 1970; London:
+ Calder and Boyars, 1971.
+
+
+ ----Disabling professions. London, Boyars, 1977, Ideas in progress series.
+
+ Eur J Pharmacol 1992 Feb 25;212(1):73-8. 5-HT3 receptor antagonists reverse helpless behaviour in
+ rats. Martin P, Gozlan H, Puech AJ Departement de Pharmacologie, Faculte de Medecine
+ Pitie-Salpetriere, Paris, France. The effects of the 5-HT3 receptor antagonists, zacopride, ondansetron and
+ ICS 205-930, were investigated in an animal model of depression, the learned helplessness test. Rats
+ previously subjected to a session of 60 inescapable foot-shocks exhibited a deficit of escape performance in
+ three subsequent shuttle-box sessions. The 5-HT3 receptor antagonists administered i.p. twice daily on a
+ chronic schedule (zacopride 0.03-2 mg/kg per day; ondansetron and ICS 205-930: 0.125-2 mg/kg per day)
+ reduced the number of escape failures at low to moderate daily doses. This effect was not observed with the
+ highest dose(s) of zacopride, ondansetron and ICS 205-930 tested.. These results indicate that 5-HT3
+ antagonists may have effects like those of conventional antidepressants in rats.
+
+
+ Neuropharmacology 1992 Apr;31(4):323-30. Presynaptic serotonin mechanisms in rats subjected to
+ inescapable shock. Edwards E, Kornrich W, Houtten PV, Henn FA. "After exposure to
+ uncontrollable shock training, two distinct groups of rats can be defined in terms of their performance in
+ learning to escape from a controllable stress. Learned helpless rats do not learn to terminate the
+ controllable stress, whereas non-learned helpless rats learn this response as readily as naive control rats
+ do." "These results implicate presynaptic serotonin mechanisms in the behavioral deficit caused by
+ uncontrollable shock. In addition, a limbic-hypothalamic pathway may serve as a control center for the
+ behavioral response to stress."
+
+
+ Neurochem Int 1992 Jul;21(1):29-35.
+ In vitro neurotransmitter release in an animal model of depression. Edwards E, Kornrich W, van
+ Houtten P, Henn FA. "Sprague-Dawley rats exposed to uncontrollable shock can be separated by a subsequent
+ shock escape test into two groups: a "helpless" (LH) group which demonstrates a deficit in escape behavior,
+ and a "nonlearned helpless" (NLH) group which shows no escape deficit and acquires the escape response as
+ readily as naive control rats (NC) do." "The major finding concerned a significant increase in endogenous
+ and K(+)-stimulated serotonin (5-HT) release in the hippocampal slices of LH rats. There were no apparent
+ differences in acetylcholine, dopamine and noradrenaline release in the hippocampus of LH rats as compared
+ to NLH and NC rats. These results add further support to previous studies in our laboratory which implicate
+ presynaptic 5-HT mechanisms in the behavioral deficit caused by uncontrollable shock."
+
+
+ Psychiatry Res 1994 Jun;52(3):285-93. In vivo serotonin release and learned helplessness.
+ Petty F, Kramer G, Wilson L, Jordan S Mental Health Clinic, Dallas Veterans Affairs Medical Center, TX.
+ Learned helplessness, a behavioral depression caused by exposure to inescapable stress, is considered to be
+ an animal model of human depressive disorder. Like human depression, learned helplessness has been
+ associated with a defect in serotonergic function, but the nature of this relationship is not entirely
+ clear. We have used in vivo microdialysis brain perfusion to measure serotonin (5-hydroxytryptamine, 5HT) in
+ extracellular space of medial frontal cortex in conscious, freely moving rats. Basal 5HT levels in rats
+ perfused before exposure to tail-shock stress did not themselves correlate with subsequent learned
+ helplessness behavior. However, 5HT release after stress showed a significant increase with helpless
+ behavior. These data support the hypothesis that a cortical serotonergic excess is causally related
+ to the development of learned helplessness.
+
+
+ Pharmacol Biochem Behav 1994 Jul;48(3):671-6. Does learned helplessness induction by haloperidol
+ involve serotonin mediation? Petty F, Kramer G, Moeller M Veterans Affairs Medical Center,
+ Dallas 75216. Learned helplessness (LH) is a behavioral depression following inescapable stress. Helpless
+ behavior was induced in naive rats by the dopamine D2 receptor blocker haloperidol (HDL) in a dose-dependent
+ manner, with the greatest effects seen at 20 mg/kg (IP). Rats were tested 24 h after injection. Haloperidol
+ (IP) increased release of serotonin (5-HT) in medial prefrontal cortex (MPC) as measured by in vivo
+ microdialysis. Perfusion of HDL through the probe in MPC caused increased cortical 5-HT release, as did
+ perfusion of both dopamine and the dopamine agonist apomorphine. Our previous work found that increased 5-HT
+ release in MPC correlates with the development of LH. The present work suggests that increased DA release in
+ MPC, known to occur with both inescapable stress and with HDL, may play a necessary but not sufficient role
+ in the development of LH. Also, this suggests that increased DA activity in MPC leads to increased 5-HT
+ release in MPC and to subsequent behavioral depression.
+
+
+ Arzneimittelforschung 1975 Nov; 25(11):1737-44. [Central action of WA-335-BS, a substance with
+ peripheral antiserotonin and antihistaminic activity]. Kahling J, Ziegler H, Ballhause H. "In
+ rats and mice the serotonin and histamine antagonistic drug . . . (WA 335-BS) caused
+ stronger central sedative effects than did cyproheptadine. WA 335-BS also displayed stronger activity
+ against reserpine- and central tremorine-induced effects than did cyproheptadine and it slightly enhanced
+ d-amphetamine-induced
+
+ effects:
+ therefore it may have antidepressant properties. WA 335-BS proved to be
+ very effective against isolation-induced aggression in male mice. The comparatively small
+ anxiolytic effects may have been caused in part by the central antiserotonin properties." "The results of
+ our animal studies suggest WA 335-BS to be an antidepressant with sedative properties."
+
+
+ Neuroscience 2000;100(4):749-68. Behavioral, neurochemical and endocrinological characterization of
+ the early social isolation syndrome. Heidbreder CA, Weiss IC, Domeney AM, Pryce C, Homberg J,
+ Hedou G, Feldon J, Moran MC, Nelson P. "Rearing rats in isolation has been shown to be a relevant paradigm
+ for studying early life stress and
+ understanding the genesis of depression and related affective disorders. Recent studies from
+ our laboratory point to the relevance of studying the social isolation syndrome as a function of home caging
+ conditions."
+
+
+
+ Stroke 1991 Nov;22(11):1448-51. Platelet secretory products may contribute to neuronal
+ injury. Joseph R, Tsering C, Grunfeld S, Welch KM. BACKGROUND: We do not fully understand the
+ mechanisms for neuronal damage following cerebral arterial occlusion by a thrombus that consists mainly of
+ platelets. The view that certain endogenous substances, such as glutamate, may also contribute to neuronal
+ injury is now reasonably well established. Blood platelets are known to contain and secrete a number of
+ substances that have been associated with neuronal dysfunction. Therefore, we hypothesize that a high
+ concentration (approximately several thousand-fold higher than in plasma, in our estimation) of locally
+ released platelet secretory products derived from the causative thrombus may contribute to neuronal injury
+ and promote reactive gliosis. SUMMARY OF COMMENT: We have recently been able to report some direct support
+ for this concept. When organotypic spinal cord cultures were exposed to platelet and platelet products, a
+ significant reduction in the number and the size of the surviving neurons occurred in comparison with those
+ in controls. We further observed that serotonin, a major platelet product, has neurotoxic properties. There
+ may be other platelet components with similar effect.
+ CONCLUSIONS: The hypothesis of platelet-mediated neurotoxicity gains some support from these recent in
+ vitro findings. The concept could provide a new area of research in stroke, both at the clinical and
+ basic levels.
+
+
+ Am J Psychiatry 1981 Aug;138(8):1082-5.
+ Tryptophan metabolism in children with attentional deficit disorder. Irwin M, Belendiuk K,
+ McCloskey K, Freedman DX The authors present the first report, to their knowledge, of hyperserotonemia in
+ children with attentional deficit disorder who had normal intelligence. Hyperserotonemic children had
+ significantly lower levels of plasma total and protein-bound tryptophan and a higher percentage of free
+ tryptophan than those with normal serotonin levels. Plasma kynurenine did not differ, suggesting that the
+ hyperserotonemia is not due to a blockade of the kynurenine pathway but may reflect on increase in tissue
+ tryptophan uptake and use.
+
+
+ J Neuropsychiatry Clin Neurosci 1990 Summer;2(3):268-74.
+ Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine
+ levels and intelligence. Cook EH, Leventhal BL, Heller W, Metz J, Wainwright M, Freedman DX
+ "Whole-blood serotonin (5-HT) and plasma norepinephrine (NE) were studied in 16 autistic children, 21
+ siblings of autistic children, and 53 parents of autistic children. Both plasma NE and whole-blood
+ 5-HT were negatively correlated with vocabulary performance."
+
+
+ "Eighteen subjects were hyperserotonemic (whole-blood 5-HT greater than 270 ng/ml). For these subjects,
+ plasma NE was significantly higher than for subjects without hyperserotonemia."
+
+
+ Biol Psychiatry 1998 Dec 15;44(12):1321-8. Cerebrospinal fluid monoamines in Prader-Willi
+ syndrome. Akefeldt A, Ekman R, Gillberg C, Mansson JE "The behavioral phenotype of Prader-Willi
+ syndrome (PWS) suggests hypothalamic dysfunction and altered neurotransmitter regulation. The purpose of
+ this study was to examine whether there was any difference in the concentrations of monoamine metabolites in
+ the cerebrospinal fluid (CSF) in PWS and non-PWS comparison cases." "The concentrations of
+ dopamine and particularly serotonin metabolites were increased in the PWS group. The differences were
+ most prominent for 5-hydroxyindoleacetic acid. The increased concentrations were found in all PWS cases
+ independently of age, body mass index, and level of mental retardation." "The findings implicate
+ dysfunction of the serotonergic system and possibly also of the dopamine system
+
+ in PWS individuals . . . ."
+
+
+ Pharmacol Biochem Behav 1976 Jul;5(1):55-61. The role of serotonergic pathways in isolation-induced
+ aggression in mice. Malick JB, Barnett A Male mice that became aggressive following four weeks
+ of social isolation were treated with seven known serotonin receptor antagonists. All of the
+ antiserotonergic drugs selectively antagonized the fighting behavior of the isolated mice; the
+ antiaggressive activity was selective since, at antifighting doses, none of the drugs either
+ significantly altered spontaneous motor activity
+
+ or impaired inclined-screen performance. Antagonism of 5-HTP-induced head-twitch was used as an in
+ vivo measure of antiserotonergic activity and a statistically significant correlation existed between
+ potency as an antiserotonergic and potency as an antiaggressive. PCPA, a serotonin depletor,
+ also significantly antagonized isolation-induced aggression for at least 24 hr postdrug
+ administration. The interrelationship between cholinergic and serotonergic mechanisms in the mediation of
+ isolation aggression was investigated. The involvement of serotonergic systems in isolation-induced
+ aggression is discussed.
+
+
+ Probl Endokrinol (Mosk) 1979 May-Jun;25(3):49-52
+ [Role of serotonin receptors of the medial-basal hypothalamus in the mechanisms of negative feedback of
+ the hypophyseal-testicular complex]. Naumenko EV, Shishkina GT. "Administration of serotonin
+ into the lateral ventricle of the brain of male rats, against the background of complete isolation of the
+ medial-basal hypothalamus was accompanied by the block of the compensatory elevation of the blood
+ testosterone level following unilateral castration."
+
+
+ Encephale 1994 Sep-Oct;20(5):521-5. [Can a serotonin uptake agonist be an authentic antidepressant?
+ Results of a multicenter, multinational therapeutic trial]. Kamoun A, Delalleau B, Ozun M The
+ classical biochemical hypothesis of depression posits a functional deficit in central neurotransmitter
+ systems particularly serotonin (5-HT) and noradrenaline. The major role suggested for 5-HT in this theory
+ led to the development of a large number of compounds which selectively inhibit 5-HT uptake. Numerous
+ clinical trials have demonstrated the antidepressant efficacy of such types of serotoninergic agents,
+ supporting 5-HT deficit as the main origin of depression. Therefore, everything seemed clear:
+ depression was caused by 5-HT deficit. Tianeptine is clearly active in classical animal models
+ predictive of antidepressant activity, and is also active in behavioral screening tests: it antagonizes
+ isolation induced aggression in mice and behavioral despair in rats. Biochemical studies have
+ revealed that in contrast to classical tricyclic antidepressant,
+ tianeptine stimulates 5-HT uptake
+
+ in vivo in the rat brain. This somewhat surprising property was observed in the cortex and the hippocampus
+ following both acute and chronic administrations. This increase in 5-HT uptake has also been confirmed in
+ rat platelets after acute and
+ chronic administrations. Moreover, in humans, a study in depressed patients demonstrated that tianeptine
+ significantly increased platelet 5-HT uptake after a single administration as well as after 10 and 28
+ days of treatment. The antidepressant activity of tianeptine has been evaluated in controlled studies
+ versus reference antidepressants. Another study aiming to compare the antidepressant efficacy of
+ tianeptine versus placebo and versus imiporamine is presented. 186 depressed patients were
+ included in this trial. They presented with either Major Depression, single episode (24.6%) or Major
+ Depression recurrent (66.8%) or Bipolar Disorder (depressed) (8.6%).
+
+
+ Psychopharmacology (Berl) 1998 Oct;139(3):255-60.
+ Ca2+ dependency of serotonin and dopamine release from CNS slices of chronically isolated rats.
+ Jaffe EH. "We have used chronic isolated housing as an animal model of depression." "The following questions
+ were addressed: first, if there is a change in the depolarization dependent release of DA and 5-HT from
+ these CNS structures, and second, if the release is through the classical exocytotic mechanism. A
+ significant increase in KCl stimulated release of 5-HT was observed in chronically isolated animals when
+ compared to controls.
+
+ 5-HT release was completely abolished from controls or isolated animals, when slices were incubated with
+ Krebs containing zero Ca2+/10 mM Mg2+, the inorganic Ca2+ channel blockers, Cd2+ or Ni2+ and the calmodulin
+ inhibitor, trifluoperazine." "The basal release of DA and 5-HT was similar in control and isolated
+ animals and was not affected by the Ca2+ channel antagonists. The results suggest that extracellular
+ Ca2+-dependent release of 5-HT and, to a lesser degree, of DA, is increased in this chronic animal model
+ of depression in several CNS structures."
+
+
+
+ Gen Pharmacol 1994 Oct;25(6):1257-1262.
+ Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of
+ plasma hemoglobin; the protective action of calmodulin antagonists. Koren-Schwartzer N,
+ Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
+ 1. Injection of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level,
+ accompanied by an increase in P(i). Concomitant to these changes, the activity of cytosolic
+ phosphofructokinase, the rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of
+ anaerobic glycolysis was also reflected by a marked increase in lactate content in brain. 2. Brain
+ glucose 1,6-bisphosphate level was decreased, whereas fructose 2,6-bisphosphate was unaffected
+ by serotonin. 3. All these serotonin-induced changes in brain, which are characteristic for cerebral
+ ischemia, were prevented by treatment with the calmodulin (CaM) antagonists, trifluoperazine or
+ thioridazine. 4.. Injection of serotonin also induced a marked elevation of plasma hemoglobin,
+ reflecting lysed erythrocytes, which was also prevented by treatment with the CaM antagonists.
+ 5.
+ The present results suggest that CaM antagonists may be effective drugs in treatment of many
+ pathological conditions and diseases in which plasma serotonin levels are known to increase.
+
+
+ Gen Pharmacol 1994 Oct;25(6):1257-1262.
+ Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of
+ plasma hemoglobin; the protective action of calmodulin antagonists. Koren-Schwartzer N,
+ Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
+ 1. Injection of serotonin (5-hydroxytryptamine) to rats, induced a dramatic fall in brain ATP level,
+ accompanied by an increase in P(i). Concomitant to these changes, the activity of cytosolic
+ phosphofructokinase, the rate-limiting enzyme of glycolysis, was significantly enhanced. Stimulation of
+ anaerobic glycolysis was also reflected by a marked increase in lactate content in brain. 2. Brain
+ glucose 1,6-bisphosphate level was decreased, whereas fructose 2,6-bisphosphate was unaffected
+ by serotonin. 3. All these serotonin-induced changes in brain, which are characteristic for cerebral
+ ischemia, were prevented by treatment with the calmodulin (CaM) antagonists, trifluoperazine or
+ thioridazine. 4. Injection of serotonin also induced a marked elevation of plasma hemoglobin, reflecting
+ lysed erythrocytes, which was also prevented by treatment with the CaM antagonists. 5. The present results
+ suggest that CaM antagonists may be effective drugs in treatment of many pathological conditions and
+ diseases in which plasma serotonin levels are known to increase.
+
+
+
+ J Neural Transm 1998;105(8-9):975-86. Role of tryptophan in the elevated serotonin-turnover in
+ hepatic encephalopathy. Herneth AM, Steindl P, Ferenci P, Roth E, Hortnagl H. "The increase of
+ the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased
+ turnover of serotonin (5-HT)." "These results provide further evidence for the role of tryptophan in the
+ elevation of brain 5-HT metabolism and for a potential role of BCAA in the treatment of HE."
+
+
+ Tugai VA; Kurs'kii MD; Fedoriv OM. [Effect of serotonin on Ca2+ transport in mitochondria conjugated
+ with the respiratory chain]. Ukrainskii Biokhimicheskii Zhurnal, 1973 Jul-Aug, 45(4):408-12.
+
+
+ Kurskii MD; Tugai VA; Fedoriv AN.
+ [Effect of serotonin and calcium on separate components of respiratory chain of mitochondria in some
+ rabbit tissues].
+ Ukrainskii Biokhimicheskii Zhurnal, 1970, 42(5):584-8.
+
+
+
+ Watanabe Y; Shibata S; Kobayashi B. Serotonin-induced swelling of rat liver mitochondria.
+ Endocrinologia Japonica, 1969 Feb, 16(1):133-47.
+
+
+ Mahler DJ; Humoller FL. The influence of serotonin on oxidative metabolism of brain
+ mitochondria. Proceedings of the Society for Experimental Biology and Medicine, 1968 Apr,
+ 127(4):1074-9.
+
+
+ Eur J Pharmacol 1994 Aug 11;261(1-2):25-32. The effect of alpha 2-adrenoceptor antagonists in
+ isolated globally ischemic rat hearts. Sargent CA, Dzwonczyk S, Grover G.J. "The alpha
+ 2-adrenoceptor antagonist, yohimbine, has been reported to protect hypoxic myocardium. Yohimbine has several
+ other activities, including 5-HT receptor antagonism, at the concentrations at which protection was found."
+ "Pretreatment with yohimbine (1-10 microM) caused a concentration-dependent increase in reperfusion left
+ ventricular developed pressure and a reduction in end diastolic pressure and lactate dehydrogenase release.
+ The structurally similar compound rauwolscine (10 microM) also protected the ischemic myocardium. In
+ contrast, idozoxan (0.3-10 microM) or tolazoline (10 microM) had no protective effects. The
+ cardioprotective effects of yohimbine were partially reversed by 30 microM 5-HT. These results indicate
+ that the mechanism for the cardioprotective activity of yohimbine may involve 5-HT receptor antagonistic
+ activity."
+
+
+
+
+ Zubovskaia AM. [Effect of serotonin on some pathways of oxidative metabolism in the mitochondria of
+ rabbit heart muscle]. Voprosy Meditsinskoi Khimii, 1968 Mar-Apr, 14(2):152-7.
+
+
+ Warashina Y.
+ [On the effect of serotonin on phosphorylation of rat liver mitochondria]. Hoppe-Seylers
+ Zeitschrift fur Physiologische Chemie, 1967 Feb, 348(2):139-48.
+
+
+ Eur Neuropsychopharmacol 1997 Oct;7 Suppl 3:S323-S328. Prevention of stress-induced morphological
+ and cognitive consequences.. McEwen BS, Conrad CD, Kuroda Y, Frankfurt M, Magarinos AM,
+ McKittrick C. Atrophy and dysfunction of the human hippocampus is a feature of aging in some individuals,
+ and this dysfunction predicts later dementia. There is reason to believe that adrenal glucocorticoids may
+ contribute to these changes, since the elevations of glucocorticoids in Cushing's syndrome and during normal
+ aging are associated with atrophy of the entire hippocampal formation in humans and are linked to deficits
+ in short-term verbal memory. We have developed a model of stress-induced atrophy of the hippocampus of rats
+ at the cellular level, and we have been investigating underlying mechanisms in search of agents that will
+ block the atrophy. Repeated restraint stress in rats for 3 weeks causes changes in the hippocampal formation
+ that include suppression of 5-HT1A receptor binding and atrophy of dendrites of CA3 pyramidal neurons, as
+ well as impairment of initial learning of a radial arm maze task.
+ Because serotonin is released by stressors and may play a role in the actions of stress on nerve cells,
+ we investigated the actions of agents that facilitate or inhibit serotonin reuptake. Tianeptine
+ is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT reuptake, as
+ well as with desipramine. Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy
+ of dendrites of CA3 pycamidal neurons, whereas neither fluoxetine (10 mg/kg/day) nor
+ desipramine (10 mg/kg/day) had any effect. Tianeptine treatment also prevented the stress-induced
+ impairment of radial maze learning.
+
+ Because corticosterone- and stress-induced atrophy of CA3 dendrites is also blocked by phenytoin, an
+ inhibitor of excitatory amino acid release and actions, these results suggest that serotonin released by
+ stress or corticosterone may interact pre- or post-synaptically with glutamate released by stress or
+ corticosterone, and that the final common path may involve interactive effects between serotonin and
+ glutamate receptors on the dendrites of CA3 neurons innervated by mossy fibers from the dentate gyrus.
+ We discuss the implications of these findings for treating cognitive impairments and the risk for
+ dementia in the elderly.
+
+
+ © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
+
+
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+
+
+
+ Intuitive knowledge and its development
+
+
+
+
+ Intuitive knowledge and its development
+
+
+
+
+ Understanding consciousness is necessary for understanding life. Variations of consciousness, such
+ as dementia, depression, delusion, or insight, originality, curiosity have to be understood
+ biologically.
+
+
+
+
+ To understand our ability to know and discover, I think it's valuable to consider foolishness along with
+ wisdom, since "knowledge" consists of both. Scientists have been notorious for opposing new discoveries, but
+ the mental rigidity of old age is so general, and well known, that many people have believed that it was
+ caused by the death of brain cells. Individual cells do tend to become less adaptive with aging, and
+ metabolism generally slows down with aging, but even relatively young and mentally quick people are
+ susceptible to losing their ability to understand new ideas.
+
+
+ I think our use of language is both the means by which understanding can be preserved, encapsulated, and
+ disseminated, and a great impediment to understanding. At first, words are continuous with the intuitive
+ framework in which they are learned, but they gradually become relatively independent and abstract. Things
+ can be learned without directly experiencing them. Even though words gradually change through use, the
+ simple fact that they have a degree of dependability allows them to function even when there is no active
+ thought. Uncritical listening is possible, and if a person can say something, it seems to be easy to believe
+ that it's true. By the age of 25, our language has usually given us many assumptions about the nature of the
+ world.
+
+
+ Verbal formulations of one sort are given up for new verbal formulations, in the process called education.
+ Sometimes graduate students seem to have lost all common sense. It's as if their hard-drive had been
+ reformatted to allow their professors to download onto it. But common sense, usually, is just what Einstein
+ called it, an accumulation of prejudices.
+
+
+ Children learn language so easily that many people have seriously believed that a certain language was
+ inherited by people of each ethnic group. Bilingual people were thought to be intellectually inferior
+ (though it turned out that bilingualism actually increases a person's mental abilities--possibly because of
+ the brain development known to be produced by learning1.) Eventually, people learned that the children of
+ immigrants were as capable of learning the language of the new country as the native children were.
+
+
+ Then, explaining the mystery of language learning took a new form, that didn't seem foolish to most
+ professional anthropologists and linguists. The first and most important step in the new theory was to
+ declare that simple learning theory was inadequate to explain the development of language. Language
+ developed, just as the silly racial theory had thought, out of our genetic endowment, except that what we
+ inherited was now said to be a Universal Language, with its Universal Rules embedded in our chromosomes.
+ Then, the speed with which children learn language was to be explained as the "innateness" of all of the
+ complex stuff of language, with only a few things needing to be actually learned--those minor details that
+ distinguish English from Eskimo or Zapotec.
+
+
+
+ Although the phrase "genetic epistemology" was coined by Jean Piaget, a major philosophical and scientific
+ theme of the 20th century has been the idea that the "forms" of knowledge, for perceiving space, or logical
+ relations, or language patterns, are derived from our genes, and that they are somehow built into the
+ arrangement of our brain cells so that we spontaneously think in certain ways, and don't have the capacity
+ to transcend the nature of our inherited brain. In that view, children have their own pre-logical way of
+ thinking, and their thought (and language development) must proceed through certain stages, each governed by
+ some "structural" process in the nervous system. The only thing wrong with the idea of innate knowledge is
+ that people use it to tell us what we can't know, in other words, to rationalize stupidity. Of course, they
+ wouldn't like to phrase it that way, because they consider their "genetic epistemology of symbolic forms" to
+ be the essence and the totality of intelligence, and that people who allow their thoughts to be structured
+ entirely by experience are just confused.
+
+
+
+ Years ago, I had been criticizing Noam Chomsky's theory of language so much, that I thought I might have
+ misjudged or inappropriately depreciated his general attitude toward consciousness, so I asked him some
+ questions about the intelligence of animals. His response confirmed my view that he subscribed to the most
+ extreme form of "genetic epistemology":
+
+
+ "I don't know whether there is a common animal ability to manipulate images and generalize. In fact, I doubt
+ it very much. Thus the kind of "generalization" that leads to knowledge of lanugage from sensory experience
+ seems to me to involve principles such as those of universal grammar as an innate property, for reasons I
+ have explained elsewhere, and I see no reason to believe that these principles underlie generalization in
+ other animals. Nor do I think that the kinds of generalization that lead a bird to gain knowledge of how to
+ build a nest, or to sing its song, or to orient itself spatially, are necessarily part of the human ability
+ to generalize."
+
+
+ All of the textbooks that I have seen that discuss the issue of animal intelligence have taken a position
+ like that of Chomsky--that any knowledge animals have is either rigidly instinctual, or else is just a set
+ of movements that have been mechanically learned. In other words, there isn't anything intelligent about the
+ complex things that animals may do. Konrad Lorenz and the ethologists explained animal behavior in terms of
+ chains of reflexes that are "triggered" by certain sensations or perceptions. This claim that animals'
+ behavior just consists of mechanical chains of reflexes strictly follows Descartes' doctrine, and Chomsky
+ has consistently acknowledged that his theory is Cartesian. The claim that children have their own
+ non-logical way of understanding things is very similar to the doctrine about animals, in the way it limits
+ real rational understanding to adult human beings.
+
+
+
+ The awareness of young animals is particularly impressive to me, because we know the short time they have
+ had in which to learn about the world. Any instance in which a young animal understands a completely novel
+ situation, in a way that is fully adequate and workable, demonstrates that it is capable of intellectual
+ generalization.
+
+
+ Beyond that, I think animal inventiveness can teach us about our own capacity for inventiveness, which both
+ the genetic and the behaviorist theories of knowledge totally fail to explain.
+
+
+ Spiders that build architecturally beautiful webs have been favorite subjects for theorizing about the
+ instinctive mechanisms of behavior. When spiders were sent up on an orbiting satellite, they were in a
+ situation that spiders had never experienced before. Spiders have always taken advantage of gravity for
+ building their webs, and at first, the orbiting spiders made strange little muddled arrangements of
+ filaments, but after just a few attempts, they were able to build exactly the same sort of elegant
+ structures that spiders normally build. (My interpretation of that was that spiders may be more intelligent
+ than most neurobiologists.)
+
+
+ Nesting birds often swoop at people or animals who get too close to their nest. Early last summer, I had
+ noticed some blue jays that seemed to be acting defensive whenever I went into one part of the yard. On a
+ very hot day at the end of summer, a couple of plump jays were squawking and apparently trying to get my
+ attention while I was watering the front yard, and I idly wondered why they would be acting that way so late
+ in the year. I had gone around the house to water things in the back yard, and the birds came over the
+ house, and were still squawking, and trying to get my attention. I realized that their excitement didn't
+ have anything to do with their nest, and looking more carefully, I saw that they were young birds. As it
+ dawned on me that they were interested in the water squirting out of the hose, I aimed the stream up towards
+ them, and they got as close to it as they could. Since the force of the stream might have hurt them, I put
+ on a nozzle that made a finer spray, and the birds immediately came down to the lowest tip of the branch,
+ where they could get the full force of the mist, holding out their wings, and leaning into the spray so that
+ it ruffled their breast feathers. Their persistence had finally paid off when they got me to understand what
+ they wanted, and they were enjoying the cool water. As new young birds, I don't know how they understood
+ hoses and squirting water, but it was clear that they recognized me as a potentially intelligent being with
+ whom they could communicate.
+
+
+ For a person, that wouldn't have seemed like a tremendously inventive response to the hot weather, but for
+ young birds that hadn't been out of the nest for long, it made it clear to me that there is more inventive
+ intelligence in the world than is apparent to most academic psychologists and ethologists.
+
+
+
+ Early porpoise researchers were surprised when a porpoise understood a sequence in which one tone was
+ followed by two, and then by three, and answered by producing a series of four tones. The porpoise had
+ discovered that people knew how to count.
+
+
+ Experiments with bees show the same sort of understanding of numbers and intentions. An experimenter set out
+ dishes of honey in a sequence, doubling the distance each time. After the first three dishes had been found
+ by scouts, the bees showed up at the fourth location before the honey arrived, extrapolating from the
+ experimenter's previous behavior and inferring his intentions.
+
+
+ Once I noticed that an ant seemed to be dozing at the base of every maple leaf, and that there were several
+ aphids on each leaf. I was getting very close, trying to understand why the ant was sitting so quietly.
+ Apparently my odor gave the ant a start, and he leaped into activity, racing up the leaf, and giving each
+ aphid a tap as he passed. When he had reached the end of the leaf and had touched every aphid, his agitation
+ suddenly disappeared, and he returned to his spot at the base of the leaf. Although I knew that ants could
+ count very well, as demonstrated by experiments in which an ant had to describe a complex route to a dish of
+ honey, it was the apparent emotion that interested me. It reminded me of the hostess who counted her dishes
+ before the guests left.
+
+
+ When the brains of such different kinds of animal work in such similar ways, in situations that contain many
+ new components, I don't think it's possible to conclude anything except that intelligence is a common
+ property of animals, and that it comprises "generalization" and much more. It's obvious that they grasp the
+ situation in a realistic way. The situation has structured their awareness. Some people might say that they
+ have "modeled the situation in their mind," but it's enough to say that they understand what's going on.
+ With that understanding, motivations and intentions form part of the perception, since the situation is a
+ developing process. Ordinarily, we say that we "infer" motivations and intentions and "deduce" probable
+ outcomes, but that implies that the situation is static, rather than continuous with its origin and outcome.
+ In reality, these understandings and expectations are part of the direct perception. It isn't a matter of
+ "intelligence" operating upon "sensations," but of intelligence inhering in the grasping of the situation.
+ (In Latin, intelligo
+ meant "I perceive." I suspect that a Roman might have perceived the word intelligens as being derived from roots such as tele--from Greek, or tela, web, warp thread--and
+ ligo or lego, connoting the binding in or gathering of what is distant or extended.)
+
+
+ This view of a generalized animal intelligence wouldn't seem strange, except that the history of official
+ western philosophy, the doctrine of genetic determinism in biology, and the habits that form with the rigid
+ uses of language, have offered another way of looking at it. The simple intelligence of an animal would
+ disrupt all of that important stuff, so it has become mandatory to dismiss all examples of intelligent
+ behavior by animals as "mere anthropomorphizing." Sadly, this has also meant that most intelligent behavior
+ by humans has also been dismissed.
+
+
+ The cellular development of an organism used to be described as a process in which everything is
+ predetermined by the genes, but the interactions between an embryo and its environment are now known to be
+ crucial in shaping the process of maturation, so that the real organism (the phenotype) doesn't necessarily
+ reflect its genetic make-up (genotype); the term "phenocopy" acknowledges this process.
+
+
+
+ London taxi drivers were recently found to have an enlargement of part of the hippocampus, compared to the
+ brains of other people, and the difference was greater, in proportion to the time they had been driving
+ taxis. Their brains have been shaped by their activities.
+
+
+ If the brain's cellular anatomy is so radically affected by activity even in adulthood, then the concept of
+ awareness as a process in which consciousness takes its form from the situation shouldn't be problematic. If
+ a bee and a porpoise can draw similar conclusions from similar experiences, then the world is being grasped
+ by both in an objective way.
+
+
+ The environment shapes the organism's response, and the momentary response contributes to the development of
+ the supporting processes and apparatuses. So the ability to respond is the basic question. If the richly
+ grasped situation contains its own implications, there is no need for explaining the ability to perceive
+ those implications in terms of some prearranged neurological code, except for the ability to respond
+ complexly and appropriately. Any specific interpretation or behavior which is predetermined is going to
+ function as an impediment to understanding. Verbal formulations often have the function of creating a
+ stereotyped and inappropriate response.
+
+
+ The "genetic epistemologists" confuse their own verbal interpretations with the real ways that understanding
+ develops, and when a child doesn't yet know all of the connotations of a specific word, the psychologist
+ ascribes a pre-logical brain function to the child.3 The similar failure to perceive and to communicate
+ accounts for the foolish things ethologists have said about animal intelligence.
+
+
+
+ The process in which an organism responds to a situation is continuous with the process of communication.
+ The organism understands that in certain situations a response can be elicited, and so it acts accordingly.
+
+
+ Communication is a response that is directed toward eliciting a response from another. The idea that an
+ animal might have an intention, or a desire to communicate or respond, has been obsessively denied by most
+ official western philosophers, who see that as a uniquely human quality, but some philosophers have even
+ denied that quality to humans. For them, consciousness is a passive receptacle for units of meaning and
+ logic, like a mail bin at the post-office, where letters are received, sorted, and distributed. Maybe
+ computers work that way, but there is nothing in living substance that works like that.
+
+
+ Consciousness is participation, in the sense that there is a response of an organism to events. Even dreams
+ and hallucinations have their implied reference to something real.
+
+
+ If a violin has been soaked in water, it will sound very odd when it's played. Its various parts won't
+ resonate properly. Similarly, the living substance has to be in a particular state to resonate properly with
+ its environment.
+
+
+ People have proposed that visual experience involves the luminescence of nerves in the optical system.
+ Presumably, similar analogs of events could occur in various tissues when we are conscious of sounds,
+ tastes, smells, etc. But whether or not our auditory nerves are singing when we experience music, no one
+ questions the existence of some sort of responsive activity when we are being conscious of something.
+ Activating certain brain areas will make us conscious of certain things, and that activation can be a
+ response to sensory nerve impulses, or to brain chemicals produced in dreaming or drug-induced
+ hallucinations, or to electrical stimulation, or to the act of remembering.
+
+
+
+ The history of the prefrontal leukotomy or lobotomy, in which undesirable behaviors were surgically removed,
+ was closely associated with the development of surgical treatments for epilepsy.
+
+
+ Natalya Bekhtereva was exploring alternative treatments for epilepsy, implanting fine wire electrodes into
+ the abnormal parts of the brain, and surrounding areas, to discover the nature of the electrical events that
+ were associated with the seizures. In the process, she discovered that meanings and intentions corresponded
+ to particular electrical patterns. She found that giving certain kinds of stimulation to healthy parts of
+ the brain could stimulate the development of ways of functioning that by-passed the seizure-prone parts of
+ the brain. Extending this, seeing that creating new patterns of nervous activity could overcome sickness,
+ she proposed that creativity, the activation of the brain in new ways, would itself be therapeutic. Some
+ people, such as Stanislav Grof, advocated the therapeutic use of LSD with a rationale that seems similar,
+ for example to overcome chronic pain by changing its meaning, putting it into a different relation to the
+ rest of experience. "In general, psychedelic therapy seems to be most effective in the treatment of
+ alcoholics, narcotic-drug addicts, depressed patients, and individuals dying of cancer." 2 Since LSD shifts
+ the balance away from serotonin dominance toward dopamine dominance, its effect can be to erase the habits
+ of learned helplessness. Stress and pain also leave their residue in the endorphin system, and the
+ anti-opiates such as naloxone can relieve depression, improve memory, and restore disturbed pituitary
+ functions, for example leading to the restoration of menstrual rhythms interrupted by stress or aging. The
+ amazing speed with which young animals can solve problems is undoubtedly a reflection of their metabolic
+ vigor, and it is probably partly because they haven't yet experienced the paralysis that can result from
+ repeated or prolonged and inescapable stress. Many of the factors responsible for the metabolic intensity of
+ youth can be used therapeutically, even after dullness has developed. The right balance of amino acids and
+ carbohydrates, and the avoidance of the antimetabolic unsaturated fatty acids, can make a great difference
+ in mental functioning, even though we still don't know what the ideal formulas are.
+
+
+ While chemical -- nutritional -- hormonal approaches can help to restore creativity, the work of people like
+ Bekhtereva shows that the exercise of creativity can help to restore biochemical and physiological systems
+ to more normal functioning. Learning new general principles or new languages can be creatively restorative.
+
+ NOTES AND REFERENCES
+
+
+ 1. Proc Natl Acad Sci U S A 2000 Apr 11;97(8):4398-403. Navigation-related structural change in the
+ hippocampi of taxi drivers. Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RS, Frith
+ CD. Structural MRIs of the brains of humans with extensive navigation experience, licensed London taxi
+ drivers, were analyzed and compared with those of control subjects who did not drive taxis. The posterior
+ hippocampi of taxi drivers were significantly larger relative to those of control subjects. A more anterior
+ hippocampal region was larger in control subjects than in taxi drivers. Hippocampal volume correlated with
+ the amount of time spent as a taxi driver (positively in the posterior and negatively in the anterior
+ hippocampus). These data are in accordance with the idea that the posterior hippocampus stores a spatial
+ representation of the environment and can expand regionally to accommodate elaboration of this
+ representation in people with a high dependence on navigational skills. It seems that there is a capacity
+ for local plastic change in the structure of the healthy adult human brain in response to environmental
+ demands.
+
+
+ 2. ("History of LSD Therapy," Stanislav Grof, M.D. Chapter 1 of LSD Psychotherapy, "1980, 1994 by Stanislav
+ Grof. Hunter House Publishers, Alameda, California, ISBN 0-89793-158-0).
+
+
+ 3. There is an example of this argument about the nature of reasoning in New Scientist magazine, December 9,
+ 2000. P. Johnson-Laird found that more than 99% of Princeton University students were unable to solve a
+ logical puzzle correctly. Ira Noveck of the Claude Bernard University in Lyon believes this may result
+ simply from people's difficulty interpreting the language of the puzzles.
+
+
+ Fiziol Cheloveka 2000 Mar-Apr;26(2):5-9 [The cerebral organization of creativity. I. The development of a
+ psychological test]. Starchenko MG, Vorob'ev VA, Kliucharev VA, Bekhtereva NP, Medevedev SV.
+
+
+
+ Fiziol Cheloveka 1998 Jul-Aug;24(4):55-63 [Brain processing of visually presented verbal stimuli at
+ different levels of their integration. II. The orthographic and syntactic aspects]. Vorob'ev VA, Korotkov
+ AD, Pakhomov SV, Rozhdestvenskii DG, Rudas MS, Bekhtereva NP, Medvedev SV.
+
+
+ Neurosci Behav Physiol 1986 Jul-Aug; 16(4):333-9 The systemic approach to the stability and plasticity of
+ neurophysiological processes during adaptive brain activity. Vasilevskii VN The problem of the stability and
+ adaptability of regulatory processes is considered, taking as a point of departure N. P. Bekhtereva's theory
+ regarding stable pathological states, and inflexible and adaptable links in control systems. The need to
+ introduce a probabilistic approach is emphasized. Generalizations are made on materials relating to the
+ connectability of the separate components of the biorhythms of functional systems, and to the stability of
+ their amplitude-frequency characteristics. The corpus of facts permitted the successful development in
+ clinical practice of functional biocontrol and feedback.
+
+
+ Neurosci Behav Physiol 1986 Jul-Aug; 16(4):322-33. A study of the connectedness among distant neuronal
+ populations in the human brain during mental activity. Bekhtereva NP, Medvedev SV, Krol EM In this article,
+ we present the results of a study of connectedness among distant neuronal populations in human deep-brain
+ structures. The time characteristics involved and the stability of the connections between different
+ neuronal populations during monotonous mental activity are discussed. We show that a stable connectedness
+ does correlate with mental activity; however, the connections themselves do not correlate with one another.
+ We also show that the individual connections, the elements of the system which make mental activity
+ possible, can function with various degrees of rigidity or flexibility.
+
+
+ Dokl Akad Nauk SSSR 1986;289(5):1276-80 [Physiologic role of changes in the human neuron discharge rate
+ during a single mental act]. Bekhtereva NP, Gogolitsyn IuL, Pakhomov SV.
+
+
+
+ Dokl Akad Nauk SSSR 1985;285(5):1233-5 [Neurons-detectors of errors in subcortical structures of human
+ brain]. Bekhtereva NP, Kropotov IuD, Ponomarev VA.
+
+
+ Neurosci Behav Physiol 1985 Jan-Feb;15(1):27-32 Bioelectrical correlates of protective mechanisms of the
+ brain. Bekhtereva NP.
+
+
+ Fiziol Zh SSSR Im I M Sechenova 1984 Aug;70(8):1092-9 [Neurochemical aspects of therapeutic electric
+ stimulation]. Bekhtereva NP, Dambinova SA, Gurchin FA, Smirnov VM, Korol'kov AV. Comparative analysis of the
+ CSF and blood protein-peptide composition in Parkinsonian patients performed with the aid of indwelled
+ electrodes prior to and after therapeutic electrical stimulation (TES) of the brain subcortical structures,
+ revealed a therapeutic effect in the form of reduced muscular rigidity and a mental activation with a
+ positive emotional response. After the TES the protein content in the biological fluids tended to become
+ normalized and the the range of low-molecular protein-peptide fractions changed. A high-performance liquid
+ chromatography, bidimensional electrophoresis and thin-layer chromatography revealed about 5-6 factors of
+ peptide nature with the molecular mass less than 5000 daltons in the CSF and blood after the TES. These
+ factors were shown to exert a biological effect upon muscle preparation of the leech.
+
+
+ Fiziol Zh SSSR Im I M Sechenova 1984 Jul;70(7):892-903 [Relationships of distantly located neuronal
+ populations in the human brain in the realization of the thinking process]. Bekhtereva NP, Medvedev SV,
+ Krol' EM The time characteristics of the interneuronal connections as well as interrelationships among
+ distant neuronal populations of the human brain deep structures were studied during monotonous mental
+ activity. It was shown that stable interrelationships could be considered as a correlate of mental activity
+ though the connections themselves were not of the correlative nature. These connections, being the elements
+ of the activity--maintaining system, could be of various degree of rigidity.
+
+
+
+ Fiziol Zh SSSR Im I M Sechenova 1984 Jul;70(7):881-91 [Reflection of the semantic characteristics of the
+ thinking process in the impulse activity of neurons]. Bekhtereva NP The paper deals with the progress in
+ research into the problem of reflection of semantic characteristics of psychological tests in impulse
+ activity of neurons and neuronal assemblies. The high dynamicity of brain correlates of thinking in most
+ brain zones is stressed. Advantages and limits of different technical approaches as well as the most urgent
+ tasks to be solved are discussed.
+
+
+ Fiziol Zh SSSR Im I M Sechenova 1984 Jul;70(7):1071-5 [Natal'ia Petrovna Bekhtereva]. Iliukhina VA Biography
+
+
+ Hum Physiol 1982 Sep-Oct;8(5):303-16 Cerebral organization of emotional reactions and states. Bekhtereva NP,
+ Kambarova DK, Ivanov GG
+
+
+ Zh Nevropatol Psikhiatr Im S S Korsakova 1980;80(8):1127-33 [Bioelectric correlates of the brain's
+ protective mechanisms]. Bekhtereva NP The author substantiates the necessity of searching for new means
+ producing a therapeutic effect on the brain of epileptic patients that would be similar, in principle, to
+ the brain's own protective mechanisms. This can be done, in the author's opinion, on the basis of studying
+ the most probable bioelectric equivalents of the protective mechanisms. The author suggests a new method for
+ suppressing the epileptogenic focus. This suppression, close to the physiological one, is effected by
+ applying a weak sinusoidal current to the focus via intracerebrally implanted electrodes. Data on the
+ suppression of the epileptiform activity within the zone of the current application, as well as data
+ confirming the local character of the current action are presented. The place of the new method in the
+ system of complex therapy, particularly of epilepsy, is determined with consideration of the role of the
+ stable pathological state. Probable neurophysiological mechanisms of the sinusoidal current action on the
+ epileptogenic focus are discussed.
+
+
+
+ Vestn Akad Med Nauk SSSR 1979;(7):30-7 [Potentials of neurophysiology in the study of a resistant
+ pathological state]. Bekhtereva NP
+
+
+ Act Nerv Super (Praha) 1976;18(3):157-67 The neurophysiological code of simplest mental processes in man.
+ Bekhtereva NP
+
+
+ Vestn Akad Med Nauk SSSR 1975;(8):8-19 [Cerebral organization of human emotions]. Bekhtereva NP, Smirnov VM
+
+
+ Fiziol Zh SSSR Im I M Sechenova 1973 Dec;59(12):1785-802 [Principles of the organization of the structure of
+ the space-time code of short-term verbal memory]. Bekhtereva NP, Bundzen PV, Kaidel VD, David EE.
+
+
+ Vopr Neirokhir 1972 Jan-Feb;36(1):7-12 [Therapeutic electric stimulation of deep brain structures].
+ Bekhtereva NP, Bondarchuk AN, Smirnov VM, Meliucheva LA
+
+
+
+ Vestn Akad Med Nauk SSSR 1972;27(9):43-9 [Principles of functional organization of the human brain].
+ [Article in Russian] Bekhtereva NP.
+
+
+ Fiziol Zh SSSR Im I M Sechenova 1971 Dec;57(12):1745-61 [Functional reorganization of the activity of human
+ brain neuron populations during short-term verbal memory]. Bekhtereva NP, Bundzen PV, Matveev IuK,
+ Kaplunovskii AS
+
+
+ From a biography by the Archives Jean Piaget: "His researches in developmental psychology and genetic
+ epistemology had one unique goal: how does knowledge grow? His answer is that the growth of knowledge is a
+ progressive construction of logically embedded structures superseding one another by a process of inclusion
+ of lower less powerful logical means into higher and more powerful ones up to adulthood. Therefore,
+ children's logic and modes of thinking are initially entirely different from those of adults."
+
+
+ © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Iron's Dangers
+
+
+ Iron's Dangers
+
+
+ Q: You believe iron is a deadly substance. Why?
+
+
+ Iron is a potentially toxic heavy metal. In excess, it can cause cancer, heart disease, and other illnesses.
+
+
+ Q: Could you tell us about some of these studies?
+
+
+ In the 1960s the World Health Organization found that when iron supplements were given to anemic people in
+ Africa, there was a great increase in the death rate from infectious diseases, especially malaria. Around
+ the same time, research began to show that the regulation of iron is a central function of the immune
+ system, and that this seems to have evolved because iron is a basic requirement for the survival and growth
+ of cells of all types, including bacteria, parasites, and cancer. The pioneer researcher in the role of iron
+ in immunity believed that an excess of dietary iron contributed to the development of leukemia and lymphatic
+ cancers. Just like lead, mercury, cadmium, nickel and other heavy metals, stored iron produces destructive
+ free radicals. The harmful effects of iron-produced free radicals are practically indistinguishable from
+ those caused by exposure to X-rays and gamma rays; both accelerate the accumulation of age-pigment and other
+ signs of aging. Excess iron is a crucial element in the transformation of stress into tissue damage by free
+ radicals.
+
+
+ For about 50 years, it has been known that blood transfusions damage immunity, and excess iron has been
+ suspected to be one of the causes for this. People who regularly donate blood, on the other hand, have often
+ been found to be healthier than non-donors, and healthier than they were before they began donating.
+
+
+ In one of Hans Selye's pioneering studies, he found that he could experimentally produce a form of
+ scleroderma (hardening of the skin) in animals by administering large doses of iron, followed by a minor
+ stress. He could prevent the development of the condition by giving the animals large doses of vitamin E,
+ suggesting that the condition was produced by iron's oxidative actions.
+
+
+
+ Excess iron's role in infectious diseases is now well established, and many recent studies show that it is
+ involved in degenerative brain diseases, such as Parkinson's, ALS (Lou Gehrig's disease), Huntington's
+ chorea, and Alzheimer's disease. Iron is now believed to have a role in skin aging, atherosclerosis, and
+ cataracts of the lenses of the eyes, largely through its formation of the "age pigment."
+
+
+ Q: How does excess iron accelerate our aging process?
+
+
+ During aging, our tissues tend to store an excess of iron. There is a remarkably close association between
+ the amount of iron stored in our tissues and the risk of death from cancer, heart disease, or from all
+ causes. This relationship between iron and death rate exists even during childhood, but the curve is
+ downward until the age of 12, and then it rises steadily until death. The shape of this curve, representing
+ the iron burden, is amazingly similar to the curves representing the rate of death in general, and the rate
+ of death from cancer. There is no other relationship in biology that I know of that has this peculiar shape,
+ with its minimum at the age of 12, and its maximum in old age at the time of death.
+
+
+ One of the major lines of aging research, going back to the early part of this century, was based on the
+ accumulation of a brown material in the tissues known as "age-pigment." The technical name for this
+ material, "lipofuscin," means "fatty brown stuff." In the 1960s, the "free radical theory" of aging was
+ introduced by Denham Harman, and this theory has converged with the age-pigment theory, since we now know
+ that the age-pigment is an oxidized mass of unsaturated fat and iron, formed by uncontrolled free radicals.
+ Until a few years ago, these ideas were accepted by only a few researchers, but now practically every doctor
+ in the country accepts that free radicals are important in the aging process. A nutrition researcher in San
+ Diego suspected that the life-extending effects of calorie restriction might be the result of a decreased
+ intake of toxins. He removed the toxic heavy metals from foods, and found that the animals which ate a
+ normal amount of food lived as long as the semi-starved animals. Recently, the iron content of food has been
+ identified as the major life-shortening factor, rather than the calories. [Choi and Yu, Age vol. 17, page
+ 93, 1994.]
+
+
+ Q: Exactly how much iron do we need to eat?
+
+
+ Children's nutritional requirements are high, because they are growing, but there are indications that in
+ the U.S. even children eat too much iron.
+
+
+ Some researchers are concerned that the iron added to cereals is contributing to the incidence of leukemia
+ and cancers of the lymphatic tissues in children. [Goodfield, 1984.] During the time of rapid growth,
+ children are less likely than adults to store too much iron. At birth, they have a large amount of stored
+ iron, and this decreases as they "grow into it." It is after puberty, when growth slows and the sex hormones
+ are high, that the storage of iron increases. [Blood, Sept., 1976.] In a study of the "malnourished"
+ children of migrant fruit pickers in California, these children who were "seriously anemic" were actually
+ more resistant to infectious diseases than were the "well nourished" middle class children in the same
+ region.
+
+
+ If the normal amount of dietary iron causes an increased susceptibility to infections even in children, and
+ if a subnormal amount of iron slows the aging process, I think we are going to have to reconsider our ideas
+ of nutritional adequacy, to look at the long range effects of diet, as well as the immediate effects. My
+ current studies have to do with analyzing our ability to handle stress safely, in relation to our diet. I
+ believe our nutritional recommendations for iron have to be revised sharply downward.
+
+
+ Q. Don't women need extra iron?
+
+
+
+ That's a misunderstanding.
+
+
+ Doctors generally don't realize that only a few milligrams of iron are lost each day in menstruation. The
+ real issue is that you can hardly avoid getting iron, even when you try.
+
+
+ Women absorb iron much more efficiently than men do. From a similar meal, women will normally absorb three
+ times as much iron as men do. When pregnant, their higher estrogen levels cause them to absorb about nine
+ times as much as men. Every time a woman menstruates, she loses a little iron, so that by the age of 50 she
+ is likely to have less iron stored in her tissues than a man does at the same age, but by the age of 65
+ women generally have as much excess iron in their tissues as men do. (During those 15 years, women seem to
+ store iron at a faster rate than men do, probably because they have more estrogen.) At this age their risk
+ of dying from a heart attack is the same as that of men. Some women who menstruate can donate blood
+ regularly without showing any tendency to become anemic.
+
+
+ Since the custom of giving large iron supplements to pregnant women has been established, there has been an
+ increase in jaundice of the newborn. It has been observed that women who didn't take iron supplements during
+ pregnancy have healthy babies that don't develop jaundice. I have suggested that this could be because they
+ haven't been poisoned by iron. Those supplements could also be a factor in the increased incidence of
+ childhood cancer.
+
+
+ Q: Don't you need iron supplements if you are anemic?
+
+
+ In general, no.
+
+
+
+ Many doctors think of anemia as necessarily indicating an iron deficiency, but that isn't correct. 100 years
+ ago, it was customary to prescribe arsenic for anemia, and it worked to stimulate the formation of more red
+ blood cells. The fact that arsenic, or iron, or other toxic material stimulates the formation of red blood
+ cells doesn't indicate a "deficiency" of the toxin, but simply indicates that the body responds to a variety
+ of harmful factors by speeding its production of blood cells. Even radiation can have this kind of
+ stimulating effect, because growth is a natural reaction to injury. Between 1920 and 1950, it was common to
+ think of "nutritional growth factors" as being the same as vitamins, but since then it has become common to
+ use known toxins to stimulate the growth of farm animals, and as a result, it has been more difficult to
+ define the essential nutrients. The optimal nutritional intake is now more often considered in terms of
+ resistance to disease, longevity or rate of aging, and even mental ability.
+
+
+ An excess of iron, by destroying vitamin E and oxidizing the unsaturated fats in red blood cells, can
+ contribute to hemolytic anemia, in which red cells are so fragile that they break down too fast. In aging,
+ red cells break down faster, and are usually produced more slowly, increasing the tendency to become anemic,
+ but additional iron tends to be more dangerous for older people.
+
+
+ Anemia in women is caused most often by a thyroid deficiency (as discussed in the chapter on thyroid), or by
+ various nutritional deficiencies. Estrogen (even in animals that don't menstruate) causes dilution of the
+ blood, so that it is normal for females to have lower hemoglobin than males. Q. What should I do if my
+ doctor tells me I'm anemic? Is there any situation in which a person needs to take iron supplements?
+
+
+ Iron deficiency anemia does exist, in laboratory situations and in some cases of chronic bleeding, but I
+ believe it should be the last-suspected cause of anemia, instead of the first. It should be considered as a
+ possible cause of anemia only when very specific blood tests show an abnormally low degree of iron
+ saturation of certain proteins. Usually, physicians consider the amount of hemoglobin or of red cells in the
+ blood as the primary indicator of a need for iron, but that just isn't biologically reasonable.
+
+
+
+ If a large amount of blood is lost in surgery, a temporary anemia might be produced, but even then it would
+ be best to know whether the iron stores are really depleted before deciding whether an iron supplement would
+ be reasonable. Liver (or even a water extract of wheat germ) can supply as much iron as would be given as a
+ pill, and is safer.
+
+
+ Q. What foods contain iron?
+
+
+ Flour, pasta, etc., almost always contain iron which has been artificially added as ferrous sulfate, because
+ of a federal law. Meats, grains, eggs, and vegetables naturally contain large amounts of iron. A few years
+ ago, someone demonstrated that they could pick up a certain breakfast cereal with a magnet, because of the
+ added iron. Black olives contain iron, which is used as a coloring material. You should look for "ferrous"
+ or "ferric" or "iron" on the label, and avoid foods with any added iron. Many labels list "reduced iron,"
+ meaning that iron is added in the ferrous form, which is very reactive and easily absorbed.
+
+
+
+ Q.: Why does federal law require the addition of iron to those foods?
+
+
+ Industrially processed grains have most of the nutrients, such as vitamin E, the B vitamins, manganese,
+ magnesium, etc., removed to improve the products' shelf life and efficiency of processing, and the
+ government required that certain nutrients be added to them as a measure to protect the public's health, but
+ the supplementation did not reflect the best science even when it was first made law, since food industry
+ lobbyists managed to impose compromises that led to the use of the cheapest chemicals, rather than those
+ that offered the greatest health benefits. For example, studies of processed animal food had demonstrated
+ that the addition of iron (as the highly reactive form, ferrous sulfate, which happens to be cheap and easy
+ to handle) created disease in animals, by destroying vitamins in the food. You should read the label of
+ ingredients and avoid products that contain added iron, when possible.
+
+
+ Q: Can cooking in an iron frying pan put iron into food?
+
+
+ Yes, especially if the food is acidic, as many sauces are. The added iron will destroy vitamins in the food,
+ besides being potentially toxic in itself.
+
+
+ Q: What about aluminum?
+
+
+ Aluminum and iron react similarly in cells and are suspected causes of Alzheimer's disease.
+
+
+ The aluminum industry started propagandizing more than 50 years ago about the "safety" of aluminum utensils,
+ claiming that practically none of the toxic metal gets into the food. Recent research showed that coffee
+ percolated in an aluminum pot contained a large amount of dissolved aluminum, because of coffee's acidity.
+
+
+ Q: What kind of cooking pots or utensils are safe?
+
+
+ Glass utensils are safe, and certain kinds of stainless steel are safe, because their iron is relatively
+ insoluble. Teflon-coated pans are safe unless they are chipped.
+
+
+
+ Q: How do I know which stainless steels are safe?
+
+
+ There are two main types of stainless steel, magnetic and nonmagnetic. The nonmagnetic form has a very high
+ nickel content, and nickel is allergenic and carcinogenic. It is much more toxic than iron or aluminum. You
+ can use a little "refrigerator magnet" to test your pans. The magnet will stick firmly to the safer type of
+ pan.
+
+
+ Q: Why is there iron in most multi-vitamin and mineral products?
+
+
+ Although several researchers have demonstrated that iron destroys vitamins, there is enough wishful thinking
+ in industry, government, and the consuming public, that such mistakes can go on for generations before
+ anyone can mobilize the resources to bring the truth to the public. 10 years ago, I thought it was a hopeful
+ sign of increased awareness of iron's danger when the manufacturer of a new iron product mentioned in the
+ Physician's Desk Reference that it hadn't yet been reported to cause cancer.
+
+
+ Q. I can't avoid all those foods, especially the bread and grains. What can I do to keep the iron I ingest
+ from harming me?
+
+
+ Iron destroys vitamin E, so vitamin E should be taken as a supplement. It shouldn't be taken at the same
+ time as the iron-contaminated food, because iron reacts with it in the stomach. About 100 mg. per day is
+ adequate, though our requirement increases with age, as our tissue iron stores increase. Coffee, when taken
+ with food, strongly inhibits the absorption of iron, so I always try to drink coffee with meat. Decreasing
+ your consumption of unsaturated fats makes the iron less harmful. Vitamin C stimulates the absorption of
+ iron, so it might be a good idea to avoid drinking orange juice at the same meal with iron-rich foods. A
+ deficiency of copper causes our tissues to retain an excess of iron, so foods such as shrimp and oysters
+ which contain abundant copper should be used regularly.
+
+
+ Q: How does copper help us?
+
+
+ Copper is the crucial element for producing the color in hair and skin, for maintaining the elasticity of
+ skin and blood vessels, for protecting against certain types of free radical, and especially for allowing us
+ to use oxygen properly for the production of biological energy. It is also necessary for the normal
+ functioning of certain nerve cells (substantia nigra) whose degeneration is involved in Parkinson's disease.
+ The shape and texture of hair, as well as its color, can change in a copper deficiency. Too much iron can
+ block our absorption of copper, and too little copper makes us store too much iron. With aging, our tissues
+ lose copper as they store excess iron. Because of those changes, we need more vitamin E as we age.
+
+
+ SUMMARY:
+
+ Iron is a potentially toxic heavy metal; an excess can cause cancer, heart disease, and other illnesses.
+
+
+ Other heavy metals, including lead and aluminum, are toxic; pans and dishes should be chosen carefully.
+
+
+ Iron causes cell aging.
+
+
+ Drinking coffee with iron rich foods can reduce iron's toxic effects.
+
+
+ Use shrimp and oysters, etc., to prevent the copper deficiency which leads to excess storage of iron.
+
+
+ Avoid food supplements which contain iron.
+
+
+ Take about 100 units of vitamin E daily; your vitamin E requirement increases with your iron consumption.
+
+ GLOSSARY:
+
+ Free radicals are fragments of molecules that are very destructive to all cells and system of the body.
+
+
+ Respiration refers to the absorption of oxygen by cells, which releases energy. The structure inside the
+ cell in which energy is produced by respiration is called the mitochondrion. Oxidation refers to the
+ combination of a substance with oxygen. This can be beneficial, as in normal respiration that produces
+ energy, or harmful, as in rancidity, irradiation, or stress reactions. Antioxidants: Vitamin E and vitamin C
+ are known as antioxidants, because they stop the harmful free-radical chain reactions which often involve
+ oxygen, but they do not inhibit normal oxidation processes in cells. "Chain breaker" would be a more
+ suitable term. It is often the deficiency of oxygen which unleashes the dangerous free-radical processes.
+ Many substances can function as antioxidants/chain breakers: thyroxine, uric acid, biliverdin, selenium,
+ iodine, vitamin A, sodium, magnesium, and lithium, and a variety of enzymes. Saturated fats work with
+ antioxidants to block the spread of free-radical chain reactions. Age pigment is the brown material that
+ forms spots on aging skin, and that accumulates in the lens of the eye forming cataracts, and in blood
+ vessels causing hardening of the arteries, and in the heart and brain and other organs, causing their
+ functions to deteriorate with age. It is made up of oxidized unsaturated oils with iron.
+
+
+ Anemic means lacking blood, in the sense of not having enough red blood cells or hemoglobin. It is possible
+ to have too much iron in the blood while being anemic. Anemia in itself doesn't imply that there is
+ nutritional need for iron.
+
+
+ REFERENCES
+
+
+ Allen, D. R., et al., "Catechol adrenergic agents enhance hydroxyl radical generation in xanthine oxidase
+ systems containing ferritin: Implications for ischemia reperfusion," Arch. Biochem. Biophys. 315(2),
+ 235-243, 1994.
+
+
+ M. Bartal, et al., "Lipid peroxidation in iron deficiency anemia--Reply," Acta Haematol. 91(3), 170, 1994.
+
+
+ R. J. Bergeron, et al., "Influence of iron on in vivo proliferation and lethality of L1210 cells," J.
+ Nutrition 115(3), 369-374, 1985.
+
+
+
+ P. Carthew and A. G. Smith, "Pathological mechanisms of hepatic tumor formation in rats exposed chronically
+ to dietary hexachlorobenzene," J. Applied Toxicology 14(6), 447-52, 1994.
+
+
+ Chen, Y., et al., "Weak antioxidant defenses make the heart a target for damage in copper-deficient rats,"
+ Free Radical Biol. Med. 17(6), 529-536, 1994.
+
+
+ J. J. C. Chiao, et al., "Iron delocalization occurs during ischemia and persists on reoxygenation of
+ skeletal muscle," J. Lab. Clin. Med. 124(3), 432-438, 1994.
+
+
+ Choi, J. H. and B. P. Yu, "Modulation of age-related alterations of iron, ferritin, and lipid peroxidation
+ in rat serum," Age 17(3), 93-97, 1994.
+
+
+ P. C. Elwood, "Iron, magnesium, and ischemic heart disease," Proc. of Nutrition Society 53(3), 599-603,
+ 1994.
+
+
+ J. Goodfield, An Imagined World, Penguin Books, N.Y., 1984.
+
+
+ M. Galleano and S. Puntarulo, "Mild iron overload effect on rat liver nuclei," Toxicol. 93(2-3), 125-34,
+ 1994.
+
+
+ E. C. Hirsch, "Biochemistry of Parkinson's disease with special reference to the dopaminergic systems," Mol.
+ Neurobiol. 9(1-3), 135-142, 1994.
+
+
+ G. M. Kainova, et al., "Activation of endogenous lipid peroxidation in the brain during oxidation stress
+ induced by iron and its prevention by vitamin E," Bull. Exp. Biol. & Med. 109(1), 43-45, 1989.
+
+
+
+ S. Kiechl, et al., "Body iron stores and presence of carotid atherosclerosis--results from the Bruneck
+ study," Arterioscler. Thromb. 14(10), 1625-1630, 1994.
+
+
+ A. V. Kozlov, et al., "Role of endogenous free iron in activation of lipid peroxidation during ischemia,"
+ Bull. Exp. Biol. Med. 99(1), 1984.
+
+
+ D. J. Lamb and D. S. Leake, "Iron released from transferrin at acidic pH can catalyse the oxidation of low
+ density lipoprotein," FEBS Lett 352(1), 15-18, 1994.
+
+
+ E. E. Letendre, "Importance of iron in the pathogenesis of infection and neoplasm," Trends in Biochemical
+ Sci., April, 1985, 166-168.
+
+
+ V. M. Mann, et al., "Complex 1, iron and ferritin in Parkinson's disease substantia nigra," Ann. of
+ Neurology 36(6), 876-81, 1994.
+
+
+ Z. Maskos and W. H. Koppenol, "Oxyradicals and multivitamin tablets," Free Radical Biol. & Med. 11,
+ 669-670, 1991.
+
+
+ S. Ozsoylu, "Lipid peroxidation in iron deficiency anemia," Acta Haematol. 91(3), 170, 1994.
+
+
+ Pecci, L., et al., "Aminoethylcystein ketimine decarboxylated dimer protects submitochondrial particles from
+ lipid peroxidation at a concentration not inhibitory of electron transport," Biochem. Biophys. Res. Commun.
+ 205(1), 264-268, 1994.
+
+
+ M. Savoiardo, et al., "Magnetic resonance imaging in progressive supranuclear palsy and other parkinsonian
+ disorders," J. Neural Trans. (suppl. 42), 93-110, 1994.
+
+
+ J. J. Strain, "Putative role of dietary trace elements in coronary heart disease and cancer," Brit. J.
+ Biomed. Sci. 51(3), 241-251, 1994.
+
+
+ Vanrensburg, S. J., et al., "Lipid peroxidation and platelet membrane fluidity--implications for Alzheimer's
+ disease?", Neuroreport 5(17), 2221-2224, 1994.
+
+
+ L. J. Wesselius, et al., "Increased release of ferritin and iron by iron-loaded alveolar macrophages in
+ cigarette smokers," Amer. J. Respir. Crit. Care Med. 150(3), 690-695, 1994.
+
+
+ Transfusions: Amer. J. of Surgery 155, p. 43, 1988. *A Finnish study, two years ago, indicated that high
+ iron stores may increase heart attack risk: In People magazine, 1994: "Is iron a killer?" Dr. Jerome L.
+ Sullivan, director of clinical labs of Veterans Affairs Medical Center at Charleston, S.C., in 1983 proposed
+ that excess iron contributes to heart attacks. University of Kuopio in Finland: Large-scale study (nearly
+ 2,000 men, for up to five years; next to smoking, excess stored iron is the most significant identifiable
+ risk factor for heart attacks. It is a stronger risk factor for heart attack than high blood pressure and
+ cholesterol.
+
+
+ *Dec. 7, page 6E, Register Guard (Eugene, OR): US studies showed a weak connection between iron and heart
+ disease, and a weak connection with the iron in red meat. Epidemiologists at the Pacific Northwest
+ Laboratory in Washington have reported that the greater the concentration of iron in a person's blood, the
+ greater his or her risk of cancer. Richard Stevens and his co-workers found the connection from examining
+ cancer rates in more than 8,000 people who participated in the l971 National Health and Nutrition
+ Examination survey. A second Finnish study with similar findings accompanied Stevens's report in the
+ International Journal of Cancer, and suggets that there may be cause for concern. Register Guard (Eugene,
+ OR), Jan. 16, 95; p 7A: Number of heart failures doubles, AP: 1982-92, heart disease death rate dropped
+ 24.5%; number of cases of congestive heart failure doubled during roughly the same period. It killed 39,000
+ Americans in 1991, costs system $40 billion per year. Cancer is the biggest killer of women under 64, heart
+ disease far surpasses cancer in women of ages 65-84.
+
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
+
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+
+ BSE - mad cow - scrapie, etc.: Stimulated amyloid degeneration and the toxic fats
+
+
+ BSE - mad cow - scrapie, etc.: Stimulated amyloid degeneration and the toxic fats
+
+
+
+
+ I have written before about the protective effects of carbon dioxide and progesterone, especially for
+ the brain, and how the structure of cell water is affected by adsorbed and dissolved materials, and by
+ metabolic energy. In the high energy (rested) state, cell water behaves as if it were colder than its
+ real temperature, and this affects the behavior of proteins and fats in the cell, allowing “oily”
+ surfaces to remain in contact with the more orderly water. Carbon dioxide spontaneously combines with
+ the amino groups in proteins, stabilizing the normal functional conformation. The loss of carbon dioxide
+ affects the structure of all proteins in the body, and the loss of cellular energy affects the structure
+ of the intracellular proteins and their associated molecules.
+
+
+ In scrapie and many other degenerative diseases (the amyloidoses), proteins condense into fibrils that
+ tend to keep enlarging, with a variety of very harmful effects. The condensation of the “amyloid”
+ proteins is sensitive to temperature, and a slight increase in the disorder of the water can induce
+ functional proteins to change their conformation so that they spontaneously associate into fibrous
+ masses. In the absence of sufficient carbon dioxide, all proteins are susceptible to structural
+ alteration by the addition of sugars and fats and aldehydes, especially under conditions that favor
+ lipid peroxidation.
+
+
+ The amyloidoses affect different tissues in different ways, but when they occur in the brain, they
+ produce progressive loss of function, with the type of protein forming the fibrils determining the
+ nature of the functional loss. The protein which carries thyroid hormone and vitamin A, transthyretin,
+ can produce nerve and brain amyloid disease, but it can also protect against other amyloid brain
+ diseases; in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and the “prion diseases”
+ (scrapie, kuru, CJD, BSE, etc.) amyloid particles are formed by different proteins. The transthyretin
+ protein which is binding small molecules resists condensation into the amyloid fibrils, but without its
+ normal vitamin A and thyroid hormone, it can create toxic fibrils. (Raghu, et al., 2002.)
+
+
+ Around 1970 I read E. J. Field’s suggestion that aging tissues and tissues affected by viral diseases
+ showed some similar structures (“inclusion bodies”) under the electron microscope. In following up those
+ observations, it turned out that old tissues appeared to develop antigens “identical with, or similar
+ to,” scrapie-infected young tissues. The premature aging caused by removal of the thymus gland in
+ newborn animals produced similar results.
+
+
+ Field’s group and others (e.g., Alpers) were clearly showing that the scrapie infection involved
+ proteins, but not viruses with nucleic acids. In one of Field’s last publications (1978), he even
+ suggested that the infectious process might depend on a structural rearrangement of the host’s
+ molecules, similar to the idea which is now known as the “prion hypothesis.” Field’s suggestion was an
+ important advance in the theory of aging, and the evidence supporting it is now voluminous, but that
+ work has been omitted from the official histories.
+
+
+ Although phenomena of “imprinting” and non-genetic inheritance had been established earlier, the
+ dogmatism of genetics led the scientific establishment to reject everything that challenged the primacy
+ of DNA. When I mentioned to my professors (in 1971) the evidence that scrapie was transmitted without
+ nucleic acid, I could see from their reactions that it would be a very long time before much progress
+ would be made in understanding the degenerative brain diseases. When the exact structure of the
+ “infectious” protein was later worked out, and the 1997 Nobel Prize awarded (to Stanley Prusiner), I was
+ surprised that no one from Field’s group was included. (In 1976, a nobel prize had been awarded to D.C.
+ Gajdusek, for his promotion of the idea of “slow viruses” in general, and particularly for arguing that
+ scrapie, CJD and kuru were caused by slow viruses.)
+
+
+ In reading Prusiner’s autobiographical statements, I was even more surprised to see that he claimed to
+ have been puzzled to find out, around 1983, that the infectious agent was a protein. I had thought that
+ my professors were lethargic authoritarians when they refused to look at the evidence in 1970-72, but
+ Prusiner’s expression of puzzlement so many years later over the absence of nucleic acid in the
+ infectious agent is hard to account for.
+
+
+ In my own research in 1971, I was interested in another kind of age-related “inclusion body,” which was
+ variously called lipofuscin, age pigment, and ceroid pigment. This brown (yellow autofluorescent)
+ pigment contained proteins and metals, as well as polyunsaturated lipids, and overlapped in many ways
+ with the amyloid bodies. All of these inclusion bodies were known to be associated with radiation
+ injury, aging, and hormonal-nutritional imbalances. Excess of estrogen, polyunsaturated fatty acids, and
+ oxidative metals were major factors in the development of lipofuscin, and estrogen was also known to
+ cause other types of “inclusion bodies” to develop in cells.
+
+
+ Although very little was known about the composition of the inclusion bodies (they were usually thought
+ to be organelles damaged by free radical activity, or antibodies resulting from autoimmunity), their
+ involvement in aging and degenerative disease was clear, and it was widely known that
+ ionizing radiation accelerated their formation. But it was just at this time that the national research
+ priorities of the U.S. were redirected toward genetic explanations for all major diseases, with for
+ example the “war on cancer” centering on the concepts of the “oncogene” and the cancer virus. Since the
+ “slow virus” of cancer, or the viral oncogene, requires activation by something in the environment, its
+ function is to distract the public’s attention from those environmental causes of disease, viz.,
+ radiation and chemical pollution.
+
+
+ The U.S. Public Health Service has historically been one of the branches of the military, and currently
+ has 6000 commissioned officers. It has been intimately involved in all aspects of chemical, biological,
+ and nuclear warfare, and it has participated in many covert projects, including experimentation on
+ people without their knowledge. For decades, information on radiation injury to the public was hidden,
+ classified, altered, or destroyed by the PHS. During the radiation disaster at Three Mile Island, they
+ calmly defended the interests of the nuclear industry.
+
+
+ After the April, 1986 catastrophe at the reactor in Chernobyl, some of the food being imported into the
+ U.S. was so highly radioactive that the FDA secretly seized it, to prevent the public from being
+ concerned. The first cow found to have BSE in England was in November, 1986, several months after
+ England’s pastures had been heavily contaminated by rainfall carrying radioactive material from
+ Chernobyl, which soaked into the soil and continued to contaminate crops for years (and will continue,
+ for centuries). The number of sick cows increased rapidly to a peak in 1992. Human deaths from the
+ similar disease (“variant CJD”) began a few years later.
+
+
+ In June, 2000, a wildfire burned across southern Washington, turning the radioactive vegetation on the
+ Hanford Nuclear Site into radioactive smoke, contaminating a wide area, including farms, dairies, and
+ orchards. In 2003, the first cow in the U.S. with BSE was reported, from a dairy a few miles from the
+ Hanford Site.
+
+
+ Beginning in 1946, Bikini Island was used to test atomic bombs. In 1954, they began to test hydrogen
+ bombs in the Pacific; some of the bombs were deliberately designed to vaporize whole
+ islands, so that the effects of radioactive fallout could be studied. In 1954, the first child with kuru
+ was reported in the rainy highlands of New Guinea.
+
+
+ Within two years, hundreds of people in that area (of the Fore tribe) were dying from kuru, with the
+ mortality highest among the women; in some villages, the majority of the women died
+ from the disease, but by 1957 the mortality was falling rapidly. Between 1957 and 1964, 5% of the
+ population of the Fore tribe died of the disease, according to D.C. Gajdusek, who had been sent by the
+ U.S. Army to investigate the disease. Although Gajdusek graduated in 1946 from Harvard medical school as
+ a pediatrician, in his autobiography he said that when he was drafted in 1951, the army assigned him to
+ work in virology. In 1958, Gajdusek became director of the NIH laboratories for neurological and
+ virological research. This was a remarkable achievement for someone who had supposedly only done some
+ scattered field-work in infectious diseases, and whose purpose in going to New Guinea had been to study
+ ''child growth and development in primitive cultures.'' The only published reason I have found that
+ might be a basis for making him head of neurology, was his sending a diseased Fore brain to Fort Detrick
+ in 1957.
+
+
+ Gajdusek claimed to have seen the Fore people eating dead relatives, but his figures show that the
+ disease was already in rapid decline when he arrived. He took photographs which were widely published in
+ the US, supposedly showing cannibalism, but 30 years later, he said the photographs showed people eating
+ pork, and that he had seen no cannibalism. (At the time Gajdusek was observing kuru in New Guinea, the
+ influence of “cannibalism” on brain function was already in the news, because of the discovery by J.V.
+ McConnell that the behavior of “trained” flatworms could be transmitted to other worms by chopping them
+ up and feeding them to the naive worms.)
+
+
+ Harvard medical school, in association with the military program centered at Fort Detrick,
+ Fredericksburg, Maryland, was active in biological warfare in the 1940s, and I think it’s more plausible
+ to see Gajdusek as a trouble-shooter for the biological warfare establishment, than as a biological
+ researcher. One of his biographers has written that the idea of associating kuru with scrapie was
+ suggested to him by a veterinarian, and that Gajdusek had responded by claiming to have experiments in
+ progress to test that theory, four years before the experiments were actually made.
+
+
+ In other words, the slow virus theory for which Gajdusek was given the Nobel Prize is scientific junk,
+ which Gajdusek has repeatedly reinterpreted retrospectively, making it seem to have been anticipatory of
+ the prion theory. Whatever actually caused kuru, I think the army was afraid that it was the result of
+ radioactive fallout from one of its bomb tests, and that Gajdusek’s job was to explain it away.
+
+
+ I suspect that kuru was the result of an unusual combination of malnutrition (the women were vegetarian)
+ and radiation. In the very short time that Gajdusek spent in New Guinea, he claimed to have done studies
+ to eliminate all of the alternative causes, nutritional, toxic, anthropological, bacterial causes,
+ studies that would normally have required several years of well organized work. I don’t think he
+ mentioned the possibility of radiation poisoning.
+
+
+ In 1998 Congress commissioned a study of the health effects of radiation from bomb testing, and although
+ the study examined the effects of only part of the bomb tests, it concluded that they had killed 15,000
+ Americans. No one has tried to accurately estimate the numbers killed in other countries.
+
+
+ Even very low doses of ionizing radiation create an inflammatory reaction (Vickers, et al., 1991), and
+ there is evidence that the inflammatory state can persist as long as the individual lives;
+ in Japan, the “acute phase” proteins are still elevated in the people who were exposed to
+ radiation from the atomic bombs. The acute phase proteins that are increased by malnutrition and
+ radiation increase the tendency to form amyloid deposits. Strong radiation can even cause, after a delay
+ of more than a year, the development of vacuoles, which are the most obvious feature of the “prion”
+ brain diseases. The persistent inflammatory reaction eventually produces cellular changes, but these
+ were originally overlooked because of the theory that radiation is harmful only when it produces
+ immediate changes in the DNA.
+
+
+ Radiation damage to the brain is most visible early in life, and in old age. In 1955, Alice Stewart
+ showed that prenatal x-rays increase the incidence of brain cancer, leukemia, and other cancers. In
+ 1967, a study in Japanese bomb survivors found that prenatal exposure to radiation had reduced their
+ head size and brain size. In 1979, Sternglass and Bell showed extremely close correspondence between
+ scores on the SAT and prenatal exposure to radiation.
+
+
+ Serum amyloid A, which can increase 1000-fold under the influence of proinflammatory cytokines,
+ resulting from irradiation, stress, trauma, or infection, is an activator of phospholipase A2 (PLA2),
+ which releases fatty acids. Some of the neurodegenerative states, including amyloid-prion diseases,
+ involve activated PLA2, as well as increases in the toxic breakdown products of the polyunsaturated
+ fatty acids, such as 4-hydroxynonenal. The quantity of PUFA in the tissues strongly determines the
+ susceptibility of the tissue to injury by radiation and other stresses. But a diet rich in PUFA will
+ produce brain damage even without exceptional stressors, when there aren’t enough antioxidants, such as
+ vitamin E and selenium, in the diet.
+
+
+ Amyloidosis has traditionally been thought of as a condition involving deposits mainly in blood vessels,
+ kidneys, joints and skin and in extracellular spaces in the brain, and the fact that the “amyloid”
+ stained in a certain way led to the idea that it was a single protein. But as more proteins--currently
+ about 20--were identified in amyloid deposits, it was gradually realized that the deposits can be
+ identified inside cells of many different tissues, before the larger, very visible, extracellular
+ deposits are formed.
+
+
+ There is evidence of a steady increase in the death rate from amyloidosis. It kills women at a younger
+ age than men, often at the age of 50 or 60.
+
+
+ Serum amyloid P is called “the female protein” in hamsters, because of its association with
+ estrogen; castrated (or estrogen treated) males also produce large amounts of it, and
+ its excess is associated with the deposition of amyloid (Coe and Ross, 1985). It can bind other amyloid
+ proteins together, accelerating the formation of fibrils, but this function is probably just a variation
+ of a normal function in immunity, tissue repair, and development.
+
+
+ Estrogen increases the inflammation-associated substances such as IL-6, C-reactive protein, and amyloid,
+ and liberates fatty acids, especially the unstable polyunsaturated fatty acids. It also increases
+ fibrinogen and decreases albumin, increasing the leakiness of capillaries. The decrease of albumin
+ increases the concentration of free fatty acids and tryptophan, which would normally be bound to
+ albumin.
+
+
+ In the U.S. and Europe, livestock are fed large amounts of high-protein feeds, and currently these
+ typically contain fish meal and soybeans. The estrogenic materials in soybeans increase the animals’
+ tendency toward inflammation (with increased serum amyloid).
+
+
+ Officially, BSE appeared because cows were fed slaughter-house waste containing tissues of sheep that
+ had died of scrapie. Scrapie was a nerve disease of sheep, first reported in Iceland in the 18th
+ century. When I was studying the digestive system and nutrition of horses, I learned that it was common
+ for horses in Norway to be fed dried fish during the winter. This abundant food was probably used for
+ sheep, as well as for horses. The extra protein provided by fish meal is still important for sheep in
+ areas where pastures are limited, but it has now become common to use it to increase productivity and
+ growth throughout the lamb, beef, and dairy industries, as well as in most lab chows fed to experimental
+ animals, such as the hamsters used for testing the infectivity of the diseased tissues.
+
+
+ Increased dietary polyunsaturated fatty acids (PUFA) suppress the activity of the ruminal bacteria which
+ are responsible for the hydrogenation-detoxication of PUFA in the animal’s diet. This allows the
+ unstable fats, 98% of which are normally destroyed, to pass into the animals’ tissues and milk.
+
+
+ The polyunsaturated fats in fish are very unstable, and when they get past the bacterial saturases
+ (biohydrogenases) in the rumen that normally protect ruminants from lipid peroxidation, they are likely
+ to cause their toxic effects more quickly than in humans, whose antioxidant systems are highly
+ developed. The toxic effects of polyunsaturated fats involve altered (immunogenic) protein structure,
+ decreased energy metabolism, and many inflammatory effects produced by the prostaglandin-like
+ substances. Marine fish are now so generally polluted with dioxin, that in Japan there is a clear
+ association between the amount of fish in a person’s diet (their body content of EPA and DHA) and the
+ amount of dioxin in their body.
+
+
+ Radiation and many kinds of poisoning cause early peroxidation of those highly unsaturated fats, and the
+ breakdown products accelerate the changes in the folding and chelating behavior of proteins. The
+ accumulation of altered proteins is associated with the degenerative diseases. The role of toxic metals
+ in brain inflammation is well established (e.g., aluminum, lead, mercury: Campbell, et
+ al., 2004; Dave, et al., 1994; Ronnback and Hansson, 1992).
+
+
+ The “prion hypothesis” has the value of weakening the fanaticism of the DNA-genetics doctrine, but it
+ has some problems. There are now several examples in which other degenerative diseases have been
+ transmitted by procedures similar to those used to test the scrapie agent. (e.g., Goudsmit, et al.,
+ 1980; Xing, et al., 2001; Cui, et al., 2002.) Experimental controls haven’t been adequate to distinguish
+ between the pure prion and its associated impurities. Gajdusek burned a sample of the infective hamster
+ brain to ash, and found that it still retained “infectivity.” He argued that there was a mineral
+ template that transmitted the toxic conformation to normal proteins. Others have demonstrated that the
+ active structure of the infective agent is maintained by a carbohydrate scaffolding, or that the
+ infectivity is destroyed by the frequency of ultraviolet light that destroys the active lipid of
+ bacterial endotoxin, lipopolysaccharide.
+
+
+ But simply injuring the brain or other organ (by injecting anything) will sometimes activate a series of
+ reactions similar to those seen in aging and the amyloidoses. When a slight trauma leads to a prolonged
+ or expanding disturbance of structure and function, the process isn’t essentially different from
+ transmitting a condition to another individual. The problem is being “transmitted” from the initial
+ injury, recruiting new cells, and passing the disturbed state on to daughter cells in a disturbed form
+ of regeneration. Keloids, hypertrophic scars, are analogous to the dementias in their overgrowth of
+ connective tissue cells: In the aging or injured brain, the glial cells (mainly
+ astrocytes) proliferate, in reparative processes that sometimes become exaggerated and harmful.
+
+
+ When tissue phospholipids contain large amounts of polyunsaturated fatty acids, large amounts of
+ prostaglandins are immediately formed by any injury, including low doses of ionizing radiation. The
+ liberated free fatty acids have many other effects, including the formation of highly reactive
+ aldehydes, which modify DNA, proteins, and other cell components.
+
+
+ Animals which are “deficient” in the polyunsaturated fatty acids have a great resistance to a variety of
+ inflammatory challenges. Their tissues appear to be poor allergens or antigens, since they can be easily
+ grafted onto other animals without rejection. Something related to this can probably be seen in the data
+ of human liver transplants. Women’s livers are subjected to more lipid peroxidation than men’s, because
+ of the effects of estrogen (increasing growth hormone and free fatty acids, and selectively mobilizing
+ the polyunsaturated fatty acids and increasing their oxidation). Liver transplants from middle-aged
+ female donors fail much more often (40 to 45%) than livers from male donors (22 to 25%), and other
+ organs show the same effect. The autoimmune diseases are several times as common in women as in men,
+ suggesting that some tissues become relatively incompatible with their own body, after prolonged
+ exposure to the unstable fatty acids. If we consider the healthy function of the immune system to be the
+ removal or correction of injured tissue, it’s reasonable to view the random interactions of oxidized
+ fats with proteins as exactly the sort of thing our immune system takes care of.
+
+
+ The serum amyloids A and P and the closely related lipoproteins are considered to be important parts of
+ our “innate immunity,” operating in a more general way than the familiar system of specific acquired
+ immunities.
+
+
+ The amyloids and lipoproteins are powerfully responsive to bacterial endotoxin, LPS, and their
+ structural feature that binds it, the “pleated sheet” structure, appears to also be what allows the
+ amyloids to form amorphous deposits and fibrils under some circumstances. Our innate immune system is
+ perfectly competent for handling our normal stress-induced exposures to bacterial endotoxin, but as we
+ accumulate the unstable fats, each exposure to endotoxin creates additional inflammatory stress by
+ liberating stored fats. The brain has a very high concentration of complex fats, and is highly
+ susceptible to the effects of lipid peroxidative stress, which become progressively worse as the
+ unstable fats accumulate during aging.
+
+
+ More than 60 years ago, a vitamin E deficiency was known to cause a brain disease, sometimes associated
+ with sterility and muscular dystrophy. The symptoms of the brain disease were similar to those of “mad
+ cow disease,” and the condition is now usually called “crazy chick disease.” Veterinarians are usually
+ taught that it is caused by a selenium deficiency, but it is actually the result of an excess of PUFA in
+ the diet, and is exacerbated by increased iron or other oxidants, and prevented by increased vitamin E,
+ selenium, or substitution of saturated fats for the unsaturated.
+
+
+ Terminology, established by tradition and thoughtless memorization, obscures many of the commonalities
+ in the various brain diseases. Brain inflammation (Betmouni and Perry, 1999; Perry, et al., 1998),
+ myelination disorders, edema, overgrowth of the astroglia, and circulatory changes are common
+ occurrences in most of the degenerative encephalopathies, but traditional textbook descriptions have
+ created the impression that each disease is pathologically very distinct from the others. The current
+ classification of “the prion diseases” is reifying a group of symptoms that aren’t specific to any
+ specific known cause. And standard laboratory procedures for preparing brain sections for microscopic
+ examination may cause brain cells to shrink to 5% of their original volume (Hillman and Jarman, Atlas of the cellular structure of the human nervous system, 1991), so the
+ objectivity of pathological studies shouldn’t be over-estimated.
+
+
+ According to a 1989 study (Laura Manuelidis, neuropathology department at Yale), 13% of the people who
+ had died from “Alzheimer’s disease” actually had CJD. Between 1979 and 2000, the number of people dying
+ annually from Alzheimer’s disease increased 50-fold. Very competent neuropathologists differ radically
+ in their descriptions of the dementia epidemic.
+
+
+ By some tests, the “prion” resembles the LPS endotoxin. One of the interesting developments of the prion
+ theory is that a particular structure that appears when the prion becomes toxic, the “beta pleated
+ sheet,” is also a feature of most of the normal proteins that can form amyloid, and that this structure
+ is directly related to binding and eliminating the bacterial LPS. If the prion theory is correct about
+ the conversion of a normal protein into the pleated sheet, it isn’t necessarily correct about the
+ incurability of the condition. The innate immune system should be able to inactivate the prion just as
+ it does the bacterial endotoxin, if we remove the conditions that cause the innate immune reaction to
+ amplify the inflammation beyond control.
+
+
+ In the prion diseases, the severely damaged brain appears to have a “pathological overactivity” of the
+ serotonergic systems (Fraser, et al., 2003). This is an interesting parallel to Alzheimer’s disease,
+ since it has been known for several years that the blood platelets have an increased tendency to release
+ serotonin in that more common form of dementia. Serotonin itself is toxic to nerves, and is part of the
+ adaptive system that gets out of control during prolonged inflammation. Serotonin is an important
+ activator of the phospholipases.
+
+
+ The modification of proteins’ structure by glycosylation is involved in the development of the toxic
+ form of the “prionic” protein, as well as in all the degenerative processes of aging. Until the ability
+ to use sugar is impaired, cells produce enough carbon dioxide to protect proteins against random
+ glycation, but with each exposure to free polyunsaturated fatty acids, the ability to use glucose is
+ damaged. In the dementias, the brain has a greatly reduced ability to use glucose.
+
+
+ One of estrogen’s central effects is to shift metabolism away from the oxidation of glucose, decreasing
+ carbon dioxide production. There is a much higher incidence of Alzheimer’s disease in women, and
+ estrogen exposure exacerbates all of the changes that lead to it, such as shifts in nerve transmitters,
+ increased vascular leakiness, and the increased production of the acute phase proteins.
+
+
+ Everything that is known about the “always fatal” prionic diseases, the diseases of disturbed protein
+ folding, suggests that they can be avoided and even reversed by systematically reversing the processes
+ that amplify inflammation.
+
+
+ People who take aspirin, drink coffee, and use tobacco, have a much lower incidence of Alzheimer’s
+ disease than people who don’t use those things. Caffeine inhibits brain phospholipase, making it
+ neuroprotective in a wide spectrum of conditions. In recent tests, aspirin has been found to prevent the
+ misfolding of the prion protein, and even to reverse the misfolded beta sheet conformation, restoring it
+ to the harmless normal conformation. Nicotine might have a similar effect, preventing deposition of
+ amyloid fibrils and disrupting those already formed (Ono, et al., 2002). Vitamin E, aspirin,
+ progesterone, and nicotine also inhibit phospholipase, which contributes to their antiinflammatory
+ action. Each of the amyloid-forming proteins probably has molecules that interfere with its toxic
+ accumulation.
+
+
+ Thyroid hormone, vitamins A and E, niacinamide (to inhibit systemic lipolysis), magnesium, calcium,
+ progesterone, sugar, saturated fats, and gelatin all contribute in basic ways to prevention of the
+ inflammatory states that eventually lead to the amyloid diseases. The scarcity of degenerative brain
+ disease in high altitude populations is consistent with a protective role for carbon dioxide.
+
+
+ The relatively sudden acceptability of the idea of non-genetic transmission doesn't mean that Lamarck
+ has been rehabilitated by the scientific establishment; it could just be that it's the most politically
+ acceptable way to explain the outbreaks of deadly disease caused by the industrialization of foods and
+ the exposure of the population to dangerous levels of radiation.
+
+
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+ disease process rather than a surgical artefact. This disease process may be related to a localized
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+
+
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+ as the Prion Diseases have been widely reported as lacking any inflammatory elements despite the many
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+
+
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+
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+ deposition is accelerated by oral administration of semipurified amyloid fibrils extracted from
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+ semipurified bovine AA amyloid fibrils or semipurified human light chain-derived (A(lambda)) amyloid
+ fibrils for 10 days. After 3 weeks, each mouse was subjected to inflammatory stimulation by subcutaneous
+ injection with a mixture of complete Freund's adjuvant supplemented with Mycobacterium butyricum.”
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+ 15 mice treated with bovine AA amyloid fibrils and 11 out of 15 mice treated with human A(lambda)
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+ alone or in amyloid fibril-treated mice without inflammatory stimulation. Our results suggest that AA
+ amyloid deposition
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+
+
+
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+ antigensand bacteria. In the past several years it has been determined that both of
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+ (snRNPs). Both CRP and SAP have nuclear transport signals which facilitate their entry into the nuclei
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+
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+ Maki M, Kasagi F, Kodama K, Macphee DG, Kyoizumi S. “The well-documented increases in malignant tumours
+ in the A-bomb survivors have recently been supplemented by reports that non-cancer diseases, including
+ cardiovascular disease, may also have increased in incidence with increasing radiation dose.
+ Given that low-level inflammatory responses are widely accepted as a significant risk factor for
+ such diseases, we undertook a
+ detailed investigation of the long-term effects of ionizing radiation on the levels of the
+ inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) in A-bomb survivors.” “Blood
+ samples were taken from 453 participants in a long-term epidemiological cohort of A-bomb survivors.”
+
Higher CRP levels also correlated with age, male gender, body mass index and a
+ history of myocardial infarction. After adjustments for these factors, CRP levels still appeared
+ to have increased significantly with increasing radiation dose (about 28% increase at 1Gy,
+
+
+
+
+ “Our results appear to indicate that exposure to A-bomb radiation has caused significant
+ increases in inflammatory activity that are still demonstrable in the blood of A-bomb survivors and
+ which may lead to increased risks of cardiovascular disease and other non-cancer diseases.”
+
+
+ Immunol Rev. 2000 Oct;177:52-67. Chemokines and chemokine receptors in inflammation of the
+ nervous system: manifold roles and exquisite regulation. Huang D, Han Y, Rani MR, Glabinski
+ A, Trebst C, Sorensen T, Tani M, Wang J, Chien P, O'Bryan S, Bielecki B, Zhou ZL, Majumder S, Ransohoff
+ RM.
+
+
+ Am J Med Genet. 1989 Dec;34(4):562-8. Mortality rate of amyloidosis in Japan: secular trends and
+ geographical Variations. Imaizumi Y. “The death rate in Japan from amyloidosis was analyzed
+ using Japanese Vital Statistics for 1969-1985. The amyloidosis death rate has increased
+ gradually year by year for both sexes.” “The mean age at death from amyloidosis gradually
+ increased year by year for both sexes, although the age was 11-23 years shorter for males and
+ 20-25 years shorter for females than that of the general population.”
+
+
+ Stroke. 1991 Nov;22(11):1448-51. Platelet secretory products may contribute to neuronal
+ injury. Joseph R, Tsering C, Grunfeld S, Welch KM.
+
+
+ J Neurochem. 1997 Jul; 69(1): 266-72.
+ Aggregation of beta-amyloid peptide is promoted by membrane phospholipid metabolites elevated in
+ Alzheimer's disease brain. Klunk WE, Xu CJ, McClure RJ, Panchalingam K, Stanley JA,
+ Pettegrew JW. “A beta peptides have been shown to be toxic to neurons in cell culture, and this toxicity
+ is critically dependent on the aggregation of the peptide into cross-beta-pleated sheet fibrils. Also,
+ in vivo and postmortem NMR studies have shown changes in certain brain membrane phospholipid metabolites
+ in normal aging and more extensive alterations in patients with Alzheimer's disease. The finding that
+ membrane phospholipids affect the aggregation of A beta suggests that the abnormalities in membrane
+ metabolism found in Alzheimer's disease could affect the deposition of A beta in vivo.” “Certain
+ metabolites (glycerophosphocholine, glycerophosphoethanolamine, and alpha-glycerophosphate) augment the
+ aggregation of A beta. Other membrane phospholipid metabolites (phosphocholine, phosphoethanolamine, and
+ inositol-1-phosphate) have no effect.We conclude that increased membrane phospholipid
+ metabolite concentrations may play a role in the deposition of A beta seen in normal aging and the even
+ greater deposition of A beta observed in Alzheimer's disease.”
+
+
+ J Pharm Sci. 1971 Feb; 60(2): 167-80. Experimental modification of the chemistry and biology of
+ the aging process. Kormendy CG, Bender AD.
+
+
+ Radiobiologiia. 1990 May-Jun;30(3):317-20. [Cholesterol and fatty acids of the nuclei and
+ chromatin of the rat thymus at long intervals following gamma irradiation] Kulagina TP.
+ “The FFA content in the homogenate, nuclei and chromatin of rat thymus drastically increased 60 min
+ after the last exposure. In a month, the FFA content of nuclei and chromatin dropped to control levels,
+ whereas that of the homogenate remained high throughout the entire period of observation and sharply
+ increased by the third month.”
+
+
+ J Neuropathol Exp Neurol. 1968 Jan; 27(1): 157-8.
+ Amyloid in late postradiation necrosis of brain. Mandybur TJ, Gore y.
+
+
+ Hepatology. 1995 Dec;22(6):1754-62. Effect of donor age and sex on the outcome of liver
+ transplantation. Marino IR, Doyle HR, Aldrighetti L, Doria C, McMichael J, Gayowski T, Fung
+ JJ, Tzakis AG, Starzl TE.
+
+
+ Brain Res. 673(1), 149-152, 1995. "Glucose deprivation increases aspartic acid release from
+ synaptosomes of aged mice,"M. Martinez, et al., "...in the absence of glucose in the medium
+ of incubation aspartate and glutamate release was higher in old than in young animals." "...there is an age-dependent dysfunction in this process linked to energy metabolism disturbance."
+
+
+ Neurobiol Aging. 1995 Nov-Dec; 16(6): 977-81. Estrogen induction of glial heat shock proteins:
+ implications for hypothalamic Aging. Mydlarski MB, Liberman A, Schipper HM. “In the aging
+ mammalian hypothalamus, a unique subpopulation of glial cells accumulates peroxidase-positive
+ cytoplasmic inclusions distinct from lipofuscin. In adult rodents, this senescence-dependent glial
+ granulation is accelerated by administration of estradiol valerate.” “Our findings indicate that
+ estrogen elicits a heat shock response and subsequent granulation in astrocytes residing in
+ estradiol receptor-rich brain regions including the arcuate nucleus and the wall surrounding the third
+ ventricle but not in estradiol receptor-deficient regions such as the striatum and corpus callosum. The
+ heat shock proteins induced by estrogen, namely, the 27, 72, and 90 kDa stress proteins, are upregulated
+ in astrocytes in response to oxidative challenge supporting our hypothesis that estrogen mediates
+ senescent changes in the rodent hypothalamus through oxidative mechanisms.”
+
+
+ Proc. Natl. Acad. Sci. USA, vol. 44, pp. 712-717 (1958): "Epigenetic Control Systems".
+ D. L. Nanney.
+
+
+ Journal of the Neurological Sciences 1995;134:61-6.
+ Mortality from motor neuron disease in Japan, 1950-1990: association with radioactive fallout from
+ atmospheric weapons testing.
+ Neilson S, Robinson I, Rose FC.
+
+
+ Biol Psychiatry. 2002 Nov 1;52(9):880-6. Nicotine breaks down preformed Alzheimer's beta-amyloid
+ fibrils in vitro. Ono K, Hasegawa K, Yamada M, Naiki H. “The antiamyloidogenic effect of
+ nicotine may be exerted not only by the inhibition of fAbeta formation but also by the disruption of
+ preformed fAbeta.”
+
+
+ Res Immunol. 1998 Sep-Oct; 149(7-8): 721-5. The contribution of inflammation to acute and
+ chronic neurodegeneration. Perry VH, Bolton SJ, Anthony DC, Betmouni S.
+
+
+
+ Neurology. 1966 Oct;16(10):957-62. Myxedema and ataxia. Cerebellar alterations and "neural myxedema
+ bodies".
+ Price TR, Netsky MG.
+
+
+ Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1580-5. Epub 2003 Feb 03.
+ Short-term administration of omega 3 fatty acids from fish oil results in increased transthyretin
+ transcription in old rat hippocampus. Puskas LG, Kitajka K, Nyakas C, Barcelo-Coblijn G,
+ Farkas T.
+
+
+ Arch Biochem Biophys. 2002 Apr 1;400(1):43-7. Inhibition of transthyretin amyloid fibril
+ formation by 2,4-dinitrophenol through tetramer stabilization.
+ Raghu P, Reddy GB, Sivakumar B.
+
+
+ Br J Ind Med. 1992 Apr;49(4):233-40. Chronic encephalopathies induced by mercury or lead:
+ aspects of underlying cellular and molecular mechanisms. Ronnback L, Hansson E.
+
+
+ Radiat Res. 1967 Mar; 30(3): 640-53. Radiation studies on mice of an inbred tumor-resistant
+ strain. The alteration of endogenous susceptibility to amyloidosis by x-irradiation.
+ Rosenblum WI, Goldfeder A, Ghosh AK.
+
+
+ Neurotoxicology 15(3), 493-502, 1994."Phosphoinositide second messengers in cholinergic
+ excitotoxicity," K. Savolainen, et al. "Acetylcholine is a powerful excitotoxic
+ neurotransmitter in the brain. By stimulating calcium-mobilizing receptors, acetylcholine, through
+ G-proteins, stimulates phospholipase C and cause the hydrolysis of a membrane phospholipid...."Female
+ sex and senescence increase the sensitivity of rats to cholinergic excitotoxicity."
+
+
+ Int J Radiat Oncol Biol Phys. 1995 Jan 1;31(1):57-64. Radiation-induced changes in the profile
+ of spinal cord serotonin, prostaglandin synthesis, and vascular permeability. Siegal T,
+ Pfeffer MR. “Serotonin levels were unchanged at 2, 14,and 56 days after radiation but
+ increased at 120 and 240 days in the irradiated cord segments when compared to both the nonirradiated
+ thoracic and cervical segments (p < 0.01) and age-matched controls (p < 0.03).”
+ “In the first 24 h after radiation, a 104% increase in microvessel permeability was observed
+ which returned to normal by 3 days. Normal permeability was maintained at 14 and 28 days, but at 120 and
+ 240 days a persistent and significant increase of 98% and 73% respectively above control level was
+ noted.”
+
+
+ Annual Meeting of the American Psychological Association, New York, New York, September 3, 1979, "Fallout and the Decline of Scholastic Aptitude Scores," Ernest Sternglass and Stephen Bell.
+
+
+ Acta Neuropathol (Berl). 1995; 90(2): 135-41. Cerebral beta amyloid deposition in patients with
+ malignant neoplasms: its prevalence with aging and effects of radiation therapy on vascular
+ amyloid. Sugihara S, Ogawa A, Nakazato Y, Yamaguchi H. “The prevalence of cerebral A beta
+ deposits was about two times higher in the patients who had received brain radiation therapy (27.8%)
+ compared to non-radiated patients (14.8%). Amyloid angiopathy was much more prominent (P < 0.05) with
+ radiation therapy (22.2%) than without (8.0%).”
+
+
+ Diabetes. 2003 Dec;52(12):2882-7. Elevation of free fatty acids induces inflammation and impairs
+ vascular reactivity in healthy subjects. Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim
+ H, Aljada A, Dandona P.
+
+
+ Arterioscler Thromb Vasc Biol. 2003 Dec 29. Effect of Lower Dosage of Oral Conjugated Equine
+ Estrogen on Inflammatory Markers and Endothelial Function in Healthy Postmenopausal Women.
+ Wakatsuki A, Ikenoue N, Shinohara K, Watanabe K, Fukaya T. {Oral estrogen) “... increases plasma
+ C-reactive protein (CRP) and interleukin-6 (IL-6) concentration. The proinflammatory effect
+ of oral ERT may explain the increased risk of coronary heart disease (CHD) associated with this
+ treatment.”
+
+
+ Am J Pathol. 1997 Jun; 150(6): 2181-95. Free fatty acids stimulate the polymerization of tau and
+ amyloid beta peptides.
+ In vitro evidence for a common effector of pathogenesis in Alzheimer's disease. Wilson
+ DM, Binder LI. “We have discovered that free fatty acids (FFAs) stimulate the assembly of both amyloid
+ and tau filaments in vitro.” “Utilizing fluorescence spectroscopy, unsaturated FFAs were also
+ demonstrated to induce beta-amyloid assembly.” [These results] “...suggest that cortical
+ elevations of FFAs may constitute a unifying stimulatory event driving the formation of two of the
+ obvious pathogenetic lesions in Alzheimer's disease.”
+
+
+ Lab Invest. 2001 Apr; 81(4): 493-9. Transmission of mouse senile amyloidosis. Xing Y,
+ Nakamura A, Chiba T, Kogishi K, Matsushita T, Li F, Guo Z, Hosokawa M, Mori M, Higuchi K. “In mouse
+ senile amyloidosis, apolipoprotein A-II polymerizes into amyloid fibrils (AApoAII) and deposits
+ systemically. Peripheral injection of AApoAII fibrils into young mice induces systemic amyloidosis....”
+ “We isolated AApoAII amyloid fibrils from the livers of old R1.P1-Apoa2(c) mice and injected them with
+ feeding needles into the stomachs of young R1.P1-Apoa2(c) mice for 5 consecutive days. After 2 months,
+ all mice had AApoAII deposits in the lamina propria of the small intestine. Amyloid deposition extended
+ to the tongue, stomach, heart, and liver at 3 and 4 months after feeding. AApoAII suspended in drinking
+ water also induced amyloidosis.” “Amyloid deposition was induced in young mice reared in the same cage
+ for 3 months with old mice who had severe amyloidosis. Detection of AApoAII in feces of old mice and
+ induction of amyloidosis by the injection of an amyloid fraction of feces suggested the propagation of
+ amyloidosis by eating feces. Here, we substantiate the transmissibility of AApoAII amyloidosis and
+ present a possible pathogenesis of amyloidosis, ie, oral transmission of amyloid fibril conformation,
+ where we assert that exogenous amyloid fibrils act as templates and change the conformation of
+ endogenous amyloid protein to polymerize into amyloid fibrils.”
+
+
+
+
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+
+
+
+
+ Meat physiology, stress, and degenerative physiology The US Department of
+ Agriculture claims that the Pure Food and Drugs Act of 1906 and the Meat Inspection Act of the same year were
+ passed because the food industry demanded them. Ordinary historians believe that Upton Sinclair's 1905 serial
+ publication of his novel about the meat industry, The Jungle, caused the public and Theodore Roosevelt to
+ pressure Congress to pass the laws. Sinclair's descriptions of the use of poisonous preservatives and deodorants
+ to disguise the smell of rotten meat angered the public and the president enough to overcome the industry
+ pressure that had kept the US Congress from regulating the commercial food supply long after European
+ governments had begun regulating food production and sales.Before the government's intervention, it was common
+ practice to soak all kinds of meat in water or chemical solutions to increase their weight. At present, the US
+ Department of Agriculture, through the mass media and funding the training of food technologists and "meat
+ scientists," now takes the position that it is natural for meat to leak water after it is packaged, and says it
+ is perfectly legal for meat producers to soak the meat in water with chemicals until it has increased its weight
+ by 8%. The chemicals, such as trisodium phosphate (in a solution strength as high as 12%), are chosen because
+ they powerfully stimulate swelling and water retention. Considerable amounts of some chemicals, such as sodium
+ citrate, are allowed to add to the weight of the meat. The use of ozone and hydrogen peroxide to deodorize meat
+ causes instantaneous oxidative changes, including lipid peroxidation and protein carbonyl formation, as well as
+ increasing water retention.Most supermarket meat is now packaged with thick diapers so the buyer won't notice
+ that he is paying for a sizeable amount of pink water. The USDA has an internet site, and consumer hotlines, to
+ inform angry consumers that they are mistaken if they believe that meat shouldn't leak. They explain that meat
+ is now "bred" to contain less fat, and so it contains more water, and that it is simply the leanness of the meat
+ that accounts for its poor flavor.Before the slaughtered animal is put into the soaking solution to gain a
+ specific amount of weight, the animal has almost always been treated in ways that cause it to go to slaughter in
+ a state of massive edema. Even before the meat is soaked, the animal has been treated to maximize its water
+ retention.Muscle physiologists and endocrine physiologists know that fatigue, stress and excess estrogen can
+ cause the tissues to swell hugely, increasing their weight and water content without increasing their protein
+ content.As soon as cheap synthetic estrogens, such as DES, became available in the 1940s, their use in animals
+ was promoted because it was clear that they caused massive water retention. Women who suffer from
+ hyperestrogenism always have a problem with water retention, but they have never been known to suffer from
+ over-developed skeletal muscles. In fact, in humans of both sexes, an excess of estrogen has been commonly
+ associated with sarcopenia, muscular dystrophy, and atrophy of the skeletal muscles. Similar observations have
+ been made in a variety of animals. Meat scientists are the only people I know of who have ever referred to
+ estrogen as an anabolic steroid, in the sense of "building muscle."When it was publicized around 1970 that DES
+ is powerfully carcinogenic, after it had been used for several decades in the meat industry, its use was
+ outlawed, but its illegal use continued and was overlooked by the US government. The Swiss government has
+ rejected meat from a large producer in Kansas because it contained DES. Other estrogens are openly used, and the
+ US government continues to apply pressure to other countries to accept meat exports containing estrogens.There
+ are many ways to increase the water content of meat, besides feeding estrogen to the animal and soaking the meat
+ after slaughter. Everything that causes water retention and tissue swelling in the living animal, that is, every
+ kind of stress, fatigue, poisoning, malnutrition and injury, will make the animal gain weight, without consuming
+ expensive nutritious food. Crowding, fright, and other suffering increase water retention and accelerate the
+ breakdown of fats and proteins.The water content of meat shouldn't be increased by any of those methods, not
+ only because it is a form of stealing from the consumer, but because it makes the product toxic and
+ unappetizing, and makes the production process a degrading experience. Any chemicals, such as estrogen or
+ arsenic, that remain in the meat are of course harmful to the consumer, but the changes they produce in the
+ animals' tissues are the main problem. When grains and soybeans are used for fattening animals, their
+ characteristic fatty acids are present in the meat, and are harmful to the consumer, but their complex
+ degradation products, such as isoprene, acrolein, and isoprostanes, remain, along with the complex changes they
+ induce in every aspect of the tissue. The reactive products of oxidative fat degradation stimulate, among other
+ things, the adaptive/defensive production of polyamines, small molecules derived from amino acids. The
+ polyamines, in turn, can be oxidized, producing highly toxic aldehydes, including acrolein (Sakata, et al.,
+ 2003). These molecules stimulate cell multiplication, and alter, at least temporarily, the way the cell's genes
+ function.An excess of water stimulates cell division, and an important mechanism in producing that effect is the
+ increased production of polyamines by the enzyme ornithine decarboxylase. This enzyme is activated by an excess
+ of water (hypotonicity), by estrogen, and by stress.Besides stimulating cell division and modifying the cell's
+ state of differentiation (including developmental imprinting), the polyamines also contribute to nerve cell
+ excitation and excitotoxicity. Estrogen and excess water can contribute to nerve cell excitation, for example
+ producing convulsive seizures. The polyamines are increased during seizures, and they can affect the stability
+ of the nerve cells, for example contributing to cocaine's seizure-sensitizing action. Although they tend to
+ block free radicals, they accelerate nerve injury (Yatin, et al., 2001), and can contribute to breakdown of the
+ blood-brain barrier (Wengenack, et al., 2000, Koenig, et al., 1989).The polyamines are increased in cancers, and
+ therapies to block their formation are able to stop the growth of various cancers, including prostate, bowel,
+ and breast cancer. Metabolites of the polyamines in the urine appear to be useful as indicators of cancer and
+ other diseases. (In pancreatic cancer, Yamaguchi, et al., 2004; in cervical cancer, Lee, et al., 2003; in adult
+ respiratory stress syndrome, Heffner, et al., 1995.) The quantity of polyamines in the urine of cancer
+ patients has been reported to be 20 times higher than normal (Jiang, 1990). Polyamines in the red blood cells
+ appear to indicate prognosis in prostate cancer (Cipolla, et al., 1990).The prostaglandins in semen have been
+ suspected to have a role in producing cervical cancer (Fernandez, et al., 1995).In protein catabolism, one fate
+ of the protein's nitrogen is to be converted to the polyamines, rather than to urea. In plants, at least, these
+ small molecules help cells to balance osmotic stresses.Adding water to meat, or stressing the animals before
+ slaughter, will increase the meat's content of the polyamines, but the longer the meat is stored, the greater
+ will be the production of reactive oxygen products and polyamines. The deliberate "aging" of meat is
+ something that the meat scientists often write about, but it has a peculiar history, and is practiced mainly in
+ the English speaking cultures. When a supermarket in Mexico City began selling U.S.-style meat for the American
+ colony, I got some T-bone steaks and cooked them for some of my Mexican friends. The meat wasn't water-logged
+ (it was 1962, and the beef had been grown in Mexico), but it had been aged for the American customers, and
+ though my friends ate the steaks for the sake of politeness, I could see that they found it difficult. In
+ Mexico, even in the present century, butcher shops often don't have refrigeration, and they don't need it
+ because they sell the meat immediately. The fresh meat tastes fresh. Traditionally, liver is sold only on the
+ day of slaughter, because its high enzyme content causes it to degrade much faster than the muscle meats. When
+ it is fresh, it lacks the characteristic bad taste of liver in the US. Both the liver and the muscles
+ contain a significant amount of glycogen when they are fresh, if the animal was healthy. At first, the lack of
+ oxygen causes the glycogen to be metabolized into lactic acid, and some fatty acids are liberated from their
+ bound form, producing slight changes in the taste of the meat. But when the glycogen has been depleted, the
+ anaerobic metabolism accelerates the breakdown of proteins and amino acids.In the absence of oxygen, no carbon
+ dioxide is produced, and the result is that the normal disposition of ammonia from amino acids as urea is
+ blocked, and the polyamines are formed instead. The chemical names of two of the main poly-amines are suggestive
+ of the flavors that they impart to the aging meat: Cadaverine and putrescine. After two or three weeks of aging,
+ there has been extensive breakdown of proteins and fats, with the production of very complex new mixtures of
+ chemicals.Mexicans, despite their low average income, have a very high per capita consumption of meat, as do
+ several other Latin American countries. Argentina has a per capita meat consumption of nearly a pound a day.
+ There is a lot of theorizing about the role of meat in causing cancer, for example comparing Japan's low
+ mortality from prostate cancer, and their low meat consumption, with the high prostate cancer mortality in the
+ US, which has a higher meat consumption. But Argentina and Mexico's prostate cancer mortality ranks very
+ favorably with Japan's. If meat consumption in the US contributes to the very high cancer rate, it clearly
+ isn't the quantity of meat consumed, but rather the quality of the meat.The polar explorer Vilhjalmur Stefansson
+ was interested in the health effects of a diet based on meat, because of his observation that fresh meat
+ prevented scurvy much more effectively than the fruits and vegetables carried by other polar explorers. He
+ commented on the importance of culture and learning in shaping food preferences:"In midwinter it occurred to me
+ to philosophize that in our own and foreign lands taste for a mild cheese is somewhat plebeian; it is at least a
+ semi-truth that connoisseurs like their cheeses progressively stronger. The grading applies to meats, as in
+ England where it is common among nobility and gentry to like game and pheasant so high that the average
+ Midwestern American or even Englishman of a lower class, would call them rotten. "I knew of course that,
+ while it is good form to eat decayed milk products and decayed game, it is very bad form to eat decayed fish. I
+ knew also that the view of our populace that there are likely to be "ptomaines" in decaying fish and in the
+ plebeian meats; but it struck me as an improbable extension of the class-consciousness that ptomaines would
+ avoid the gentleman's food and attack that of a commoner. "These thoughts led to a summarizing query; If it
+ is almost a mark of social distinction to be able to eat strong cheeses with a straight face and smelly birds
+ with relish, why is it necessarily a low taste to be fond of decaying fish? On that basis of philosophy, though
+ with several qualms, I tried the rotten fish one day, and if memory serves, liked it better than my first taste
+ of Camembert. During the next weeks I became fond of rotten fish."Since Stefansson's observations nearly a
+ century ago, most Americans have become accustomed to the taste of half-spoiled meat, as part of the process of
+ adapting to an industrial-commercial food system. Tests done by food technologists have found that most
+ Americans prefer the taste of synthetic strawberry flavor in ice cream to the taste of ice cream made with real
+ strawberries. If it took Stefansson only a few weeks to become fond of rotten fish, it isn't surprising that the
+ public would, over a period of many decades, learn to enjoy a diet of stale foods and imitation
+ foods. Polyamines are increased in stressed and stored vegetables, as in aged meats. This defensive
+ reaction retards tissue aging, and researchers are testing the application of polyamines to fruits to retard
+ their ripening. A plastic surgeon, Vladimir Filatov, discovered that tissue stored in the cold stimulated the
+ healing process when used for tissue reconstruction, such as corneal transplants. He found that stressed plant
+ tissues developed the same tissue stimulants. Another pioneer of tissue transplantation, L.V. Polezhaev, saw
+ that degenerating tissue produced factors that seem to activate stem cells.Although the diffusion of these
+ stimulating factors from stressed tissues normally functions to accelerate healing and tissue regeneration,
+ under less optimal conditions they are undoubtedly important factors in tissue degeneration and tumor formation.
+ For example, the bystander effect (contributing to delayed radiation damage, and producing a field of
+ precancerous changes around a cancer), in which substances diffusing from injured tissues damage surrounding
+ cells, involves disturbances in polyamine metabolism.The direct, optimal effects of the polyamines are
+ protective, but when excessive, prolonged, or without maintained cellular energy, they become harmful.The
+ expression of genes involves their physical arrangement and accessibility to enzymes and substrates. The
+ negatively charged nucleic acids are associated with positively charge proteins, the histones. The very small
+ positively charged polyamines can powerfully modify the interactions between histones and DNA. In recent years
+ people have begun to speak of the "histone code," as a kind of expansion of the idea of the "genetic code." But
+ the polyamines, produced in response to stress, might be thought of as a complex expansion of the "histone
+ code."The addition of small molecules, methyl and acetyl groups, to the large molecules can regulate the
+ expression of genes, and these patterns can be passed on transgenerationally, or modified by stress. Barbara
+ McClintock's "controlling factors" were mobile genes that caused the genome to be restructured under the
+ influence of stress. Her discoveries were the same as those made by Trofim Lysenko decades earlier, and like his
+ observations, McClintock's were angrily rejected until the 1980s, when the genetic engineering industry needed
+ some scientific background and natural precedent for their unnatural intervention in the genome.The brain is
+ extremely different from a malignant tumor, and the derangements produced by stress, by high cortisol and
+ estrogen and an excess of water, are different in the two types of organ (considering the tumor as an ad hoc
+ organ), but the polyamines have central roles in the degenerating brain and in the divergent disorganization of
+ tumors. Their importance in stress physiology is coming to be recognized, along with the meaning of "epigenetic
+ development," in which the influence of the environment becomes central, rather than just a place in which the
+ "genotype" is allowed to passively express its "genetic potential." Every developmental decision involves an
+ evaluation of resources and their optimal marshaling for adaptation. The polyamines are part of the cytoplasm's
+ equipment for controlling the genome. The ratio between the different types of polyamine governs the nature of
+ their regulation of cellular functions.The old idea, "one is what one eats," has evolved far beyond ideas of
+ simple nutritional adequacy or deprivation, and it's now commonly accepted that many things in foods have fairly
+ direct effects on our brain transmitters and hormones, such as serotonin, dopamine, adrenalin, endorphins,
+ prostaglandins, and other chemicals that affect our behavior and physiology.In 1957 James McConnell discovered
+ that when flatworms were fed other flatworms that had been trained, their performance was improved by 50%,
+ compared with normal flatworms. Later, similar experiments were done with rats and fish, showing that tissue
+ extracts from trained animals modified the behavior of the untrained animals so that it approximated that of the
+ trained animals. Georges Ungar, who did many experiments with higher animals, demonstrated changes in brain RNA
+ associated with learning, and he and McConnell believed that proteins and peptides were likely to be the type of
+ substance that transmitted the learning.A dogmatic belief that "memory molecules" would be unable to penetrate
+ the "blood-brain barrier" allowed most biologists to dismiss their work. Ungar's death, and the hostility of
+ most biologists to their work, have caused their ideas to be nearly forgotten for the last 30 years. Negatively
+ charged molecules such as ordinary proteins tend to be repelled by negative charges on the wall of capillaries,
+ but positively charged molecules spontaneously associate with cellular proteins, and easily penetrate the
+ barrier. Highly positively charged molecules tend to concentrate in the brain (Jonkman, et al., 1983), and
+ people are currently attempting to use the principle to deliver antibodies (which are normally excluded from the
+ brain) therapeutically to the brain by combining them with small positively charged molecules (Herve, et al.,
+ 2001). This affinity of the brain for positively charged molecules is gradually being recognized as an important
+ factor in the toxicity of ammonia and guanidine derivatives. As mentioned earlier, even endogenous polyamines
+ can be involved in disruption of the blood-brain barrier.So, apart from the question of exactly what molecules
+ were responsible for the learning transfer produced by McConnell and Ungar, there should be no doubt that
+ polyamines derived from food can enter tissues, especially the brain. People who eat meat from stressed animals
+ are substantially replicating the experiments of McConnell and Ungar, except that people normally eat a variety
+ of foods, and each type of food will have had slightly different experiences in its last days of life. But the
+ deliberate aging of meat is subjecting it to a standardized stress--two or three weeks of cold storage. Because
+ of the great generality of genetic processes, it wouldn't be surprising if cold storage of vegetables turned out
+ to produce polyamine patterns similar to those of cold storage meats. Air pollution and other stressful growing
+ conditions cause vegetables to have very high levels of polyamines.Prolonged exposure to certain patterns of
+ polyamines might produce particular syndromes, but the mere fact of increasing the total quantity of polyamines
+ in our diet is likely to increase the incidence of stress-related diseases. Experiments with cells in culture
+ show that added polyamines can produce a variety of extremely harmful changes, but so far, there has been almost
+ no investigation of their specific regulatory functions, of their "code."Besides rejecting stale foods produced
+ under stressful conditions, there are probably some specific ways that we can protect ourselves from polyamine
+ poisoning.When the organism is functioning efficiently, its respiration is producing an abundance of carbon
+ dioxide, which protectively modifies many systems and structures. Adequate carbon dioxide protects against
+ fatigue, cellular and vascular leakiness, edema and swelling.Increasing carbon dioxide will tend to direct
+ ammonia into urea synthesis, and away from the formation of polyamines. Bicarbonate protects against many of the
+ toxic effects of ammonia, and since carbon dioxide spontaneously reacts with amino groups, it probably helps to
+ inactivate exogenous polyamines. This could account for some of the protective effects of carbon dioxide (or
+ high altitude), for example its anti-seizure, anticancer, and antistress effects.Other things that protect
+ against excessive polyamines are procaine and other local anesthetics (Yuspa, et al., 1980), magnesium, niacin,
+ vitamin A, aspirin, and, in some circumstances, caffeine. Since endotoxin stimulates the formation of
+ polyamines, a diet that doesn't irritate the intestine is important. Tryptophan and methionine contribute to the
+ formation of polyamines, so gelatin, which lacks those amino acids and is soothing to the intestine, should be a
+ regular part of the diet.Because the polyamines intensity the neurotoxic and carcinogenic effects of estrogen
+ and of polyunsaturated fats, those three types of substance should be considered as a functional unit in making
+ food choices. (Grass-fed organic beef fresh from a local farm would be a reasonable choice.) Unfortunately, the
+ meat industry has maximized all of those dangers, just for the increased weight of their
+ product. REFERENCES
Biull Eksp Biol Med 1993 Jun;115(6):600-2. Ornithine
+ decarboxylase and malignant growth. Berezov TT. Clin Cancer Res. 1999 Aug;5(8):2035-41. Prognostic value of
+ ornithine decarboxylase and polyamines in human breast cancer: correlation with clinicopathologic parameters.
+ Canizares F, Salinas J, de las Heras M, Diaz J, Tovar I, Martinez P, Penafiel R. J Clin
+ Gastroenterol. 1989 Aug;11(4):434-41. Intestinal autointoxication: a medical leitmotif. Chen TS, Chen PS. The
+ idea that putrefaction of the stools causes disease, i.e., intestinal autointoxication, originated with
+ physicians in ancient Egypt. They believed that a putrefactive principle associated with feces was absorbed in
+ to the general circulation, where it acted to produce fever and pus. This description of the materia peccans
+ represented the earliest forerunner of our present notion of endotoxin and its effect. The ancient Greeks
+ extended the concept of putrefaction to involve not only the residues of food, but also those of bile, phlegm,
+ and blood, incorporating it into their humoral theory of disease. During the 19th century, the early biochemical
+ and bacteriologic studies lent credence to the idea of ptomaine poisoning--that degradation of protein in the
+ colon by anerobic bacteria generated toxic amines. Among the leading proponents of autointoxication was
+ Metchnikoff, who hypothesized that intestinal toxins shortened lifespan. The toxic process, however, was
+ reversed by the consumption of lactic acid-producing bacteria that changed the colonic microflora and prevented
+ proteolysis. The next logical step in treatment followed in the early 20th century when surgeons, chief among
+ them Sir W. Arbuthnot Lane, performed colectomy to cure intestinal autointoxication. By the 1920s, the medical
+ doctrine fell into disrepute as scientific advances failed to give support. However, the idea persists in the
+ public mind, probably as an extension of the childhood habit of toilet training. Prog Urol.
+ 1992 Feb;2(1):50-7. [The diagnostic value of erythrocyte polyamines (EPA) in prostatic adenocarcinoma (PA):
+ apropos of 100 patients] [Article in French] Cipolla B, Guille F, Quemener V, Leveque JM, Moulinoux JP, Lobel
+ B.Arch Oral Biol. 2003 Apr;48(4):323-7. Time profile of putrescine, cadaverine, indole and skatole in human
+ saliva. Cooke M, Leeves N, White C.Hum Reprod. 2003 May;18(5):959-68. Nitric oxide inhibits polyamine-induced
+ apoptosis in the human extravillous trophoblast cell line SGHPL-4. Dash PR, Cartwright JE, Whitley
+ GS.Carcinogenesis. 1999 Mar;20(3):493-7. Promotion of intestinal carcinogenesis by dietary methionine. Duranton
+ B, Freund JN, Galluser M, Schleiffer R, Gosse F, Bergmann C, Hasselmann M, Raul F.Br J Cancer. 1995
+ Nov;72(5):1194-9. Evaluation of the significance of polyamines and their oxidases in the aetiology of human
+ cervical carcinoma. Fernandez C, Sharrard RM, Talbot M, Reed BD, Monks N.J Clin Pathol. 1991 May;44(5):410-5.
+ Seminal polyamines as agents of cervical carcinoma: production of aneuploidy in squamous epithelium. Fletcher S,
+ Neill WA, Norval M. The effects of several polyamines found in seminal fluid on the cell cycle and ploidy of
+ three cervical cell lines and of primary epithelial cells cultured from cervical biopsy specimens were monitored
+ by fluorescent flow cytometry. The rate of cell growth did not change but there were indications of either
+ hypodiploidy or hyperdiploidy in some cultures at certain concentrations of spermine and spermidine. An
+ interaction of exogenous polyamines with the DNA of cervical cells was shown to occur, leading to changes in
+ ploidy with, perhaps, the potential to induce or promote dysplasia.Biochem Biophys Res Commun. 1977 Jul
+ 11;77(1):57-64. Activation of thyroid ornithine decarboxylase (ODC) in vitro by hypotonicity; a possible
+ mechanism for ODC induction. Friedman Y, Park S, Levasseur S, Burke G.Anal Biochem. 1988 Oct;174(1):88-96.
+ Apparent ornithine decarboxylase activity, measured by 14CO2 trapping, after frozen storage of rat tissue and
+ rat tissue supernatants. Gaines DW, Friedman L, McCann PP. "Ornithine decarboxylase (ODC) activity of rat
+ tissues was measured by the standard 14CO2 trapping method after frozen storage (-60 or -70 degrees C) of the
+ tissues or their 105,000g supernatants." "In the frozen supernatants of liver and spleen, ODC activity changed
+ only slightly after 1 day but increased 29 and 14%, respectively, by 30 days; activity in kidney supernatant
+ decreased 17% after 1 day and remained near that level at 30 days." "With AOA, the ODC activities of the fresh
+ and frozen supernatants were similar, indicating that the large increase in apparent ODC activity in frozen
+ tissue was due to artifacts from the metabolism of ornithine via the mitochondrial pathway. HPLC analysis of the
+ reaction products resulting from the incubation of uniformly labeled [14C]ornithine with the fresh and frozen
+ preparations indicated no increase in putrescine with the frozen preparation."J Dent Res. 1994
+ Jun;73(6):1168-72. Cadaverine as a putative component of oral malodor. Goldberg S, Kozlovsky A, Gordon D,
+ Gelernter I, Sintov A, Rosenberg M.Exp Neurol. 2002 Oct;177(2):515-20. Increased red blood cell polyamines
+ in ALS and Parkinson's disease. Gomes-Trolin C, Nygren I, Aquilonius SM, Askmark H.THE DAILY CITIZEN, April 5,
+ 1994. Robert Greene, "Soggy Chickens," AP, April 2, 1994; "Interview with Elaine Dodge," "The chickens soak up
+ to 12 percent of their weight in this water," according to Elaine Dodge of the Government Accountability Project
+ (GAP). J Anim Sci. 2004 May;82(5):1401-9. Preslaughter stress and muscle energy largely determine pork
+ quality at two commercial processing plants. Hambrecht E, Eissen JJ, Nooijent RI, Ducro BJ, Smits CH, den Hartog
+ LA, Verstegen MW.Exp Lung Res. 1995 Mar-Apr;21(2):275-86. Urinary excretion of polyamines in the adult
+ respiratory distress syndrome. Heffner JE, Ali R, Jeevanandam M.Kumamoto Igakkai Zasshi. 1969 Aug
+ 25;43(8):661-80. [Studies on relationship between progressive muscular dystrophy and estrogen] [Article in
+ Japanese] Ideta T.Biomed Chromatogr. 1990 Mar;4(2):73-7. Determination of polyamines in urine of normal human
+ and cancer patients by capillary gas chromatography. Jiang XC.Int J Biochem. 1990;22(1):67-73. Mitogenic
+ induction of ornithine decarboxylase in human mononuclear leukocytes: relationships with adenosine diphosphate
+ ribosyltransferase. Johnson DB, Markowitz MM, Joseph PE, Miller DG, Pero RW. "Inhibitors of ADPRT, nicotinamide,
+ caffeine and benzamide inhibited the induction of ODC by PHA in a concentration-dependent manner, in the range
+ (0.6-10 mM) known to inhibit ADPRT."Arzneimittelforschung. 1983;33(2):223-8. Whole body distribution of the
+ quaternary ammonium compound thiazinamium (N-methylpromethazine) and promethazine in monkey and mice. Jonkman
+ JH, Westenberg HG, Rijntjes NV, van der Kleijn E, Lindeboom SF.J Neurochem. 1989 Jan;52(1):101-9. Blood-brain
+ barrier breakdown in cold-injured brain is linked to a biphasic stimulation of ornithine decarboxylase activity
+ and polyamine synthesis: both are coordinately inhibited by verapamil, dexamethasone, and aspirin. Koenig H,
+ Goldstone AD, Lu CY. Neurology Service, V.A.Cancer Treat Rep. 1985 Jan;69(1):97-103. Enhancement of the
+ antiproliferative activity of human interferon by polyamine depletion. Kovach JS, Svingen PA.Cancer Res. 2001
+ Nov 1;61(21):7754-62. Polyamine depletion in human melanoma cells leads to G1 arrest associated with induction
+ of p21WAF1/CIP1/SDI1, changes in the expression of p21-regulated genes, and a senescence-like phenotype. Kramer
+ DL, Chang BD, Chen Y, Diegelman P, Alm K, Black AR, Roninson IB, Porter CW.Endokrinologie. 1982 Nov;80(3):294-8.
+ The effect of androgen and estrogen on food intake and body weight in rats--age dependency. Kuchar S, Mozes S,
+ Boda K, Koppel J.Endokrinologie. 1982 Nov;80(3):294-8. The effect of androgen and estrogen on food intake and
+ body weight in rats--age dependency. Kuchar S, Mozes S, Boda K, Koppel J. Cancer Lett. 2003 Nov
+ 25;201(2):121-31. Altered urinary profiles of polyamines and endogenous steroids in patients with benign
+ cervical disease and cervical cancer. Lee SH, Yang YJ, Kim KM, Chung BC.Oncol Res. 2005;15(3):113-28. Activation
+ of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells: a mechanism involving the p38 MAP kinase
+ and phosphorylation of ATF-2. Lewis JS, Vijayanathan V, Thomas TJ, Pestell RG, Albanese C, Gallo MA, Thomas
+ T.Nucleic Acids Res. 2005 Mar 23;33(6):1790-803. Print 2005. Polyamines preferentially interact with bent
+ adenine tracts in double-stranded DNA. Lindemose S, Nielsen PE, Mollegaard NE. "Polyamines, such as putrescine,
+ spermidine and spermine, have indirectly been linked with the regulation of gene expression, and their
+ concentrations are typically increased in cancer cells." "These results provide the first clear evidence for the
+ sequence-specific binding of polyamines to DNA, and thereby suggest a mechanism by which the cellular effects of
+ polyamines in terms of differential gene transcriptional activity could, at least partly, be a direct
+ consequence of sequence-specific interactions of polyamines with promoters at the DNA sequence level."Eur J
+ Biochem. 1995 Jul 1;231(1):40-4. Regulation of mammalian ornithine decarboxylase. Studies on the induction of
+ the enzyme by hypotonic stress. Lovkvist-Wallstrom E, Stjernborg-Ulvsback L, Scheffler IE, Persson
+ L.Gastroenterol Clin North Am 1988 Dec;17(4):931-40. Biochemical markers in colorectal cancer: diagnostic and
+ therapeutic implications. Luk GD, Desai TK, Conteas CN, Moshier JA, Silverman AL . Proc Natl Acad Sci
+ U S A. 2003 Jun 24;100(13):7859-64. Pronounced reduction in adenoma recurrence associated with aspirin use and a
+ polymorphism in the ornithine decarboxylase gene. Martinez ME, O'Brien TG, Fultz KE, Babbar N, Yerushalmi H, Qu
+ N, Guo Y, Boorman D, Einspahr J, Alberts DS, Gerner EW.Biochem J. 1998 Feb 1;329 ( Pt 3):453-9. Osmotic stress
+ induces variation in cellular levels of ornithine decarboxylase-antizyme. Mitchell JL, Judd GG, Leyser A, Choe
+ C.Arch Biochem Biophys. 1964 Apr;105:209-10. Occurrence of polyamines in the germs of cereals. Moruzzi G,
+ Caldarera CM.Br J Ophthalmol. 2003 Aug;87(8):1038-42. Vitreous polyamines spermidine, putrescine, and spermine
+ in human proliferative disorders of the retina. Nicoletti R, Venza I, Ceci G, Visalli M, Teti D, Reibaldi
+ A.Carcinogenesis. 1997 Oct;18(10):1871-5. Dietary polyamines promote the growth of azoxymethane-induced aberrant
+ crypt foci in rat colon. Paulsen JE, Reistad R, Eliassen KA, Sjaastad OV, Alexander J.Eur J Cancer. 1996
+ Feb;32A(2):316-21. Red blood cell polyamines, anaemia and tumour growth in the rat. Quemener V, Bansard JY,
+ Delamaire M, Roth S, Havouis R, Desury D, Moulinoux JP.Anticancer Res 1994 Mar-Apr;14(2A):443-8. Polyamine
+ deprivation: a new tool in cancer treatment. Quemener V, Blanchard Y, Chamaillard L, Havouis R, Cipolla B,
+ Moulinoux JP.J Anim Sci 1995 Jul;73(7):1982-6.Effects of ground flaxseed in swine diets on pig performance
+ and on physical and sensory characteristics and omega-3 fatty acid content of pork: I. Dietary level of
+ flaxseed. Romans JR, Johnson RC, Wulf DM, Libal GW, Costello WJ.J Anim Sci 1995 Jul;73(7):1987-99. Effects
+ of ground flaxseed in swine diets on pig performance and on physical and sensory characteristics and omega-3
+ fatty acid content of pork: II. Duration of 15% dietary flaxseed. Romans JR, Wulf DM, Johnson RC, Libal GW,
+ Costello WJ.J Clin Invest. 1972 May;51(5):1118-24. Metabolic effects of human growth hormone and of estrogens in
+ boys with Duchenne muscular dystrophy. Rudman D, Chyatte SB, Patterson JH, Gerron GG, O'Beirne I, Barlow J,
+ Jordan A, Shavin JS.Biochem Biophys Res Commun. 2003 May 23;305(1):143-9. Increase in putrescine, amine oxidase,
+ and acrolein in plasma of renal failure patients. Sakata K, Kashiwagi K, Sharmin S, Ueda S, Irie Y, Murotani N,
+ Igarashi K.Biochem Soc Trans. 2003 Apr;31(2):375-80. Polyamines and prostatic cancer. Schipper RG, Romijn JC,
+ Cuijpers VM, Verhofstad AA.Nitric Oxide. 2000 Dec;4(6):583-9. Nitric oxide synthase inhibition promotes
+ carcinogen-induced preneoplastic changes in the colon of rats. Schleiffer R, Duranton B, Gosse F, Bergmann C,
+ Raul F. "l-Arginine is metabolized either to polyamines through arginase and ornithine decarboxylase (ODC)
+ activities or to citrulline and nitric oxide (NO, nitrogen monoxide) through the NO synthase (NOS) pathway.
+ Polyamine levels and ODC activity are high in tumor cells. The aim of this study was to test whether
+ N(G)-nitro-l-arginine methyl ester (l-NAME), an inhibitor of NOS, modulates colon carcinogenesis." "In
+ l-NAME-treated rats, the number of ACF was higher than in controls by 47%. ODC activity was enhanced by 11-fold.
+ S-Adenosyl-methionine-decarboxylase activity and putrescine concentration were significantly increased in the
+ colonic mucosa of l-NAME-treated rats. The data suggest that l-NAME promotes carcinogen-induced preneoplastic
+ changes in the colon by inhibiting NOS activity and by stimulating polyamine biosynthesis."Brain Res. 1997 Nov
+ 14;775(1-2):198-202. Role of cerebral spermidine in the development of sensitization to convulsant activity of
+ cocaine and lidocaine. Shimosato K, Watanabe S, Katsura M, Ohkuma S.Melanoma Res. 1994 Aug;4(4):213-23. Cellular
+ pathways leading to melanoma differentiation: therapeutic implications. Soballe PW, Herlyn M.Rev Can Biol. 1959
+ Apr;18(1):23-52. Studies on the mechanism of the catabolic action of estrogens. Sternberg J, Pascoe-Dawson E.http://www.fsis.usda.gov/wps/portal/fsis/topics/food-safety-education/get-answers/food-safety-fact-sheets/meat-preparation/water-in-meat-and-poultry/CT_IndexJ Neurol Sci. 1989 Feb;89(2-3):189-97. Hyperestrogenemia in neuromuscular diseases. Usuki F, Nakazato O, Osame
+ M, Igata A. Rinsho Shinkeigaku. 1985 Jun;25(6):711-5. [Hyperestrogenemia in Duchenne muscular
+ dystrophy (DMD)] [Article in Japanese] Usuki F, Nakazato O, Osame M, Igata A.Neurosci Lett. 2001 Aug
+ 17;309(1):62-6. Increase of the ornithine decarboxylase/polyamine system and transglutaminase upregulation in
+ the spinal cord of aged rats. Virgili M, Necchi D, Scherini E, Contestabile A.Nat Biotechnol. 2000
+ Aug;18(8):868-72. Targeting alzheimer amyloid plaques in vivo. Wengenack TM, Curran GL, Poduslo JF.Rinsho Byori.
+ 2004 Apr;52(4):336-9. [Urine diacetylspermine as a novel tumor marker for pancreatobiliary carcinomas] [Article
+ in Japanese] Yamaguchi K, Nagano M, Torada N, Hamasaki N, Kawakita M, Tanaka M.J Neurosci Res. 2001 Mar
+ 1;63(5):395-401. Role of spermine in amyloid beta-peptide-associated free radical-induced neurotoxicity. Yatin
+ SM, Yatin M, Varadarajan S, Ain KB, Butterfield DA.Mol Endocrinol. 2003 May;17(5):831-44. Epub 2003 Jan 23.
+ Estrogen enhances depolarization-induced glutamate release through activation of phosphatidylinositol 3-kinase
+ and mitogen-activated protein kinase in cultured hippocampal neurons. Yokomaku D, Numakawa T, Numakawa Y, Suzuki
+ S, Matsumoto T, Adachi N, Nishio C, Taguchi T, Hatanaka H.Poult Sci. 2004 Mar;83(3):400-5. Water-holding
+ capacity in chicken breast muscle is enhanced by pyruvate and reduced by creatine supplements. Young JF,
+ Karlsson AH, Henckel P. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5312-6. Local anesthetics inhibit
+ induction of ornithine decarboxylase by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate. Yuspa SH,
+ Lichti U, Ben T. Exp Oncol. 2004 Sep;26(3):221-5. Role of polyamines in the function of nuclear
+ transcription factor NF-kappaB in breast cancer cells. Zaletok S, Alexandrova N, Berdynskykh N, Ignatenko N,
+ Gogol S, Orlovsky O, Tregubova N, Gerner E, Chekhun V.Arkh Patol 1995 Jul-Aug;57(4):89-92. Biological markers of
+ precancer of the large intestine. Zagrebin VM. © Ray Peat Ph.D. 2014. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Membranes, plasma membranes, and surfaces
+
+
+ Membranes, plasma membranes, and surfaces
+
+
+
+
+
+
+
+ The "essential fatty acids":
+
+
+ Suppress metabolism and promote obesity; are immunosuppressive; cause inflammation and shock; are required
+ for alcoholic liver cirrhosis; sensitize to radiation damage; accelerate formation of aging pigment,
+ cataracts, retinal degeneration; promote free radical damage and excitoxicity; cause cancer and accelerate
+ its growth; are toxic to the heart muscle and promote atherosclerosis; can cause brain edema, diabetes,
+ excessive vascular permeability, precocious puberty, progesterone deficiency....
+
+
+
+
+
+
+ Twice, editors have printed my articles on unsaturated fats, with adjoining "rebuttals," but I was
+ disappointed that all of my points were ignored, as if you could rebut an argument by just saying that you
+ emphatically disagree with it. I think it is evident that those people don't know what would be involved in
+ refuting an argument. They are annoyed that I have bothered them with some evidence, but not sufficiently
+ annoyed to cause them to try to marshal some evidence against my arguments.
+
+
+ Marketing and medical claims are intertwined with a view of life that permeates our culture. I am aware that
+ my criticism of the doctrine of the essentiality of linoleic acid threatens the large profits of many
+ people, and threatens the prestige of the most popular "theory of cell structure," but I think it is
+ important to point out that nutritional and medical advice depend on the truth of the theory of cell
+ structure and function which supports that advice, and so it is reasonable to see how sound that theory is.
+
+
+ As I understand it, the doctrine of the "essential fatty acids" goes this way:
+
+
+ 1. They are essential because they are required for making cell membranes and prostaglandins.
+
+
+ 2. Rats deprived of the unsaturated fatty acids develop a skin disease, and "lose water" through the skin.
+
+
+ 3. Human skin diseases (etc.) can be cured with polyunsaturated fats.
+
+
+ In fact, rats may get a skin disease when fed a fat-free diet, but the observation that vitamin B6 cures it
+ should have laid to rest the issue of the dietary essentiality of the polyunsaturated oils more than 50
+ years ago. Scientifically, it did, but forces greater than science have revivified the monster. Experiments
+ that confirm the disproof are done periodically--animals living generation after generation without
+ unsaturated oils in their diet or any evidence of harm, human cells growing in culture-dishes without
+ polyunsaturated fats, for example--without noticeable effect on the doctrine, which is perpetuated in many
+ effective, nonscientific ways--textbooks, advertisements, college courses, for example.
+
+
+ Now, instead of demonstrating harm from a dietary lack of the "essential" fats, the presence of the Mead
+ acid or omega-9 fatty acids is taken as evidence of a deficiency. Our cells (and animal cells) produce these
+ unsaturated fats when their special desaturase enzymes are not suppressed by the presence of exogenous
+ linoleic or linolenic acids. Normally, the inactivation of an enzyme system and the suppression of a natural
+ biological process might be taken as evidence of toxicity of the vegetable oils, but here, the occurrence of
+ the natural process is taken as evidence of a deficiency. To me, this seems very much like the "disease" of
+ having tonsils, an appendix, or a foreskin--if it is there, you have a problem, according to the aggressive
+ surgical mentality. But what is the "problem" in the case of the natural Mead or omega-9 acids? (I think the
+ "problem" is simply that they allow us to live at a higher energy level, with greater resistance to stress,
+ better immunity, and quicker healing.)
+
+
+
+ There have been arguments based on "membranes" and on prostaglandins. The absence of "good" prostaglandins
+ would seem to be an obvious problem, except that the "good" prostaglandins always turn out to have some
+ seriously bad effects when examined in other contexts. Animals that lack dietary unsaturated fats appear to
+ escape most of the problems that are associated with prostaglandins, and I think this means that many of the
+ toxic effects of the unsaturated vegetable oils result from the quantity and type of
+ "eicosanoid"/lipoxygenase products made from them.
+
+
+ One type of membrane argument had to do with the fragility of red blood cells, reasoning, apparently, that
+ the cells are "held together" by a lipid bilayer membrane. (Just what is the tensile strength of a lipid
+ bilayer? Why do fatty acids or saponins weaken blood cells, instead of reinforcing them? If the "tensile
+ strength" of a lipid layer exists, and is positive rather than negative, it is negligible in relation to the
+ tensile strength of the cytoplasm.) Another type of :"membrane" argument was that the mitochondria are
+ abnormal when animals don't get the essential fatty acids in their diet, because the mitochondria are
+ supposed to be essentially membranous structures containing the essential fatty acids. (Actually, the
+ deficient mitochondria produce more ATP than do mitochondria from animals fed the vegetable oils.) Another
+ argument is that "membrane fluidity" is a good thing, and that unsaturated essential fatty acids make the
+ membranes more fluid and thus better--by analogy with their lower bulk-phase melting temperature. (But the
+ measure of fluidity is a very limited thing on the molecular level, and this fluidity may be associated with
+ decreased cellular function, instead of the postulated increase.)
+
+
+ The most addled sort of argument about "membranes" is that animals on the diet lacking polyunsaturated oils
+ have skin that is unable to retain water because of "defective cell membranes." The skin's actual barrier
+ function is the result of mulptile layers of keratinized ("cornified," horny) cells, which have become
+ specialized by their massive production of the protein keratin--very much as red blood cells become
+ specialized by producing the protein, hemoglobin. Since these cells lose most of their water as they become
+ horny, the issue of whether they still have a "plasma membrane" seems to have little interest to
+ researchers; the same can be said regarding the cells of hair and nails. After the epidermal cells have
+ become keratinized and inert, the sebaceous glands in the skin secrete oils, which are absorbed by the
+ dense, proteinaceous cells, causing increased resistance to water absorption. The ideas of a plasma membrane
+ on the cell, and of the water-barrier function of the skin, are two distinct things, that have been blurred
+ together in a thoughtless way. It has been suggested that vitamin B6 cures the characteristic skin disorder
+ of a vitamin B6 deficiency by altering fat metabolism, but the vitamin is involved in cell division and many
+ other processes that affect the skin.
+
+
+
+ Given the fact that the "essential" oils aren't essential for the growth of cells, they can't be essential
+ for making plasma membranes (if cells must have plasma membranes), or mitochondrial membranes, or any kind
+ of membrane, but as long as there is the idea that fats mainly have the function of building membranes,
+ someone is going to argue that membranes containing vegetable oils are more fluid, or more youthful, or more
+ sensitive, or better in some way than those containing Mead acids, palmitic acid, oleic acid, stearic acid,
+ etc.
+
+
+ For over a century, people have suggested that cells are enclosed in an oily membrane, because there are
+ higher or lower concentrations of many water-soluble substances inside cells, than in the blood, lymph, and
+ other extracellular fluids, and the idea of a membrane was invoked (W. Pfeffer, 1877; E. Overton, 1895,
+ 1902) to explain how that difference can persist. (By 1904, the idea of a membrane largely made of lecithin
+ was made ludicrous by A. Nathansohn's observation that water-soaked lecithin loses its oily property, and
+ becomes very hydrophilic; the membrane was supposed to exclude water-soluble molecules while admitting
+ oil-soluble molecules.)
+
+
+ Inside the cell membrane, the cell substance was seen as a watery solution. Biochemistry, as a profession,
+ was strongly based on the assumption that, when a tissue is ground up in water, the dilute extract closely
+ reflects the conditions that existed in the living cell. Around 1970, when I tried to talk to biochemists
+ about ways to study the chemistry of cells that would more closely reflected the living state, a typical
+ response was that the idea was ridiculous, because it questioned the existence of biochemistry itself as a
+ meaningful science.. But since then, there has been a progressive recognition that organization is more
+ important in the life of a cell than had been recognized by traditional biochemistry. Still, many
+ biochemists thoughtlessly identify the chemistry of the living cell with their study of the water-soluble
+ enzymes, and relegate the insoluble residue of the cell to "membrane-associated proteins" or, less
+ traditionally, to "structural proteins." It has been several decades since the structural/contractile
+ protein of muscle was found to be an enzyme, an ATPase, but the idea that the cell itself is a sort of
+ watery solution, in which the water-soluble enzymes float, randomly mingling with dissolved salts, sugars,
+ etc., persists, and makes the idea of a semipermeable membrane seem necessary, to separate a "watery
+ internal phase" from the watery external phase. Physical chemists have no trouble with the fact that a moist
+ protein can absorb oil as well as water, and the concept that even water-soluble enzymes have oil-loving
+ interiors is well established. If that physical-chemical information had existed in Overton's time, there
+ would have been no urge to postulate an oily membrane around cells, to allow substances to pass into them,
+ in proportion to their solubility in oil.
+
+
+ Because biochemists like to study their enzymes in watery test-tube solutions, they find it easy to think of
+ the cell-substance as a watery solution. With that belief, it is natural that they prefer to think of the
+ primeval ocean as where life originated. Their definitions of chemical reactions and equilibria in the
+ water-phase (and by extension in cells) ignore the alternative reactions and equilibria that would occur in
+ an environment in which ordinary water was not the dominant medium. By this failure to consider the
+ alternatives, they have created some problems that are hard to explain. For example, the polymerization of
+ amino acids into protein is energetically expensive in water, but it is spontaneous in a relatively dry
+ environment, and this spontaneous reaction creates non-random structures with the capacity for building
+ larger structures, with stainable bilayer "membranes," and with catalytic action. (Sidney Fox, 1965, 1973.)
+ Similarly, the problem of ATP synthesis essentially disappears when it is considered in an environment that
+ controls water. The scientific basis for the origin of life in a "primeval soup" never really existed, and
+ more people are now expressing their scepticism. However, biochemists have their commitments:
+
+
+ "In the course of biological evolution, one of the first developments must have been an oily membrane that
+ enclosed the water-soluble molecules of the primitive cell, segregating them and allowing them to accumulate
+ to relatively high concentrations. The molecules and ions contained within a living organism differ in kind
+ and in concentration from those in the organism's surrounding." (Principles of Biochemistry, supposedly by
+ Lehninger, Nelson, and Cox, though Lehninger is dead and I think his name is attached to it to exploit his
+ fame.# Worth Publishers, 1993.)
+
+
+
+ Hair is composed of thoroughly dead cells, but if it is washed until it contains no sodium or potassium, and
+ then dipped in serum, or a solution of sodium and potassium, it takes up much more potassium than sodium, in
+ the way a living cell does, concentrating potassium "against the gradient." That is the sort of behavior
+ that led to the postulation of a plasma membrane, to maintain the organization that was created by expending
+ energy. "Membrane pumps" use energy, supposedly, to establish the concentration difference, and the barrier
+ membrane keeps the solutes from diffusing away. The lipid bilayer membrane was an early guess, and the pumps
+ were added later, as needed. Gilbert Ling reviewed the published studies on the various "membrane pumps,"
+ and found that the energy needed to operate them was 15 times greater than all the energy the cell could
+ possibly produce.
+
+
+ Water softeners contain an ion-exchange resin, that uses the same principle hair does to concentrate ions,
+ which is simply a selectivity based on the acidity of the resin, and the size of the ion. The resin binds
+ calcium more strongly than it binds sodium, and so the water gives up its calcium in exchange for sodium.*
+ Gilbert Ling devised many experiments that demonstrated the passivity of ion-accumulation by living cells.
+
+
+ Usually, cells are surrounded by and imbedded in materials that they have secreted, and their surfaces are
+ often covered with materials that, while remaining anchored to the cell, have a considerable affinity for
+ water. Physically, many of the molecules attached to cells are "surfactants," making the cell wettable,
+ though it isn't customary to describe them as such. The glycoproteins that give cells their characteristic
+ immunological properties are among these materials. At a certain point, there is a transition between the
+ "outside" of the cell, which is relatively passive and water-friendly, and the cell itself, in which water
+ is subordinated to the special conditions of the cell. (The postulated lipid bilayer membrane, in contrast,
+ has two phase discontinuities, one where it meets the cytoplasm, another where it meets the outside world.)
+ At this phase boundary, between two different substances, it is normal to find an electrical potential
+ difference. When two electrically different substances are in contact, it isn't surprising to find an
+ electrical double-layer at the surface. This is a passive process, which doesn't take any energy to
+ maintain, but it can account for specific arrangements of molecules in the region of the phase boundary,
+ since they are exposed to the electrical force of the electrical double-layer. That is to say that in a
+ completely inert and homogeneous substance, a "surface structure" will be generated, as a result of the
+ electrical difference between that substance and the adjoining substance. (This surface structure, if it is
+ to be described as a membrane, must be called a "wet membrane," while the lipid bilayer would be a "dry
+ membrane," since exclusion of water is its reason for existing.) Too many biologists still talk about
+ "electrogenic membrane pumps," indicating that they haven't assimilated the results of Gilbert Ling's
+ research.
+
+
+
+ To say it another way, there are several kinds of physical process that will govern the behavior of fats,
+ and fats of different types will interact in different ways with their environments. They interact complexly
+ with their environment, serving in many cases as regulatory signal-substances. To describe their role as
+ "membranes" is worse than useless.
+
+
+ Cells can be treated with solvents to remove practically all fats, yet the cells can still show their
+ characteristic membranes: Plasma membrane, mitochondrial membranes, even the myelin figures. The proteins
+ that remain after the extraction of the fats appear to govern the structure of the cell.
+
+
+ A small drop of water can float for a moment on the surface of water; this is explained in terms of the
+ organization of the water molecules near the surface. No membrane is needed to explain this reluctance to
+ coalesce, even though water has a very high affinity for water.
+
+
+ People believed in the "lipid bilayer membrane" for decades before the electron microscope was able to
+ produce an image that could be said to correspond to that theoretical structure. Osmic acid, which is
+ believed to stain fats, does produce a double layer at the surface of cells. However, the arrangement of fat
+ molecules in the lipid bilayer is such that the fatty tails of the two layers are touching each other, while
+ their acidic heads are pointed away from each other. A lipid bilayer, in other words, contains a single zone
+ of fat, bounded by two layers of acid. The "fat-staining" property of osmic acid, then, argues against the
+ lipid bilayer structure.
+
+
+
+ Osmic acid is very easily reduced electrically, forming a black product. Proteins with their sulfur
+ molecules in a reduced state, for example, would cause an osmium compound to be deposited, and the
+ appearance of two layers of osmium at the cell's phase boundary would be compatible with the idea of an
+ electrical double-layer, induced in proteins.
+
+
+ Electrically charged proteins, which are able to interact with glutathione to increase or decrease their
+ degree of reduction/electrical charge, distributed throughout the cytoplasm, would explain another feature
+ of osmic acid staining, which is incompatible with the "fat-staining" concept. Asphyxia increases the
+ stainability of cells with osmic acid, and this change seems to represent the availability of electrons,
+ rather than the distribution of fats, since the change can appear within 3 minutes. (C. Peracchia and J. D.
+ Robertson, "Increase in osmiophilia of axonal membranes of crayfish as a result of electrical
+ stimulation, asphyxia, or treatment with reducing agents," J. Cell Biol. 51, 223, 1971; N. N.
+ Bogolepov, Ultrastructure of the Brain in Hypoxia, Mir, Moscow, 1983) The amino groups of proteins might
+ also be stained by osmic acid, though asphyxia would more directly affect the disulfide groups. The
+ increased staining with silver in asphyxia similarly suggests an increase in sulfhydryls.
+
+
+ Freezing cells, and then fracturing them and coating the fragments with metal or carbon is often used to
+ "demonstrate the lipid bilayer," so it is interesting that the osmium compound that "reveals" the
+ lipid bilayer for the electron microscope destroys the apparent membrane in the freezing
+ technique. (R. James and D. Branton, "The correlation between the saturation of membrane fatty
+ acids and the presence of membrane fracture faces after osmium fixation," Biochim. Biophys. Acta 233,
+ 504-512, 1971; M. V. Nermut and B. J. Ward, "Effect of fixatives on fracture plane in red blood
+ cells," J. Microsc. 102, 29-39, 1974.)
+
+
+ So, when someone says "we need the essential fatty acids to make cell membranes," my response is likely to
+ be "no, we don't, and life probably originated on hot lava and has never needed lipid membranes."
+
+
+
+ On the third argument, that vegetable oils can be used therapeutically, I am likely to say yes, they do have
+ some drug-like actions, for example, linseed oil has been used as a purgative, but as with any drug you
+ should make sure that the side effects are going to be acceptable to you. Currently, it is popular to
+ recommend polyunsaturated oils to treat eczema and psoriasis. These oils are immunosuppressive, so it is
+ reasonable to think that there might be some pleasant consequences if a certain immunological process is
+ suppressed, but they are also intimately involved with inflammation, sensitivity to ultraviolet light, and
+ many other undesirable things. The traditional use of coal tar and ultraviolet light was helpful in
+ suppressing eczema and psoriasis, but its tendency to cause cancer has led many people to forego its
+ benefits to protect their health.
+
+
+ If you want to use a polyunsaturated oil as a drug, it is worthwhile to remember that the "essential fatty
+ acids" suppress metabolism and promote obesity; are immunosuppressive; cause inflammation and shock; are
+ required for alcoholic liver cirrhosis; sensitize to radiation damage; accelerate formation of aging
+ pigment, cataracts, retinal degeneration; promote free radical damage and excitoxicity; cause cancer and
+ accelerate its growth; are toxic to the heart muscle and promote atherosclerosis; can cause brain edema,
+ diabetes, excessive vascular permeability, precocious puberty, progesterone deficiency, skin wrinkling and
+ other signs of aging.
+
+
+ Whether any of the claimed pharmaceutical uses of the polyunsaturated oils, besides purgation, turn out to
+ be scientifically valid remains to be seen. The theoretical bases often used to back up the claimed benefits
+ are confused or false, or both.
+
+
+ People who are willing to question the validity of an "orthodox method," such as the glass microelectrode,
+ are in a position to make observations that were "forbidden" by the method and its surrounding ideology.
+ (See Davis, et al., 1970.) Their perception is freed in ways that could lead to new understanding and
+ practical solutions to old problems.
+
+
+
+ But sometimes experiments seem to be designed as advertising, rather than science. Recent studies of the
+ effects of fish oils on night vision or development of the retina, for example, seem to forget that fish oil
+ contains vitamin A, and that vitamin A has the effects that are being ascribed to the unsaturated fatty
+ acids.
+
+
+ With the financial cutbacks in university libraries, there is a risk that the giant seed-oil organizations
+ will succeed in using governmental power to regulate the alternative communication of scientific
+ information, allowing them to control both public and "scientific" opinion more completely than they do now.
+
+
+
+ ADDITIONAL REFERENCES
+
+
+
+ Gilbert N. Ling, A Revolution in the Physiology of the Living Cell, Krieger Publ., Melbourne, Florida, 1993.
+
+
+
+ G. N. Ling, "A new model for the living cell: A summary of the theory and experimental evidence for its
+ support," Int. Rev. Cytol. 26, 1, 1969.
+
+
+ G. N. Ling, A Physical Theory of the Living State, Blaisdell, New York, 1960.
+
+
+ S. W. Fox, Nature 205, 328, 1965; Naturwissenschaften 60, 359, 1973.
+
+
+ S. W. Fox and K. Dose, Molecular Evolution and the Origin of Life, Marcel Dekker, New York, 1977.
+
+
+ S. Fleischer, B. Fleischer, and W. Stoeckenius, J. Cell Ciol. 32, 193, 1967.
+
+
+
+ H. J. Morowitz and T. M. Terry, Biochem. Biophys. Acta 183, 276, 1969.
+
+
+ L. Napolitano, F. Le Baron, and J. Scaletti, J. Cell Biol. 34, 817, 1967.
+
+
+ F. W. Cope and R. Damadian, "Biological ion exchanger resins: IV. Evidence for potassium association with
+ fixed charges in muscle and brain by pulsed NMR of 39K," Physiol. Chem. Phys. 6, 17, 1974.
+
+
+ R. Damadian, "Biological ion exchanger resins. III. Molecular interpretations of cellular ion exchange,"
+ Biophys. J. 11, 773, 1971.
+
+
+
+ R. Damadian, "Biological ion exchanger resins," Ann. NY Acad. Sci. 204, 211, 1973.
+
+
+ B. V. Deryaguin, "Recent research into the ptroperties of water in thin films and in microcapillaries,"
+ pages 55-60, in The State and Movement of Water in Living Organisms, XIXth Symposium of Soc. Exp. Biol.,
+ Cambridge Univ. Press, 1964.
+
+
+ J. S. Clegg and W. Drost-Hansen, "On the density of intracellular water," J. Biol. Phys. 10, 75-84, 1982.
+
+
+
+ J. S. Clegg, "Properties and metabolism of the aqueous cytoplasm and its boundaries," Am. J. Physiol. 26,
+ R133-R151, 1984.
+
+
+ J. S. Clegg, "Intracellular water and the cytomatrix: some methods of study and current views," J. Cell
+ Biol. 99, 167S-171S, 1984.
+
+
+ W. Drost-Hansen, "Structure and properties of water at biological interfaces," in Chemistry of the Cell
+ Interface, vol. 2, pages 1-184, H. D. Brown, editor, Academic Press, 1971.
+
+
+
+ W. Drost-Hansen and J. Clegg, editors, Cell-Associated Water, Academic Press, 1979.
+
+
+ C. F. Hazlewood, "A view of the significance and understanding of the physical properties of cell-associated
+ water," pages 165-259 in Cell-Associated Water, Drost-Hansen and Clegg, editors, Academic Press, 1979.
+
+
+ P. M. Wiggins, "Water structure as a determinant of ion distribution in living tissue," J. Theor. Biol. 32,
+ 131-144, 1971.
+
+
+ R. Damadian and F. W. Cope, Physiol. Chem. Phys. 5, 511, 1973.
+
+
+
+ F. W. Cope, "A review of the applications of solid state physics concepts to biological systems," J. Biol.
+ Phys. 3, 1 1975.
+
+
+ D. N. Nasonov, Local Reaction of Protoplasm and Gradual Excitation, Israel Program for Scientific
+ Translations, Jerusalem, Office of Technical Services, U.S. Dept.of Commerce, Washington, DC, 1962.
+
+
+ A. Nathansohn, Jahrb. Wiss. Bot. 39, 607, 1904.
+
+
+ A. S. Troshin, Problems of Cell Permeability, Pergamon Press, London, 1966.
+
+
+ A. S. Troshin, Byull. Eksp. Biol. Med. 34, 59, 1952.
+
+
+
+ I. Tasaki, Nerve Excitation: A Macromolecular Approach, Thomas, Springfield, 1968.
+
+
+ Albert Szent-Gyorgyi, Bioenergetics, Academic Pressn New York, 1957.
+
+
+ Albert Szent-Gyorgyi, The Living State and Cancer, Marcel Deker, New York, 1978.
+
+
+ T. L. Davis, et al., "Potentials in frog cornea and microelectrode artifact," Amer. J. Physiol. 219(1),
+ 178-183, 1970.
+
+
+
+ NOTES:
+
+
+ # In their preface, Nelson and Cox say their book has retained "Lehninger's ground-breaking organization, in
+ which a discussion of biomolecules is followed by metabolism and then information pathways," but that at
+ every other level "this second edition is a re-creation, rather than a revision, of the original text. Every
+ chapter has been comprehensively overhauled, not just by adding and deleting information, but by completely
+ reorganizing its presentation and content...." This is reminiscent of the book published under the name of
+ Max Gerson after his death, which inserted essentially fraudulent material to support an approach that is
+ exactly what Gerson strongly advised against.
+
+
+ * This principle might be applicable to the removal of calcium from living cells, with a procedure that
+ wouldn't have the dangers of chelation. Increased consumption of sodium and magnesium should facilitate the
+ removal and excretion of abnormally retained calcium. Sodium has been found to protect tissues against
+ oxidative damage, for example during cancer therapy with cis-platinum.
+
+
+
+
+ © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Menopause and its causes
+
+
+ Menopause and its causes
+
+
+ When I was in graduate school at the University of Oregon, everyone in our lab was working on the problem of
+ reproductive aging. Previously, people in the lab had established that the ovaries didn't "run out of eggs."
+ There was never really any basis for that ridiculous belief. Many people just said it, the way they said
+ "old eggs" (but never old sperms) were responsible for birth defects, or that "estrogen is the female
+ hormone," a deficiency of which is the cause of menopausal infertility. (Old sperms have been implicated in
+ some birth defects.
+
+ People who are newly married, for example, were found to have children with fewer birth defects than people
+ of the same age who had been married a long time, suggesting that more frequent intercourse involves fresher
+ sperms.) When ovaries have been treated with x-rays to destroy their ability to ovulate, they have been
+ found to produce more estrogen than before. Ovulation is one thing, and the production of hormones is
+ another thing. You can't determine whether ovulation has occurred by measuring the hormones.
+
+
+ Knowing the large amount of work that has gone into our understanding of the age-related decline in
+ fertility, it is disturbing to see people on television and in popular health books saying that menopause
+ occurs when the "ovaries run out of eggs."
+
+
+ Around 1970, many people were saying that aging was caused by the loss of brain cells. There is a glimmer of
+ truth in that silly idea, just as there would be in saying that "aging is caused by the death of skin
+ cells," making the skin thinner and drier and less elastic. Both the brain and the skin are sources of
+ steroid hormones, and it is possible that the death of skin cells and neurons is one factor in the
+ age-related decline in the "sex steroids." An organism would be an easier thing to understand if cells just
+ did their job for a certain period of time, and then died. A man named Hayflick has given people some
+ publications to cite, when they want to simplify things by saying that aging occurs when cells have used up
+ their quota of 50 divisions, but there are many more studies that clearly show that Hayflick's limit is
+ nothing but a product of the cells' environment. The cell's environment, the signals and substances and
+ energy it receives, is complex, but real progress is being made in understanding the things involved in the
+ aging process. Luckily, the infinite complexity of the environment is channeled into an understandable array
+ of processes by the cell's systematic ways of responding.
+
+
+ I knew, from talking with L. C. Strong,1 that early reproductive maturity was associated with early death;
+ in his strains of cancer-prone mice, he showed that high estrogen was the cause of early puberty, a high
+ cancer incidence, and a relatively short life. D. A. Snowdon, et al., showed that the occurrence of
+ menopause at an early age in women is associated with a greater risk of death from all causes, including
+ strokes and coronary heart disease.2 (They saw ovarian aging as an indicator of general aging.) P. W. F.
+ Wilson, et al., reported that postmenopausal estrogen use was associated with an increased incidence of
+ heart disease and stroke.3 P. M. Wise showed that estrogen accelerates aging of the central nervous system,
+ destroying the nerves which regulate the pituitary gonadotropins, and causing ovarian failure and
+ infertility.4 Many other studies of particular tissues show that estrogen accelerates the rate of aging.
+
+
+
+ In my work with hamsters, I found that the infertility that developed at middle age was caused by a high
+ rate of oxygen consumption in the uterus, causing the oxygen needed by the developing embryo to be consumed
+ by uterine tissues, and causing suffocation of the embryo. This is the central mechanism by which the
+ estrogen-containing contraceptives work: at any stage of pregnancy, a sufficient dose of
+ estrogen kills the embryo.
+
+
+ Polvani and Nencioni,5 among others, found that in women, the onset of menopause (the first missed period,
+ suddenly increased bone loss, nervous symptoms such as depression, insomnia, and flushing) corresponds to
+ the failure to produce progesterone, while estrogen is produced at normal levels. This results in a great
+ functional excess of estrogen, because it is no longer opposed by progesterone. Typically, it takes about
+ four years for the monthly estrogen excess to disappear. They suggested that the bone loss sets in
+ immediately when progesterone fails because cortisol then is able to dominate, causing bone catabolism;
+ progesterone normally protects against cortisol. Other researchers have pointed out that estrogen dominance
+ promotes mitosis of the prolactin-secreting cells of the pituitary, and that prolactin causes osteoporosis;
+ by age 50, most people have some degree of tumefaction of the prolactin-secreting part of the pituitary. But
+ estrogen dominance (or progesterone deficiency) also clearly obstructs thyroid secretion, and thyroid
+ governs the rate of bone metabolism and repair. Correcting the thyroid and progesterone should take care of
+ the cortisol/prolactin/osteo- porosis problem.
+
+
+ P. M. Wise4 has demonstrated that the "menopausal" pituitary hormones, high levels of LH and FSH, are
+ produced because the regulatory nerves in the hypothalamus have lost their sensitivity to estrogen, not
+ because estrogen is deficient. In fact, he showed that the nerves are desensitized precisely by their
+ cumulative exposure to estrogen. If an animal's ovaries are removed when it is young, the regulatory nerves
+ do not atrophy, and if ovaries are transplanted into these animals at the normally infertile age, they are
+ fertile. But if animals are given larger doses of estrogen during youth, those nerves atrophy prematurely,
+ and they become prematurely infertile.
+
+
+ The mechanism by which estrogen desensitizes and kills brain cells is now recognized as the "excitotoxic"
+ process, in which the excitatory transmitter glutamic acid is allowed to exhaust the nerve cells. (This
+ explains the older observations that glutamic acid, or aspartic acid, or aspartame, can cause brain damage
+ and reproductive failure.) Cortisol also activates the excitotoxic system, in other brain cells, causing
+ stress-induced atrophy of those cells.6 Progesterone and pregnenolone are recognized as inhibitors of this
+ excitotoxic process.
+
+
+
+ Besides estrogen's promotion of excitotoxic cell death, leading to the failure of the gonadotropin
+ regulatory system, estrogen's stress-mimicking action probably tends to increase the secretion of LH, in
+ ways that can be corrected by supplementing progesterone and thyroid. Since Selye's work, it has been known
+ that estrogen creates the same conditions as occur in the shock phase of the stress reaction. (And shock, in
+ a potential vicious circle, can increase the level of estrogen.7) It has recently been demonstrated that
+ estrogen stimulates the adrenal glands, independently of the pituitary's ACTH. This can increase the
+ production of adrenal androgens, leading to hirsutism, and other male traits, including anabolic effects.8
+
+
+ It was established in the 1950s that estrogen "erases" memories in well trained animals. I suppose that
+ acute effect is related to the chronic toxicity that leads to cell death. (In the 1940s, DES was sold to
+ prevent miscarriages, though it was already known that it caused them; then there was the
+ argument that it slowed aging of the skin, despite the Revlon studies at the University of Pennsylvania
+ showing that it accelerates all aspects of skin aging; lately there has been talk of
+ promoting estrogen to improve memory.)
+
+
+
+ Estrogen's nerve-exciting action is known to lower seizure thresholds; premenstrual
+ epilepsy is probably another acute sign of the neurotoxicity of estrogen.
+
+
+ When fatigue and lethargy are associated with aging, the brain stimulating action of estrogen can make a
+ woman feel that she has more energy.
+ (Large doses given to rats will make them run compulsively; running wheels with odometers
+ have shown that they will run over 30 miles a day from the influence of estrogen.) Estrogen inhibits one of
+ the enzymic routes for inactivating brain amines, and so it has more general effects on the brain than just
+ the glutamate system. This generalized effect on brain amines is more like the effects of cocaine or
+ amphetamine. If that is a woman's basis for wanting to use estrogen, a monoamine oxidase inhibitor would be
+ safer.
+
+
+ The reason for the menopausal progesterone deficiency is a complex of stress-related causes. Free-radicals
+ (for example, from iron in the corpus luteum) interfere with progesterone synthesis, as do prolactin, ACTH,
+ estrogen, cortisol, carotene, and an imbalance of gonadotropins. A deficiency of thyroid, vitamin A, and
+ LDL-cholesterol can also prevent the synthesis of progesterone. Several of the things which cause early
+ puberty and high estrogen, also tend to work against progesterone synthesis. The effect of an intra-uterine
+ irritant is to signal the ovary to suppress progesterone production, to prevent pregnancy while there is a
+ problem in the uterus. The logic by which ACTH suppresses progesterone synthesis is similar, to prevent
+ pregnancy during stress. Since progesterone and pregnenolone protect brain cells against the excitotoxins,
+ anything that chronically lowers the body's progesterone level tends to accelerate the estrogen-induced
+ excitotoxic death of brain cells.
+
+
+
+ Since progesterone and pregnenolone protect brain cells against the excitotoxins, anything that chronically
+ lowers the body's progesterone level tends to accelerate the estrogen-induced excitotoxic death of brain
+ cells.
+
+
+ Chronic constipation, and anxiety which decreases blood circulation in the intestine, can increase the
+ liver's exposure to endotoxin. Endotoxin (like intense physical activity) causes the estrogen concentration
+ of the blood to rise. Diets that speed intestinal peristalsis might be expected to postpone menopause.
+ Penicillin treatment, probably by lowering endotoxin production, is known to decrease estrogen and
+ cortisone, while increasing progesterone. The same effect can be achieved by eating raw carrots (especially
+ with coconut oil/olive oil dressing) every day, to reduce the amount of bacterial toxins absorbed, and to
+ help in the excretion of estrogen. Finally, long hours of daylight are known to increase progesterone
+ production, and long hours of darkness are stressful. Annually, our total hours of day and night are the
+ same regardless of latitude, but different ways of living, levels of artificial illumination, etc., have a
+ strong influence on our hormones. In some animal experiments, prolonged exposure to light has delayed some
+ aspects of aging.
+
+
+ General aging contributes to the specific changes that lead to menopause, but the animal experiments show
+ that fertility can be prolonged to a much greater age by preventing excitotoxic exhaustion of the
+ hypothalamic nerves. The question that still needs to be more clearly answered is, to what extent can
+ general aging be prevented or delayed by protecting against the excitotoxins? Minimizing estrogen (and
+ cortisone) with optimal thyroid activity, and maximizing pregnenolone and progesterone to prevent
+ excitotoxic cell fatigue, can be done easily. A diet low in iron and unsaturated fats protects the
+ respiratory apparatus from the damaging effects of excessive excitation, and--since pregnenolone is formed
+ in the mitochondrion--also helps to prevent the loss of these hormones.
+
+ Copyright: Raymond Peat, PhD 1997
+
+ REFERENCES
+
+
+ 1. L. C. Strong, Biological Aspects of Cancer and Aging, Pergamon Press, 1968.
+
+
+
+ 2. D. A. Snowdon, et al., "Is early natural menopause a biologic marker of health and aging? Am. J. Public
+ Health 79, 709-714, 1989.
+
+
+ 3. P. W. F. Wilson, et al. [The Framingham Study], N. E. J. M. 313(17), 1038-1043, 1985
+
+
+ 4. P. M. Wise, "Influence of estrogen on aging of the central nervous system: Its role in declining female
+ reproductive function," in Menopause: Evaluation, Treatment, and Health Concerns, pages 53-70, 1989.
+
+
+ 5. Nencioni, T., and F. Polvani, Calcitonin, p. 297-305, A. Pecile, editor, Elsevier, N.Y., 1985.
+
+
+
+ 6. T. I. Belova, "Structural damage to the mesencephalic reticular formation induced by immobilization
+ stress," Bull. Exp. Biol. & Med. 108(7), 126030, 1989.
+
+
+ 7. F. Fourrier, et al., "Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock,"
+ Circ. Shock 43(4), 171-178, 1994.
+
+
+ 8. E. C. Ditkoff, et al., "The impact of estrogen on adrenal androgen sensitivity and secretion in
+ polycystic ovary syndrome," J. Clin. Endocrinol. Metab. 80(2), 603-607, 1995.
+
+
+ 9. C. Bain, et al., "Use of postmenopausal hormones and risk of myocardial infarction," Circulation 64,
+ 42-46, 1981.
+
+
+ 10. T. L. Bush, et al., "Estrogen use and all-cause mortality: Preliminary results from the Lipid Research
+ Clinics Program follow-up study," JAMA 249, 903-906, 1983.
+
+
+
+ 11. M. S. Hunter and K. L. M. Liao, "Intentions to use hormone replacement therapy in a community sample of
+ 45-year-old women," Maturitas 20(1), 13-23, 1994. (Women who expressed an intention to use hormone
+ replacement therapy at menopause reported significantly lower self-esteem, more depressed mood, anxiety, and
+ negative attitudes toward menopause. The also expressed stronger beliefs in their doctors' ability--as
+ opposed to their own--to control their menopause experience.)
+
+
+ 12. L. Dennerstein, et al., "Psychological well-being, mid-life and the menopause," Maturitas 20(1), 1-11,
+ 1994.
+
+
+
+ © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
+
+
+
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+
+
+
+ Milk in context: allergies, ecology, and some myths
+
+
+
+
+ Milk in context: allergies, ecology, and some myths
+
+
+
+
+ Food allergies are becoming much more common in recent decades, especially in industrialized countries. Most
+ attention has been given to theories about changes in people, such as the reduction in infectious diseases
+ and parasites, or vitamin D deficiency, or harmful effects from vaccinations, and little attention has been
+ given to degradation of the food supply.
+
+
+
+ Our food cultures, like linguistic and moral cultures, give us some assumptions or theories about the way
+ the world should be, and if these beliefs aren't questioned and tested, they can permeate the culture of
+ science, turning the research process into a rationalization of accepted opinions.
+
+
+ In general, those who pay for research are those with an investment in or commitment to the preservation and
+ expansion of the existing systems of production and distribution. Cheap mass production, durability and long
+ shelf-life are more important than the effects of foods on health. The biggest industries are usually able
+ to keep public attention away from the harm they do.
+
+
+ The historical economic importance of cereals and beans is reflected in the nutritional and biochemical
+ research literature, which has paid relatively little attention to basic questions about human adaptation to
+ the ecosystems. From the early petrochemical "Green Revolution" to the contemporary imposition of
+ genetically altered seeds, the accumulated economic power of the food industry has taken control of the food
+ culture.
+
+
+ In evaluating each research publication relating to nutrition and health, we should ask what alternative
+ possibilities are being neglected, for "practical" reasons, cultural preferences, and business interests.
+
+
+ Some people with an ecological concern have argued that grains and beans can most economically provide the
+ proteins and calories that people need, but good nutrition involves much more than the essential nutrients.
+
+
+ "Efficient" industrial agriculture has been concerned with cheaply producing those important nutrients, and
+ their critics have focussed on their use of toxic chemicals, on the social damage they produce, the
+ degradation of the soil, the toxic effects of genetic modification, their unsustainable use of petroleum,
+ and occasionally on the lower nutritional value of chemically stimulated crops.
+
+
+
+ I think far too little attention is being given to the effects of abnormal and stressful growth conditions
+ on the plants' natural defense systems. Plants normally synthesize some toxins and inhibitors of digestive
+ enzymes to discourage attacks by bacteria, fungi, insects, and other predators. When a plant is injured or
+ otherwise stressed, it produces more of the defensive substances, and very often they communicate their
+ stress to other plants, and the resulting physiological changes can cause changes in seeds that affect the
+ resistance of the progeny. (Agrawal, 2001)
+
+
+ One of many substances produced by plants in response to injury is chitinase, an enzyme that breaks down
+ chitin, a polysaccharide that is a structural component of fungi and insects. Chitinase, which is produced
+ by bacteria and humans, as well as by plants and other organisms, is involved in developmental processes as
+ well as in the innate immune system. In plants, the enzyme is induced by ethylene and salicylate, in animals
+ by estrogen, light damage, and infections, and can be demonstrated in polyps and cancers.
+
+
+ The two main classes of plant allergens are the stress-induced chitinases, and seed storage proteins, such
+ as gluten. The chitinase allergens are responsible for reactions to latex (which is secreted by rubber trees
+ in reaction to a wound), bananas, avocados, many other fruits and vegetables, and some types of wood and
+ other plant materials. Intensive agricultural methods are increasing the formation of the defensive
+ chemicals, and the industrialized crops are responsible for the great majority of the new allergies that
+ have appeared in the last 30 years.
+
+
+ The presence of the chitinase family of proteins in humans was first discovered in the inflamed asthmatic
+ lung. It was then found at high levels in the uterine endometrium at the time of implantation of the embryo
+ (an inflammation-like situation) and in the uterus during premature labor. Since estrogen treatment is known
+ to increase the incidence of asthma and other inflammations, the appearance of chitinase also in the uterus
+ in estrogen dominated conditions is interesting, especially when the role of estrogen in celiac disease (in
+ effect an allergy to gluten) is considered. Celiac disease is more prevalent among females, and it involves
+ the immunological cross-reaction to an antigen in the estrogen-regulated transglutaminase enzyme and the
+ gluten protein. The (calcium-regulated) transglutaminase enzyme is involved in the cross-linking of proteins
+ in keratinized cells, in fibrotic processes in the liver, and in cancer. (People with celiac disease often
+ suffer from osteoporosis and urinary stone deposition, showing a general problem with calcium regulation.)
+
+
+ This means that estrogen and stress cause the appearance of antigens in the human or animal tissues that are
+ essentially the same as the stress-induced and defensive proteins in plant tissues. A crocodile might
+ experience the same sort of allergic reaction when eating estrogen-treated women and when eating commercial
+ bananas.
+
+
+
+ The various states of the innate immune system have been neglected by immunologists, for example in relation
+ to organ transplantation. The "major histocompatibility" antigens are matched, but organ transplants still
+ sometimes fail. A study found that the livers from young men had a high survival rate when transplanted into
+ either men or women, but the livers of older women donors were rejected at a high rate when transplanted
+ into either men or women. Exposure to estrogen increases intracellular calcium and the unsaturation of fatty
+ acids in tissue lipids, and the expression of enzymes such as chitinase and transglutaminase, and the
+ various enzymes in the structure-sensitive estrogen-controlled metabolic pathways.
+
+
+ Estrogen's actions are closely and pervasively involved with the regulation of calcium, and these changes
+ affect the basic tissue structures and processes that constitute the innate immune system. Estrogen's effect
+ in increasing susceptibility to "autoimmune" diseases hasn't yet been recognized by mainstream medicine.
+
+
+ The chemist Norman Pirie argued convincingly that leaf protein had much higher nutritional value than grain
+ and bean proteins, and that it had the potential to be much more efficient economically, if it could be
+ separated from the less desirable components of leaves.
+
+
+ The amino acid composition and nutritional value of leaf protein is similar to milk protein, which is
+ understandable since cows produce milk from the amino acids produced in their rumens by bacteria digesting
+ the leaves the cows have eaten. The bacteria perform the refining processes that Pirie believed could be
+ done technologically, and they also degrade or detoxify the major toxins and allergens.
+
+
+ The nutrients produced in the cow's rumen are selectively absorbed into the cow's bloodstream, where the
+ liver can further filter out any toxins before the amino acids and other nutrients are absorbed by the udder
+ to be synthesized into milk. If cows are fed extremely bad diets, for example with a very large amount of
+ grain, the filtering process is less perfect, and some allergens can reach the milk, but since sick cows are
+ less profitable than healthy cows, dairies usually feed their cows fairly well.
+
+
+
+ In a recent study of 69,796 hospitalized newborns, a diagnosis of cow's milk allergy was made in 0.21% of
+ them. Among those whose birthweight had been less than a kilogram, 0.35% of them were diagnosed with the
+ milk allergy. Gastrointestinal symptoms were the main reason for the diagnosis, but a challenge test to
+ confirm the diagnosis was used in only 15% of the participating hospitals, and a lymphocyte stimulation test
+ was used in only 5.5% of them (Miyazawa, et al., 2009). There are many publications about milk allergies,
+ but they generally involve a small group of patients, and the tests they use are rarely evaluated on healthy
+ control subjects.
+
+
+ Several surveys have found that of children who have a diagnosed milk allergy, about 2/3 of them grow out of
+ the allergy.
+
+
+ People who have told me that they have had digestive problems with milk have sometimes found that a
+ different brand of milk doesn't cause any problem.
+
+
+ Milk with reduced fat content is required by US law to have vitamins D and A added. The vehicle used in the
+ vitamin preparation, and the industrial contaminants in the "pure" vitamins themselves, are possible sources
+ of allergens in commercial milk, so whole milk is the most likely to be free of allergens.
+
+
+ A thickening agent commonly used in milk products, carrageenan, is a powerful allergen that can cause a
+ "pseudo-latex allergy" (Tarlo, et al., 1995). It is a sulfated polysaccharide, structurally similar to
+ heparin. There are good reasons to think that its toxic effects are the result of disturbance of calcium
+ metabolism (see for example Abdullahi, et al., 1975; Halici, et al., 2008; Janaswamy and Chandrasekaran,
+ 2008).
+
+
+
+ Besides the idea of milk allergy, the most common reason for avoiding milk is the belief that the genes of
+ some ethnic groups cause them to lack the enzyme, lactase, needed to digest milk sugar, lactose, and that
+ this causes lactose intolerance, resulting in gas or diarrhea when milk is consumed. Tests have been
+ reported in which a glass of milk will cause the lactase deficient people to have abdominal pain. However,
+ when intolerant people have been tested, using milk without lactose for comparison, there were no
+ differences between those receiving milk with lactose or without it. The "intolerant" people consistently
+ tolerate having a glass with each meal.
+
+
+ When a group of lactase deficient people have been given some milk every day for a few weeks, they have
+ adapted, for example with tests showing that much less hydrogen gas was produced from lactose by intestinal
+ bacteria after they had adapted (Pribila, et al., 2000).
+
+
+ Bacterial overgrowth in the small intestine can be caused by hypothyroidism (Lauritano, et al., 2007), and
+ the substances produced by these bacteria can damage the lining of the small intestine, causing the loss of
+ lactase enzymes (Walshe, et al., 1990).
+
+
+ Another hormonal condition that probably contributes to lactase deficiency is progesterone deficiency, since
+ a synthetic progestin has been found to increase the enzyme (Nagpaul, et al., 1990). The particular
+ progestin they used lacks many of progesterone's effects, but it does protect against some kinds of stress,
+ including high estrogen and cortisol. This suggests that stress, with its increased ratio of estrogen and
+ cortisol to progesterone, might commonly cause the enzyme to decrease.
+
+
+ Two other ideas that sometimes cause people to avoid drinking milk and eating cheese are that they are
+ "fattening foods," and that the high calcium content could contribute to hardening of the arteries.
+
+
+ When I traveled around Europe in 1968, I noticed that milk and cheese were hard to find in the Slavic
+ countries, and that many people were fat. When I crossed from Russia into Finland, I noticed there were many
+ stores selling a variety of cheeses, and the people were generally slender. When I lived in Mexico in the
+ 1960s, good milk was hard to find in the cities and towns, and most women had fat hips and short legs.
+ Twenty years later, when good milk was available in all the cites, there were many more slender women, and
+ the young people on average had much longer legs. The changes I noticed there reminded me of the differences
+ I had seen between Moscow and Helsinki, and I suspect that the differences in calcium intake were partly
+ responsible for the changes of physique.
+
+
+
+ In recent years there have been studies showing that regular milk drinkers are less fat than people who
+ don't drink it. Although the high quality protein and saturated fat undoubtedly contribute to milk's
+ anti-obesity effect, the high calcium content is probably the main factor.
+
+
+ The parathyroid hormone (PTH) is an important regulator of calcium metabolism. If dietary calcium isn't
+ sufficient, causing blood calcium to decrease, the PTH increases, and removes calcium from bones to maintain
+ a normal amount in the blood. PTH has many other effects, contributing to inflammation, calcification of
+ soft tissues, and decreased respiratory energy production.
+
+
+ When there is adequate calcium, vitamin D, and magnesium in the diet, PTH is kept to a minimum. When PTH is
+ kept low, cells increase their formation of the uncoupling proteins, that cause mitochondria to use energy
+ at a higher rate, and this is associated with decreased activity of the fatty acid synthase enzymes.
+
+
+ These changes are clearly related to the anti-obesity effect of calcium, but those enzymes are important for
+ many other problems.
+
+
+ The "metabolic syndrome," that involves diabetes, hypertension, and obesity, is associated with high PTH
+ (Ahlstr"m, et al., 2009; Hjelmesaeth, et al., 2009).
+
+
+
+ Alzheimer's disease involves decreased mitochondrial activity and low levels of the uncoupling proteins.
+ There is evidence that milk drinkers are protected against dementia (Yamada, et al., 2003). Cancer involves
+ increased activity of the fatty acid synthase enzymes. Increased calcium consumption beneficially affects
+ both sets of enzymes, uncoupling proteins and fatty acid synthase.
+
+
+ Multiple sclerosis relapses consistently occur at times of high PTH, and remissions consistently occur at
+ times of low PTH (Soilu-H"nninen, et al., 3008). PTH increases the activity of nitric oxide synthase, and
+ nitric oxide is a factor in the vascular leakiness that is so important in MS.
+
+
+ There are components of milk that might protect against tooth decay by inhibiting the binding of bacteria to
+ teeth (Danielsson, et al., 2009).
+
+
+ David McCarron has published a large amount of evidence showing how calcium deficiency contributes to high
+ blood pressure. The chronic elevation of PTH caused by calcium deficiency causes the heart and blood vessels
+ to retain calcium, making them unable to relax fully.
+
+
+ Intravenous infusion of calcium can relax blood vessels and improve heart function. The suppression of PTH
+ is probably the main mechanism.
+
+
+ PTH (like estrogen) causes mast cells to release promoters of inflammation, including histamine and
+ serotonin. Serotonin and nitric oxide contribute to increasing PTH secretion.
+
+
+
+ Removal of the parathyroid gland has reduced heart problems and mortality (Costa-Hong, et al., 2007) and
+ insomnia (Esposito, et al., 2008; Sabbatini, et al., 2002) in people with kidney disease and excess PTH.
+
+
+ Increased carbon dioxide, for example when adapted to high altitude, can greatly decrease PTH. Frequent, but
+ smaller, meals can reduce PTH.
+
+
+ Cancer cells often secrete PTH and related proteins with similar effects on calcium, and the PTH stimulates
+ the growth and invasiveness of prostate cancer (DaSilva, et al., 2009) cells, and seems to be as closely
+ involved with breast cancer. The PTH-related protein is associated with calcification in breast cancer
+ (Kanbara, et al., 1994). Microscopic calcium crystals themselve produce inflammation (Denko and Whitehouse,
+ 1976).
+
+
+ Besides being an ecologically favorable source of calcium, protein, sugar, and fat, the composition of milk
+ causes it to be digested efficiently, supporting the growth of bacteria that are relatively safe for the
+ intestine and liver, and reducing the absorption of endotoxin.
+
+
+ Dividing any food into smaller meals can lower the PTH, and milk is a convenient food to use in small
+ amounts and frequently.
+
+
+ Some amino acids directly stimulate insulin secretion, decreasing blood sugar and leading to the secretion
+ of cortisol in reaction to the depression of blood glucose. The presence of lactose in milk, and of fat, to
+ slow absorption of the amino acids, helps to minimize the secretion of cortisol. The main protein of milk,
+ casein, seems to have some direct antistress effects (Biswas, et al., 2003).
+
+
+
+ Since milk's primary biological function is to support the growth of a young animal, some of its features
+ make it inappropriate as a sole food for an adult. To support cell division and growth, the methionine and
+ tryptophan content of milk is higher than would be optimal for an adult animal, and the phosphate might be
+ slightly more than needed, in relation to the calcium. Since the fetus stores a large amount of iron during
+ gestation, the iron content of milk is low, and when a young animal has used the stored iron, its continuing
+ growth requires more iron than milk provides. However, for an adult, the low iron content of milk and cheese
+ makes these foods useful for preventing the iron overload that often contributes to the degenerative
+ diseases.
+
+
+ Combining milk and cheese with fruits adds to the antistress effect. The additional sugar and potassium and
+ other minerals allow the milk protein to be used more efficiently, by moderating the secretion of cortisol,
+ and helping to inhibit the secretion of PTH.
+
+
+ Substances such as PTH, nitric oxide, serotonin, cortisol, aldosterone, estrogen, thyroid stimulating
+ hormone, and prolactin have regulatory and adaptive functions that are essential, but that ideally should
+ act only intermittently, producing changes that are needed momentarily. When the environment is too
+ stressful, or when nutrition isn't adequate, the organism may be unable to mobilize the opposing and
+ complementary substances to stop their actions. In those situations, it can be therapeutic to use some of
+ the nutrients as supplements. Calcium carbonate (eggshell or oyster shell, for example) and vitamins D and
+ K, can sometimes produce quick antistress effects, alleviating insomnia, hypertension, edema, inflammations
+ and allergies, etc., but the regular use of milk and cheese can prevent many chronic stress-related
+ diseases.
+
+ REFERENCES
+
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+
+
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+ Am Nat. 2001 May;157(5):555-69. Transgenerational consequences of plant responses to herbivory: an
+ adaptive maternal effect? Agrawal AA.
+
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+ Clin Endocrinol (Oxf). 2009 Nov;71(5):673-8. Correlation between plasma calcium, parathyroid hormone
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+
+ Ahlstr"m T, Hagstr"m E, Larsson A, Rudberg C, Lind L, Hellman P.
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+ Indian J Exp Biol. 2003 Apr;41(4):367-9. Protection of adrenocortical activity by dietary casein in
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+ opens up a new area of management of stress."
+
+
+
+ Am J Clin Nutr. 2008 Oct;88(4):877-85. Dairy calcium supplementation in overweight or obese persons:
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+
+ J Am Coll Nutr. 2005 Dec;24(6 Suppl):569S-73S. The myth of increased lactose intolerance in
+ African-Americans.
+
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+
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+ Dunaief JL.
+
+
+
+ J Urol. 2008 Sep;180(3):974-9. Epub 2008 Jul 17.Urinary stone disease in adults with celiac disease:
+ prevalence, incidence and urinary determinants.
+ Ciacci C, Spagnuolo G, Tortora R, Bucci C, Franzese D, Zingone F, Cirillo M.
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+
+ Surgery. 2007 Nov;142(5):699-703. Parathyroidectomy reduces cardiovascular events and mortality in
+ renal Hyperparathyroidism. Costa-Hong V, Jorgetti V, Gowdak LH, Moyses RM, Krieger EM, De Lima
+ JJ.
+
+
+ Caries Res. 2009;43(3):171-8. Human milk compounds inhibiting adhesion of mutans streptococci to
+ host ligand-coated hydroxyapatite in vitro.
+ Danielsson Niemi L, Hernell O, Johansson I.
+
+
+
+ Cancer Res. 2009 Sep 15;69(18):7402-11. The neuroendocrine-derived peptide parathyroid
+ hormone-related protein promotes prostate cancer cell growth by stabilizing the androgen
+ receptor. DaSilva J, Gioeli D, Weber MJ, Parsons SJ.
+
+
+ J Rheumatol. 1976 Mar;3(1):54-62. Experimental inflammation induced by naturally occurring
+ microcrystalline calcium salts. Denko CW, Whitehouse MW.
+
+
+ Dig Liver Dis. 2009 Aug;41(8):541-50. Transglutaminases in inflammation and fibrosis of the
+ gastrointestinal tract and the liver.
+ Elli L, Bergamini CM, Bardella MT, Schuppan D.
+
+
+
+ J Nephrol. 2008 Mar-Apr;21 Suppl 13:S92-6. Parathyroidectomy improves the quality of sleep in
+ maintenance hemodialysis patients with severe hyperparathyroidism. Esposito MG, Cesare CM, De
+ Santo RM, Cice G, Perna AF, Violetti E, Conzo G, Bilancio G, Celsi S, Annunziata F, Iannelli S, De Santo NG,
+ Cirillo M, Livrea A.
+
+
+ Endocrinology. 1997 Jul;138(7):2665-73. Parathyroid hormone-related protein is induced in the adult
+ liver during endotoxemia and stimulates the hepatic acute phase response.
+ Funk JL, Moser AH, Grunfeld C, Feingold KR.
+
+
+ Arch Pharm Res. 2008 Jul;31(7):891-9. Effects of calcium channel blockers on hyaluronidase-induced
+ capillary vascular permeability. Halici Z, Suleyman H, Cadirci E.
+
+
+
+ J Am Diet Assoc. 2000 May;100(5):524-8. Improved lactose digestion and intolerance among
+ African-American adolescent girls fed a dairy-rich diet. Pribila BA, Hertzler SR, Martin BR,
+ Weaver CM, Savaiano DA.
+
+
+ Dig Dis Sci. 1998 Jan;43(1):39-40.
+ Fecal hydrogen production and consumption measurements. Response to daily lactose ingestion by lactose
+ maldigesters. Hertzler SR, Savaiano DA, Levitt MD.
+
+
+ J Am Coll Nutr. 2009 Apr;28(2):142-9. Effects of dairy products on intracellular calcium and blood
+ pressure in adults with essential hypertension.
+
+ Hilpert KF, West SG, Bagshaw DM, Fishell V, Barnhart L, Lefevre M, Most MM, Zemel MB, Chow M, Hinderliter
+ AL, Kris-Etherton PM. "Consumption of dairy foods beneficially affects (Ca)(i), resulting in improved BP in
+ a subgroup defined by (Ca)(i) response."
+
+
+ Cardiovasc Diabetol. 2009 Feb 3;8:7. Parathyroid hormone, but not vitamin D, is associated with the
+ metabolic syndrome in morbidly obese women and men: a cross-sectional study.
+ Hjelmesaeth J, Hofs" D, Aasheim ET, Jenssen T, Moan J, Hager H, R"islien J, Bollerslev J.
+
+
+ Eur J Epidemiol. 2003;18(7):677-84. The Swedish coeliac disease epidemic with a prevailing twofold
+ higher risk in girls compared to boys may reflect gender specific risk factors. Ivarsson A,
+ Persson LA, Nystr"m L, Hernell O.
+
+
+ Carbohydr Res. 2008 Feb 4;343(2):364-73. Epub 2007 Oct 30. Heterogeneity in iota-carrageenan
+ molecular structure: insights for polymorph II-->III transition in the presence of calcium
+ ions. Janaswamy S, Chandrasekaran R.
+
+
+
+ Metabolism. 2002 Oct;51(10):1230-4.
+ A calcium-deficient diet caused decreased bone mineral density and secondary elevation of estrogen in
+ aged male rats-effect of menatetrenone and elcatonin.
+
+ Kato S, Mano T, Kobayashi T, Yamazaki N, Himeno Y, Yamamoto K, Itoh M, Harada N, Nagasaka A.
+
+
+ Nippon Geka Gakkai Zasshi. 1993 Apr;94(4):394-9.
+ [Immunohistological evaluation of parathyroid hormone-related protein in breast cancer with and without
+ calcification on mammography] Kanbara Y, Kono N, Nakaya M, Ishikawa Y, Fujiwara O, Kitazawa R,
+ Kitazawa S.
+
+
+ J Pak Med Assoc. 1996 Jun;46(6):128-31.
+ Changes in plasma electrolytes during acclimatization at high altitude. Khan DA, Aslam M, Khan
+ ZU.
+
+
+
+ J Am Coll Nutr. 2009 Feb;28 Suppl 1:103S-19S.
+ Milk products, dietary patterns and blood pressure management.
+
+ Kris-Etherton PM, Grieger JA, Hilpert KF, West SG.
+
+
+ Br J Cancer. 1996 Jul;74(2):200-7. A new human breast cancer cell line, KPL-3C, secretes parathyroid
+ hormone-related protein and produces tumours associated with microcalcifications in nude mice.
+ Kurebayashi J, Kurosumi M, Sonoo H.
+
+
+ J Clin Endocrinol Metab. 2007 Nov;92(11):4180-4. Association between hypothyroidism and small
+ intestinal bacterial overgrowth.
+
+
+ Lauritano EC, Bilotta AL, Gabrielli M, Scarpellini E, Lupascu A, Laginestra A, Novi M, Sottili S, Serricchio
+ M, Cammarota G, Gasbarrini G, Pontecorvi A, Gasbarrini A.
+
+
+ Bone. 2009 Oct 6. Bone involvement in clusters of autoimmune diseases: Just a complication?
+ Lombardi F, Franzese A, Iafusco D, Del Puente A, Esposito A, Prisco F, Troncone R, Valerio G.
+
+
+ Hypertension 1980 Mar-Apr;2(2):162-8.
+ Enhanced parathyroid function in essential hypertension: a homeostatic response to a urinary calcium
+ leak. McCarron DA, Pingree PA, Rubin RJ, Gaucher SM, Molitch M, Krutzik S. "Recent
+ reports . . . suggest that increased parathyroid gland function may be one of the more common endocrine
+ disturbances associated with hypertension."
+
+ "Compared to a second age- and sex-matched normotensive population, the hypertensives demonstrated a
+ significant (p less than 0.005) relative hypercalciuria. For any level of urinary sodium, hypertensives
+ excreted more calcium. These preliminary data suggest that parathyroid gland function may be
+ enhanced in essential hypertension."
+
+
+
+ Am J Med 1987 Jan 26;82(1B):27-33.
+ The calcium paradox of essential hypertension. McCarron DA, Morris CD, Bukoski R. "This
+ evidence, and the paradoxical therapeutic efficacy of both calcium channel blockers and supplemental dietary
+ calcium, can be integrated into a single theoretic construct."
+
+
+ Nephrol Dial Transplant. 2002 Oct;17(10):1854. Insomnia in maintenance haemodialysis
+ patients. Sabbatini M, Minale B, Crispo A, Pisani A, Ragosta A, Esposito R, Cesaro A,
+ Cianciaruso B, Andreucci VE.
+
+
+ J Neurol Neurosurg Psychiatry. 2008 Feb;79(2):152-7. A longitudinal study of serum 25-hydroxyvitamin
+ D and intact parathyroid hormone levels indicate the importance of vitamin D and calcium homeostasis
+ regulation in multiple sclerosis. Soilu-H"nninen M, Laaksonen M, Laitinen I, Er"linna JP,
+ Lilius EM, Mononen I.
+
+
+
+ J Nutr. 2006 Apr;136(4):1107-13. Lactose intolerance symptoms assessed by meta-analysis: a grain of
+ truth that leads to exaggeration. Savaiano DA, Boushey CJ, McCabe GP.
+
+
+ J Allergy Clin Immunol. 1995 May; 95(5 Pt 1): 933-6.
+ Anaphylaxis to carrageenan: a pseudo-latex allergy. Tarlo, S M Dolovich, J Listgarten, C
+
+
+ Gut. 1990 Jul;31(7):770-6. Effects of an enteric anaerobic bacterial culture supernatant and
+ deoxycholate on intestinal calcium absorption and disaccharidase activity. Walshe K, Healy MJ,
+ Speekenbrink AB, Keane CT, Weir DG, O'Moore RR.
+
+
+
+ Metabolism. 2003 Aug;52(8):1072-7. Dietary sodium restriction exacerbates age-related changes in rat
+ adipose tissue and liver lipogenesis. Xavier AR, Garofalo MA, Migliorini RH, Kettelhut IC.
+
+
+ Hypertension 1994 Apr;23(4):513-30. Dietary calcium and blood pressure in experimental models of
+ hypertension. A review. Hatton DC, McCarron DA.
+
+
+ Nippon Geka Gakkai Zasshi. 1993 Apr;94(4):394-9. [Immunohistological evaluation of parathyroid
+ hormone-related protein in breast cancer with and without calcification on mammography]
+ [Article in Japanese] Kanbara Y, Kono N, Nakaya M, Ishikawa Y, Fujiwara O, Kitazawa R, Kitazawa S. "It is
+ suspected that PTHrP is also one of the main factors of calcification in breast cancer."
+
+
+
+ Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku. 1998;(116):46-62. [Plant defense-related
+ proteins as latex allergens] [Article in Japanese] Yagami T.
+
+
+ J Am Geriatr Soc 2003 Mar;51(3):410-4. Association between dementia and midlife risk factors: the
+ Radiation Effects Research Foundation Adult Health Study.
+ Yamada M, Kasagi F, Sasaki H, Masunari N, Mimori Y, Suzuki G.
+
+
+ Am J Hypertens 1995 Oct;8(10 Pt 1):957-64. Regulation of parathyroid hormone and vitamin D in
+ essential hypertension. Young EW, Morris CD, Holcomb S, McMillan G, McCarron DA. "The maximal
+ stimulated PTH level was significantly higher in hypertensive than normotensive subjects in the absence of
+ measured differences in serum ionized calcium concentration, serum 1,25(OH)2-vitamin D concentration, and
+ creatinine clearance."
+
+
+
+ Mol Immunol. 2007 Mar;44(8):1977-85. Estradiol activates mast cells via a non-genomic estrogen
+ receptor-alpha and calcium influx.
+
+ Zaitsu M, Narita S, Lambert KC, Grady JJ, Estes DM, Curran EM, Brooks EG, Watson CS, Goldblum RM,
+ Midoro-Horiuti T.
+
+
+ Copyright 2011. Raymond Peat, P.O. Box 5764, Eugene OR 97405. All Rights Reserved. www.RayPeat.comNot for
+ republication without written permission.
+
+
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+
+
+
+
+
+
+ Mitonchondria and mortality:
+ Diet, exercise, and medicine, damaging or repairing respiratory metabolism
+ MAIN IDEAS AND CONTEXTS
+ Lactic acid and carbon dioxide
+ have opposing effects.
+
+ Intense exercise damages cells
+
+ in ways that cumulatively impair metabolism. There is clear evidence that glycolysis, producing lactic
+ acid from glucose, has toxic effects, suppressing respiration and killing cells. Within five
+ minutes, exercise lowers the activity of enzymes that oxidize glucose. Diabetes, Alzheimer's disease,
+ and general aging involve increased lactic acid production and
+ accumulated metabolic (mitochondrial) damage.
+
+
+ The products of glycolysis,
+ lactic acid and pyruvic acid, suppress oxidation of glucose.
+
+
+
+ Adaptation
+
+ to hypoxia or increased carbon dioxide limits the formation of lactic acid. Muscles are 50% more
+ efficient in the adapted state; glucose, which forms more carbon dioxide than fat does when oxidized,,
+ is metabolized more efficiently than fats, requiring less oxygen.
+
+
+ Lactic acidosis,
+
+ by suppressing oxidation of glucose, increases oxidation of fats, further suppressing glucose
+ oxidation.
+
+
+ Estrogen
+ is harmful to mitochondria,
+ progesterone
+ is beneficial.
+
+
+ Progesterone's brain-protective
+ and restorative effects involve mitochondrial actions.
+
+
+ Thyroid hormone, palmitic acid, and light
+ activate a crucial respiratory enzyme, suppressing the formation of lactic acid. Palmitic acid occurs in
+ coconut oit, and is formed naturally in animal tissues. Unsaturated oils have the opposite effect.
+
+
+ Heart failure, shock,
+
+ and other problems involving excess lactic acid can be treated "successfully" by poisoning glycolysis
+ with dichloroacetic acid, reducing the production of lactic acid, increasing the oxidation of glucose,
+ and increasing cellular ATP concentration. Thyroid, vitamin B1, biotin, etc., do the same.
+
+ SOME DEFINITIONS
+
+ Glycolysis:
+
+ The conversion of glucose to lactic acid, providing some usable energy, but many times less than
+ oxidation provides.
+
+
+ Lactic acid,
+
+ produced by splitting glucose to pyruvic acid followed by its reduction, is associated with calcium
+ uptake and nitric oxide production, depletes energy, contributing to cell death.
+
+
+ Crabtree effect:
+
+ Inhibition of cellular respiration by an excess of glucose; excess of glucose promotes calcium uptake by
+ cells.
+
+
+ Pasteur effect:
+ Inhibition of glycolysis (fermentation) by oxygen.
+
+
+ Randle effect:
+
+ The inhibition of the oxidation of glucose by an excess of fatty acids. This lowers metabolic
+ efficiency. Estrogen promotes this effect.
+
+
+
+ Lactated Ringer's solution:
+
+ A salt solution that has\ been used to increase blood volume in treating shock; the lactate was
+ apparently chosen as a buffer in place of bicarbonate, as a matter of convenience rather than
+ physiology. This solution is toxic, partly because it contains the form of lactate produced by bacteria,
+ but our own lactate, at higher concentrations, produces the same sorts of toxic effect, damaging
+ mitochondria,
+
+
+ Estrogenic phytotoxins
+ damage mitochondria, kill brain cells; tofu is associated with dementia.
+
+
+
+ Since reading Warburg's publications in the late 1960s and early 70s, and doing my own research on tissue
+ respiration, I have been convinced that Warbug was on the right track in seeing mitochondrial respiration as
+ the controlling influence in cell differentiation, and in seeing cancer as a reversion to a primitive form
+ of life based on a "respiratory defect." Harry Rubin's studies of cells in culture have expanded Warburg's
+ picture of the process of cancerization, showing that genetic changes occur only after the cells have been
+ transformed into cancer.
+
+
+ It is now well recognized that defective mitochondrial respiration is a central factor in diseases of
+ muscles, brain, liver, kidneys, and other organs. The common view has been that the mitochondrial defects
+ are produced by genetic defects, that are either inherited or acquired, and are irreversible.
+
+
+ Mitochondria depend on some genes in the nuclear chromosomes, but they also contain some genes, and
+ mutations in these specific mitochondrial genes have been associated with various diseases, and with aging.
+ Although these aren't the genes that the cancer establishment has focussed on as "the cause" of cancer, for
+ people interested in the achievements of Warburg and Rubin, it is important to know whether mutations in
+ these mitochondrial genes are the cause of respiratory defects, or whether a respiratory defect
+ causes the mutations. Recent research seems to show that physiological problems precede and cause the
+ mutations.
+
+
+ Warburg believed that mitochondria supported specialized cell functions by concentrating themselves in the
+ places where energy is needed. This idea has some interesting implications. For example, when the amount of
+ thyroid hormone is increased, or when the organism adapts to a high altitude, the number of mitochondria
+ increases. But in energy deficient states such as diabetes, they don't. How are these crucial organelles
+ called into existence by the hormone that increases respiration and energy, and also by the hypoxic
+ conditions of high altitudes? In both of these conditions, the availability of oxygen is limiting the
+ ability to produce energy. In both conditions, carbon dioxide concentration in tissue is higher, in
+ one case, because thyroid stimulates its production, in the other, because
+ the Haldane effect limits its loss from the lungs.
+
+
+ Could carbon dioxide, a major product of mitochondria, help to call mitochondria into existence? My answer
+ to this is "yes," and it will help to briefly explain how I see mitochondria. Although I have no hesitancy
+ in accepting that organelles can be exchanged between species, and that it is conceivable that mitochondria
+ might have been derived from symbiotic bacteria, I am reluctant to believe that something happens just
+ because it could happen. For example, Francis Crick proposed that life on earth originated
+ when genes arrived here on space dust from some other world. That's a theoretical possibility, but what's
+ the point? It just avoids explaining how the highly organized material came into existence somewhere
+ else, and it probably seriously interfered with the consideration of the ways life could arise here.
+ Similarly, some people like to think that mitochondria and chloroplasts were originally bacteria, that came
+ into symbiosis with another kind of living material, consisting of nucleus and cytoplasm. Like Crick's
+ "space germs," it can be argued that it's possible, but the problem is that this explanation can stop people
+ from thinking freshly about the nature of the various organelles, and how they came to exist. (How did cells
+ originate? How did mitochondria originate? "Germs.")
+
+
+ Since I have a view of how cells came to exist, under conditions that exist on earth, I should consider
+ whether that view doesn't also reasonably account for their various components. Sidney Fox's proteinoid
+ microspheres provide a good model for the spontaneous formation of primitive cells; variations of that idea
+ can account for the formation of organelles (such as mitochondria and nuclei within cells, and chromosomes
+ within nuclei). The value of this idea, of a self-stimulating process in mitochondrial generation, is that
+ it suggests many ways to test the idea experimentally, and it suggests explanations for developmental and
+ pathological processes that otherwise would have no coherent explanation.
+
+
+ Proteinoid microspheres and coacervates form by acquiring molecules from solution, condensing them into a
+ separate phase, with its own physical properties. At every phase boundary, there are numerous physical
+ forces, especially electronic properties, that make each kind of interface different from other kinds.
+ Small changes of pH, temperature, of salts and other solutes can alter the interfacial forces,
+ causing particles to dissolve, or grow, or fragment, or to move. In the way that carbon dioxide alters the
+ shapes and electrical affinities of hemoglobin and other proteins, I propose that it increases the stability
+ of the mitochondrial coacervate, causing it to "recruit" additional proteins from its external environment,
+ as well as from its own synthetic machinery, to enlarge both its structure and its functions.
+
+
+ In the relative absence of carbon dioxide, or excess of alternative solutes and adsorbents, such as lactic
+ acid, the stability of the mitochondrial phase would be decreased, and the mitochondria would be degraded in
+ both structure and function. As the back side of the idea that carbon dioxide stabilizes and activates
+ mitochondria, the idea that lactic acid is involved in the degrading of mitochondria can also be tested
+ experimentally, and it is already supported by a considerable amount of circumstantial evidence.
+
+
+ This combination of sensitivity to the environment, with a kind of positive feedback or inertia either
+ upward or downward, corresponds to what we actually see in mitochondrial physiology and pathology.
+
+
+ The Crabtree effect, which is the suppression of respiration by glycolysis, is often described as the simple
+ opposite of the Pasteur effect, in which respiration limits glycolysis to the rate that allows its product
+ to be consumed oxidatively. But the Pasteur effect is a normal sort of control system; when the Pasteur
+ effect fails, as in cancer, there is glycolysis which is relatively independent of respiration, causing
+ sugar to be consumed inefficiently. Embryonic tissues sometimes behave in this manner, leading to the
+ suggestion that glycolysis is closely related to growth. Unlike the logical Pasteur effect, the
+ Crabtree effect tends to lower cellular energy and adaptability. Looking at many situations in which
+ increasing the glucose supply increases lactic acid production and suppresses respiration, leading to
+ maladaptive decrease in cellular energy, I have begun thinking of lactic acid as a toxin. The use of
+ Ringer's lactate solution in medicine has led many people to assume that lactate must be beneficial, or they
+ wouldn't put it in the salt solution that is often used in emergiencies; however, I think its use here, as a
+ buffer, is simply a convenience, because of the instability of some bicarbonate solutions.
+
+
+ On the organismic level, it is clear that lactic acid is "the essence of hyperventilation," and that it
+ produces edema and malfunction on a grand scale: The panic reaction, shock lung, vascular leakiness, brain
+ swelling, and finally multiple organ failure, all can be traced to an excess of lactic acid, and the related
+ features of hyperventilated physiology.
+
+
+ Otto Warburg apparently thought of lactate as simply a sign of the respiratory defect that characterizes
+ cancer. V. S. Shapot at least hinted at its possible role in turning on the catabolic reactions leading to
+ cancer cachexia (wasting). I think a good case can be made for lactate as the cause of the
+ respiratory defect in cancer, just as it is usually the immediate cause of the respiratory derangement of
+ hyperventilation on the organismic level.
+
+
+ The Crabtree effect is usually thought of as just something that happens in tumors, and some tissues that
+ are very active glycolytically, and some bacteria, when they are given large amounts of glucose. But when we
+ consider lactate, which is produced by normal tissues when they are deprived of oxygen or are disturbed by a
+ stress reaction, the Crabtree effect becomes a very general thing. The "respiratory defect" that we can see
+ on the organismic level during hyperventilation, is very similar to the "systemic Crabtree effect" that
+ happens during stress, in which respiration is shut down while glycolysis is activated. Since oxidative
+ metabolism is many times more efficient for producing energy than glycolysis is, it is maladaptive to shut
+ it down during stress.
+
+
+ Since the presence of lactate is so commonly considered to be a normal and adaptive response to stress, the
+ shut-down of respiration in the presence of lactate is generally considered to be caused by something else,
+ with lactate being seen as an effect rather than a cause. Nitric oxide and calcium excess have been
+ identified as the main endogenous antirespiratory factors in stress, though free unsaturated fatty acids are
+ clearly involved, too. However, glycolysis, and the products of glycolysis, lactate and pyruvate,
+ have been found to have a causal role in the suppression of respiration; it is both a cause and a
+ consequence of the respiratory shutdown, though nitric oxide, calcium, and fatty acids are closely involved,
+
+
+ Since lactic acid is produced by the breakdown of glucose, a high level of lactate in the blood means that a
+ large amount of sugar is being consumed; in response, the body mobilizes free fatty acids as an additional
+ source of energy. An increase of free fatty acids suppresses the oxidation of glucose. (This is called the
+ Randle effect, glucose-fatty acid cycle, substrate-competition cycle, etc.) Women, with higher estrogen and
+ growth hormone, usually have more free fatty acids than men, and during exercise oxidize a higher proportion
+ of fatty acids than men do. This fatty acid exposure "decreases glucose tolerance," and undoubtedly
+ explains women's higher incidence of diabetes. While most fatty acids inhibit the
+ oxidation of glucose without immediately inhibiting glycolysis, palmitic acid is unusual, in its inhibition
+ of glycolysis and lactate production without inhibitng oxidation. I assume that this largely has to do with
+ its important function in cardiolipin and cytochrome oxidase.
+
+
+ Exercise, like aging, obesity, and diabetes, increases the levels of circulating free fatty acids and
+ lactate. But ordinary activity of an integral sort, activates the systems in an organized way, increasing
+ carbon dioxide and circulation and efficiency. Different types of exercise have been identified as
+ destructive or reparative to the mitochondria; "concentric" muscular work is said to be restorative to the
+ mitochondria. As I understand it, this means contraction with a load, and relaxation without a load. The
+ heart's contraction follows this principle, and this could explain the observation that heart mitochondria
+ don't change in the course of ordinary aging.
+
+
+ When a person has an accident, or surgery, and goes into shock, the degree of lactic acidema is recognized
+ as an indicator of the severity of the problem. Lactated Ringer's solution has been commonly used to
+ treat these people, to restore their blood pressure. But when prompt treatment with lactated Ringer's
+ solution has been compared with no early treatment at all, the patients who are not "rescuscitated" do
+ better than those who got the early treatment. And when Ringer's lactate has been compared with various
+ other solutions, synthetic starch solutions, synthetic hemoglobin polymer solution, or simply a concentrated
+ solution of sodium chloride, those who received the lactate solution did least well. For example, of 8
+ animals treated with another solution, 8 survived, while among 8 treated with Ringer's lactate, 6 died.
+
+
+ Mitochondrial metabolism is now being seen as the basic problem in aging and several degenerative diseases.
+ The tendency has been to see random genetic deterioration as the driving force behind mitochondrial
+ aging. Genetic repair in mitochondria was assumed not to occur. However, recently two kinds of genetic
+ repair have been demonstrated. One in which the DNA strand is repaired, and another, in which sound
+ mitochondria are "recruited" to replace the defective, mutated, "old" mitochondria.
+
+
+ In ordinary nuclear chromosomal genes, DNA repair is well known. The other kind of repair, in which
+ unmutated cells replace the. genetically damaged cells, has been commonly observed in the skin of the face:
+ During intense sun exposure, mutant cells accumulate; but after a period in which the skin hasn't been
+ exposed to the damaging radiation, the skin is made up of healthy "young" cells.
+
+
+ In the way that the skin can be seen to recover from genetic damage, that had been considered to be
+ permanent and cumulative, simply by avoiding the damaging factor, mitochondrial aging is coming to be seen
+ as both avoidable and repairable.
+
+
+ The stressful conditions that physiologically harm mitochondria are now being seen as the probable cause for
+ the mitochondrial genetic defects that accumulate with aging. Stressful exercise, which has been
+ known to cause breakage of the nuclear chromosomes, is now seen to damage mitochondrial genes, too.
+ Providing energy, while reducing stress, seems to be all it takes to reverse the accumulated mitochondrial
+ genetic damage.
+
+
+ Fewer mitochondrial problems will be considered to be inherited, as we develop an integral view of the ways
+ in which mitochondrial physiology is disrupted. Palmitic acid, which is a major component of the cardiolipin
+ which regulates the main respiratory enzyme, becomes displaced by polyunsaturated fats as aging progresses.
+ Copper tends to be lost from this same enzyme system, and the state of the water is altered as the energetic
+ processes change.
+
+
+ While the flow of carbon dioxide moves from the mitochondrion to the cytoplasm and beyond, tending to remove
+ calcium from the mitochondrion and cell, the flow of lactate and other organic ions into the mitochondrion
+ can produce calcium accumulation in the mitochondrion, during conditions in which carbon dioxide
+ synthesis, and consequently urea synthesis, are depressed, and other synthetic processes are
+ changed.
+
+
+ Glycolysis produces both pyruvate and lactate, and excessive pyruvate produces almost the same inhibitory
+ effect as lactate; since the Crabtree effect involves nitric oxide and fatty acids as well as calcium, I
+ think it is reasonable to look for the simplest sort of explanation, instead of trying to experimentally
+ trace all the possible interactions of these substances; a simple physical competition between the products
+ of glycolysis and carbon dioxide, for the binding sites, such as lysine, that would amount to a phase change
+ in the mitochondrion. Glucose, and apparently glycolysis, are required for the production of nitric
+ oxide, as for the accumulation of calcium, at least in some types of cell, and these coordinated changes,
+ which lower energy production, could be produced by a reduction in carbon dioxide, in a physical
+ change even more basic than the energy level represented by ATP. The use of Krebs cycle substances in the
+ synthesis of amino acids, and other products, would decrease the formation of C02, creating a situation in
+ which the system would have two possible states, one, the glycolytic stress state, and the other, the carbon
+ dioxide producing energy-efficient state.
+
+
+ Besides the frequently discussed interactions of excessively accumulated iron with the unsaturated fatty
+ acids, producing lipid peroxides and other toxins, the accumulated calcium very probably forms some
+ insoluble soaps with the free fatty acids which are released even from intracellular fats during stress.
+ The growth of new mitochondria probably occasionally leaves behind such useless materials,
+ combining soaps, iron, and porphyrins remaining from damaged respiratory enzymes.
+
+
+ When the background of carbon dioxide is high, circulation and oxygenation tend to prevent the anaerobic
+ glycolysis that produces toxic lactic acid, so that a given level of activity will be harmful or helpful,
+ depending on the level of carbon dioxide being produced at rest.
+
+
+ Preventively, avoiding foods containing lactic acid, such as yogurt and sauerkraut, would be helpful, since
+ bacterial lactic acid is much more toxic than the type that we form under stress. Avoiding the
+ stress-promoting antithyroid unsaturated oils is extremely important. Their role in diabetes, cancer, and
+ other age-related and degenerative diseases (and I think this includes the estrogen-promoted autoimmune
+ diseases) is well established. Avoiding phytoestrogens and other things that increase estrogen exposure,
+ such as protein deficiency, is important, because estrogen causes increased levels of free fatty acids,
+ increases the tendency to metabolize them at the expense of glucose metabolism, increases the tissue content
+ of unsaturated fatty acids, and inhibits thyroid functions.
+
+
+ Light promotes glucose oxidation, and is known to activate the key respiratory enzyme. Winter sickness
+ (including lethargy and weight gain), and night stress, have to be included within the idea of the
+ "respiratory defect," shifting to the antirespiratory production of lactic acid, and damaging the
+ mitochondria.
+
+
+ Therapeutically, even powerful toxins that block the glycolytic enzymes can improve functions in a variety
+ of organic disturbances "associated with" (caused by) excessive production of lactic acid. Unfortunately,
+ the toxin that has become standard treatment for lactic acidosis—dichloroacetic acid—is a carcinogen, and
+ eventually produces liver damage and acidosis. But several nontoxic therapies can do the same things:
+ Palmitate (formed from sugar under the influence of thyroid hormone, and found in coconut oil), vitamin
+ Bl, biotin, lipoic acid, carbon dioxide, thyroid, naloxone, acetazolamide, for example.
+ Progesterone, by blocking estrogen's disruptive effects on the mitochondria, ranks along with thyroid and a
+ diet free of polyunsaturate fats, for importance in mitochondrial maintenance.
+
+
+
+ REFERENCES
+
+ Biochim Biophys Acta 1999 Feb 9;1410(2):171-82 Mitochondrial involvement
+ in Alzheimer's
+ disease.Bonilla E, Tanji K, Hirano M, Vu TH, DiMauro S, Schon EA.
+
+
+ Rev Pneumol Clin 1986;42(5):238-41.
+ Acid-base balance and blood lactate and pyruvate levels in albino rats bred under normobaric hypoxia or
+ normoxia, after muscular work in a hypoxic or hypoxic-hypercapnic environment.
+ Quatrini U, Licciardi A.
+
+
+ Muscle Nerve 1999 Feb;22(2):258-61.
+ Acute exercise causes mitochondrial DNA deletion in rat skeletal muscle. Sakai Y, Iwamura Y,
+ Hayashi J, Yamamoto N, Ohkoshi N, Nagata H.
+
+
+ HumMol Genet 1999 Jun;8(6): 1047-52. Gene shifting:
+ a novel therapy for mitochondrial myopathy. Taivassalo T, Fu K, Johns T, Arnold D,
+ Karpati G, Shoubridge EA.
+
+
+ Brain Dev 1989;11(3):195-7. Effect of sodium dichloroacetate on human pyruvate metabolism.
+ Naito E, Kuroda Y, Toshima K, Takeda E, Saijo T, Kobashi H, Yokota I, Ito M.
+
+
+ Mech Ageing Dev 1987 Aug;39(3):281-8.
+ Lack of age-dependent changes in rat heart mitochondria.
+ Manzelmann MS, Harmon HJ.
+
+
+ Adv Shock Res 1978,1:105-16.
+ The effect of mitochondrial dysfunction on glucose metabolism during shock. Rhodes RS.
+
+
+ Biochem J 1982 Dec 15;208(3):695-701 Exercise-induced alterations of hepatic mitochondrial
+ function.
+ Tate CA, Wolkowicz PE, McMillin-Wood, J.
+
+
+ Am J Physiol 1997 Dec;273(6 Pt 2):F869-76. Neurosteroid inhibition of cell death. Waters
+ SL, Miller GW, Aleo MD, Schnellmann RG.
+
+
+ J Pharmacol Exp Ther 1990. May;253(2):628-35. Protection against hypoxic injury in isolated-perfused
+ rat heart by ruthenium red. Park Y, Bowles DK, Kehrer JP.
+
+
+ Environ Health Perspect 1984, Aug;57:281-7. Cell calcium, cell injury and cell death. Trump
+ BF, Berezesky IK, Sato T, Laiho KU, Phelps PC, DeClaris N.
+
+
+ Anesth Analg 1996 Oct;83(4):782-8.
+ Small-volume resuscitation using hypertonic saline improves organ perfusion in burned rats.
+ Kien ND, Antognini JF, Reilly DA, Moore PG.
+
+
+ Respir Physiol 1977 Dec;31(3):387-95.
+ Post-hypercapnia recovery in the dog: arterial blood acid-base equilibrium and
+ glycolysis. Saunier C, Horsky P, Hannhart B, Garcia-Carmona T, Hartemann D.
+
+
+ Am J Physiol 1997 Nov;273(5 Pt 1):C1732-8
+ Glycolysis inhibition by palmitate in renal cells cultured in a two-chamber system. Bolon C;
+ Gauthier C; Simonnet H.
+
+
+ Can J Appi Physiol 1998 Dec;23(6):558-69.
+ The role of glucose in the regulation of substrate interaction during exercise. Sidossis LS.
+
+
+ Am J Clin Nutr 1998 Mar;67(3 Suppl):527S-530S. Effect of lipid oxidation on glucose utilization in
+ humans. JequierE.
+
+
+ Ann N Y Acad Sci 1998 Nov 20;854:224-38. Mitochondrial free radical production and aging in mammals
+ and birds. Barja G.
+
+
+ Science 1999 Aug 27;285(5432): 1390-3.
+ Gene expression profile of aging and its retardation by caloric restriction. Lee CK, Klopp RG,
+ Weindruch R, Prolla TA.
+
+
+ Nucleic Acids Res 1999 Nov 15;27(22):4510-6.
+ Nitric oxide-induced damage to mtDNA and its subsequent repair. Grishko VI, Druzhyna N, LeDoux
+ SP, Wilson GL.
+
+
+ Am J Physiol 1998 Jun;274(6 Pt 1):G978-83.
+ Neural injury, repair and adaptation in the GI tract. I. New insights into neuronal injury:
+ a cautionary tale. Hall KE, Wiley JW.
+
+
+ Proc Nati Acad Sci U S A 1999 Dec 21;96(26): 14706-14711.
+ Structural details of an interaction between cardiolipin and an integral membrane protein.
+ McAuley KE, Fyfe PK, Ridge JP, Isaacs NW, Cogdell RJ, Jones MR.
+
+
+ J. Appi Physiol 1991 Apr;70(4): 1720-30..
+ .Metabolic and work efficiencies during exercise in Andean natives.
+ Hochachka PW, Stanley C, Matheson GO, McKenzie DC, Allen PS, Parkhouse WS.
+
+
+ JDev Physiol 1990 Sep;14(3): 139-46.
+ Effect of lactate and beta-hydroxybutyrate infusions on brain metabolism in the fetal sheep.
+ Harding JE, Charlton VE.
+
+
+ J Trauma 1999 Feb;46(2):286-91,
+ The effects of diaspirin cross-linked hemoglobin on hemodynamics, metabolic acidosis, and survival in
+ burned rats.: Soltero RG; Hansbrough JF.
+
+
+ J Trauma 1999 Apr;46(4):582-8; discussion 588-9, Resuscitation with lactated Ringer's solution in
+ rats with hemorrhagic shock induces immediate apoptosis. Deb S; Martin B; Sun L; Ruff P; Burris
+ D; Rich N; DeBreux S; Austin B; Rhee P.
+
+
+ Am J Physiol 1996 Oct;271(4 Pt 1):C1244-9,
+ Glucose and pyruvate regulate cytokine-induced nitric oxide production by cardiac myocytes.
+ Oddis CV; Finkel MS.
+
+
+ Biochim Biophys Acta 1999 Feb 9;1410(2):171-82. Mitochondrial involvement in Alzheimer's disease.
+ Bonilla E, Tanji K, Hirano M, Vu TH, DiMauro S, Schon EA.
+
+
+ Adv Exp Med Biol 1995,384:185-94.
+ Metabolic correlates of fatigue from different types of exercise in man. Vollestad NK.
+
+
+ J Biol Chem 1995 Jun 23;270(25): 14855-8. Nitric oxide activates the glucose-dependent mobilization
+ of arachidonic acid in a macrophage-like cell line (RAW 264.7) that is largely mediated by
+ calcium-independent phospholipase A2.
+ GrossRW; Rudolph AE; Wang J; Sommers CD; Wolf MJ.
+
+
+ © Ray Peat Ph.D. 2016. All Rights Reserved. www.RayPeat.com
+
+
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+
+ Multiple sclerosis, protein, fats, and progesterone
+
+
+ Multiple sclerosis, protein, fats, and progesterone
+
+
+
+
+
+
+
+
+
+ We are always subjected to antigenic burdens. The important question has to do with our ability to limit the
+ inflammatory response to these burdens.
+
+
+ In MS, it is clear that the inflammatory process itself is destructive, and that estrogen is a major
+ predisposing factor. Unsaturated fatty acids, and dietary imbalance of amino acids interact closely with
+ hyperestrogenism and hypothyroidism to produce the autoimmune degenerative diseases.
+
+
+ Reduction of the mediators of inflammation is better than augmenting a single antiinflammatory agent such as
+ cortisol. Although immunosuppressive drugs, including the "essential fatty acids," do alleviate inflammatory
+ symptoms temporarily, they probably contribute to the underlying pathology.
+
+
+ People with MS have chronically increased production of cortisol. This creates a distortion of protein
+ assimilation, resembling a nutritional protein deficiency. Excessive serotonin and estrogen cause a
+ relatively uncontrolled production of cortisol. A vicious circle of inflammatory mediators and amino acid
+ imbalance can result.
+
+
+ Depression, lupus, migraine, menopause, diabetes, and aging have several important metabolic features in
+ common with MS.
+
+
+
+ Popular therapies are illogical, and are likely to cause disease progression.
+
+
+ High quality protein, thyroid, pregnenolone and progesterone tend to correct the underlying pathology. These
+ are antiinflammatory, but they are not immunosuppressive or catabolic.
+
+
+ High altitude and sunny climate are associated with a low incidence of MS.
+
+
+
+
+
+
+
+ Multiple sclerosis (MS), like other autoimmune diseases, affects women more often than men (about 2 to 1),
+ has its onset during the reproductive years (especially after the age of 30, when estrogen is very high), is
+ often exacerbated premenstrually, and is sometimes alleviated by pregnancy (Drew and Chavez, 2000), when
+ progesterone is very high. Women with a high ratio of estrogen to progesterone have been found to have the
+ most active brain lesions (Bansil, et al., 1999). Most of the mediators of inflammation that are involved in
+ MS--mast cells, nitric oxide (NO), serotonin, prolactin, lipid peroxidation, free fatty acids,
+ prostaglandins and isoprostanes, and the various cytokines (IL, TNF)--are closely associated with estrogen's
+ actions, and in animals, autoimmune diseases can be brought on by treatment with estrogen (Ahmed and Talal).
+
+
+
+ The strong association of MS with estrogen has led to an illogical, but popular and well-publicized medical
+ conclusion that estrogen is protective against MS, and some have claimed that estrogen has beneficial
+ therapeutic effects. This strange way of thinking has its equivalent in the idea that, since women are much
+ more likely than men to develop Alzheimer's disease, estrogen is protective against it; or that, since women
+ have more fragile bones than men do, and their progressive bone loss occurs during the times of their
+ greatest exposure to estrogen, estrogen prevents osteoporosis.
+
+
+ In this medical environment, close associations between estrogen and degenerative diseases are acknowledged,
+ but they are given a meaning contrary to common sense by saying that the association occurs because there
+ isn't enough estrogen. The stove burns you because it isn't hot enough.
+
+
+ As Dave Barry would say, I'm not making this up. Recently well publicized articles have suggested that
+ estrogen protects the brain (even against stroke!) because it increases serotonin and NO. There is something
+ almost esthetically pleasing when so many major errors are concentrated into a single article. Nitric oxide
+ and serotonin are both neurotoxic (Joseph, et al., 1991; Skaper, et al., 1996; Parkinson, et al., 1997;
+ Santiago, et al., 1998; Barger, et al., 2000), as a result of suppressing mitochondrial respiration. NO
+ plays a major role in lipid peroxidation and demyelination. It's interesting to see serotonin and NO openly
+ associated with estrogen, whose mitochondrial toxicity has been carefully hidden from public view.
+
+
+ There are several theories about the cause of MS, old theories about genes and viruses, and newer theories
+ about bacteria, vitamin deficiencies, oil deficiencies, poisons, and reactions to vaccinations (especially
+ for hepatitis B and influenza). The only theory that has been abandoned is the 19th century psychiatric
+ theory about "hysterical paralysis," though occasionally someone does still talk about emotional causes of
+ multiple sclerosis; the term "female hysteria" has evolved into "conversion disorder."
+
+
+ Each of the main theories has a few facts that seem to support it, but neglects to account for many other
+ facts. Everyone agrees that the immune system is involved in MS in some way, but that's really where the
+ problem starts, because of the idea that inflammation is an intrinsic part of immunity. If "inflammation is
+ necessary and good," then it becomes a problem to define exactly where the boundary is between an
+ appropriate reaction and a degenerative process. Edema, reduced cellular respiration, loss of normal
+ functions, fibrosis in its various degrees, each component of inflammation can be seen in a good light, as
+ part of a "defensive immune reaction." When tissue injury leads to repair, it "must" be seen as beneficial,
+ even if it leads to the formation of a scar in place of functional tissue, because the comparison is between
+ an imagined worst possible outcome, and an imperfect recovery, rather than comparing the inflammatory
+ process with the possibility that a potentially noxious agent might have done no harm at all.
+
+
+ The simplest illustration of how inflammation relates to the organism's resources was an experiment in which
+ blood glucose was varied, while an animal was exposed to chemicals that varied from mildly irritating to
+ potentially deadly. When the animal had very low blood sugar, the mildest irritant could be deadly, but when
+ its blood glucose was kept very high, even the deadly antigens were only mildly irritating. Varying the
+ blood sodium concentration had similar, but weaker, effects.
+
+
+ There is a tendency to see inflammation not only as a normal part of immunity, but to see it as being
+ proportional to the nature of the antigen, except when the immune system has been primed for it by previous
+ contact, in which case the organism will either not react at all (because it has become immune), or it will
+ react much more violently than it did on the first exposure, because it has become allergic. But, in
+ reality, the mere concentration of glucose and sodium in the blood (and of thyroid, and many other
+ substances that aren't considered to be part of the immune system) can make a tremendous difference in the
+ degree of "immunological" reaction.
+
+
+ In the excessively sensitive condition produced by hypoglycemia, several things happen that contribute to
+ the maladaptive exaggerated inflammatory response.
+
+
+ Adrenaline increases in hypoglycemia, and, if the adrenaline fails to convert glycogen into glucose, it will
+ provide an alternative fuel by liberating free fatty acids from fat cells.
+
+
+
+ If the liberated fatty acids are unsaturated, they will cause serotonin to be secreted, and both serotonin
+ and the unsaturated fatty acids will suppress mitochondrial respiration, exacerbating the hypoglycemia. They
+ will stimulate the release of cytokines, activating a variety of immunological and inflammatory processes,
+ and they will cause blood vessels to become leaky, creating edema and starting the first stages of fibrosis.
+ Both adrenaline and serotonin will stimulate the release of cortisol, which mobilizes amino acids from
+ tissues such as the large skeletal muscles. Those muscles contain a large amount of cysteine and tryptophan,
+ which, among other effects, suppress the thyroid. The increased tryptophan, especially in the presence of
+ free fatty acids, is likely to be converted into additional serotonin, since fatty acids release tryptophan
+ from albumin, increasing its entry into the brain. Free fatty acids and increased serotonin reduce metabolic
+ efficiency (leading to insulin resistance, for example) and promote an inflammatory state.
+
+
+ Fats in the blood-stream have easy access to the brain, and the unsaturated free fatty acids produce brain
+ edema (Chan, et al., 1983, 1988). When brain edema is caused by vascular leakage, proteins that are normally
+ excluded can enter. The stimulated, excited and fatigued brain exchanges glutamine for tryptophan,
+ accelerating its uptake from the blood.
+
+
+ When a tissue is injured or stressed, antibodies are formed in response to the altered components of that
+ tissue. Therefore, we could call a bruise or a sprain an autoimmune condition, but there are no commercial
+ tests for bruised-shin antibodies. The availability of tests for specific antibodies seems to be the
+ essential factor in classifying a condition as autoimmune, as in "autoimmune thyroiditis." Unfortunately,
+ this way of using language is nested in a culture that is full of unrealistic ideas of causality, and
+ thousands of people build their careers on the search for the "mutated genes that are responsible for the
+ disease," and for the drugs that will correct the defect.
+
+
+ Early in the study of immunology, the focus was on antibodies. Even earlier, inflammation had been
+ conceptualized in terms of the "humors," and other prescientific ideas. As soon as multiple
+ sclerosis/hysterical paralysis was classified as an autoimmune disease, primitive ideas about the nature of
+ the immune system, interacting with primitive ideas about the nature of the brain and the structure of
+ cells, blended into the various theories of what the disease is.
+
+
+ Rather than seeing immunological nerve damage as the cause of all the other features of multiple sclerosis,
+ I think it's important to look at some of the general features of the condition, as contexts in which to
+ interpret the events in the nerves.
+
+
+ It has been known for a long time that the incidence of MS tends to increase with distance from the equator.
+ Incidence is low in sunny dry climates, and at high altitudes. Two clear dietary influences have been found:
+ eating pork, and horsemeat.
+
+
+ People with MS don't regulate their body temperature very well. Their nerve conduction is slow, and in
+ normal people, conduction is faster at higher temperatures, but in people with MS the conduction is slower
+ at the normal temperature of 98.6O F than at lower temperatures. A subnormal temperature is also associated
+ with old age, and with the hot flashes of menopause.
+
+
+ Brain metabolism of glucose is very low in multiple sclerosis, and in my own observations, the general
+ metabolic rate is subnormal. However, some people reason that the hypometabolism is caused by the lesions,
+ rather than vice versa.
+
+
+
+ Animals that lack the unsaturated fatty acids have a higher metabolic rate and ability to use glucose,
+ converting it to CO2 more readily, have a greater resistance to toxins (Harris, et al., 1990; even cobra
+ venom: Morganroth, et al., 1989), including endotoxin (Li, et al., 1990)--preventing excessive vascular
+ leakage--and to immunological damage (Takahashi, et al., 1992), and to trauma, and their neuromuscular
+ response is accelerated while fast twitch muscles are less easily fatigued (Ayre and Hulber, 1996).
+
+
+ In people with MS, the blood is more viscous, and the platelets tend to clump together more easily. Their
+ cortisol level is higher than normal, and their pituitary adrenal-cortex-stimulating hormone is harder to
+ suppress. This is a condition that is also seen in depression and old age. Despite the chronically elevated
+ cortisol, people with MS typically have hypoglycemia. They are occasionally found to have low blood sodium,
+ hyponatremia, but this is hard to determine when the blood's water content is variable. Their prolactin is
+ likely to be high, and this can result from high estrogen, high serotonin, low sodium, or low thyroid.
+ Drinking too much water can increase prolactin, and can damage the nerves' myelin enclosures; too much
+ serotonin tends to cause excessive drinking. Disturbances of blood glucose, sodium, and water content can
+ disrupt the brain's myelin structure. High estrogen disturbs the blood osmotically, making it retain too
+ much water in relation to the solutes, and this relates to many of estrogen's effects; since simple osmotic
+ variations can damage the myelin structures, it seems that this mechanism should be investigated thoroughly
+ before it is assumed that the immunological events are primary.
+
+
+ Mast cells, which promote inflammation by releasing substances such as histamine and serotonin (and make
+ blood vessels leaky), are more numerous in the brain in multiple sclerosis than in normal brains. Since
+ platelet clumping releases serotonin, and also because serotonin excess is suggested by so many other
+ features of MS, serotonin antagonists (ondansetron and ketanserin, for example) have been used
+ therapeutically with success.
+
+
+ Estrogen causes mast cells to release their inflammatory mediators, and it causes platelets to aggregate,
+ releasing their serotonin. Since estrogen dominance is closely associated with the presence of active brain
+ lesions, antiestrogen therapy would seem obvious in MS. Progesterone counteracts estrogen's effects on both
+ mast cells and platelets.
+
+
+
+ Aspirin protects against a variety of inflammatory processes, but it's most famous for the inhibition of
+ prostaglandins. While aspirin is often used to relieve pain in MS, and another inhibitor of prostaglandin
+ synthesis, indomethacin, has been used therapeutically in MS, it would seem appropriate to investigate more
+ carefully aspirin's possible role in preventing or relieving MS.
+
+
+ A simple protein deficiency has many surprising effects. It lowers body temperature, and suppresses the
+ thyroid, but it increases inflammation and the tendency of blood to clot. Since the brain and heart and
+ lungs require a continuous supply of essential amino acids if they are to continue functioning, in the
+ absence of dietary protein, cortisol must be produced continuously to mobilize amino acids from the
+ expendable tissues, which are mainly the skeletal muscles. These muscles have a high concentration of
+ tryptophan and cysteine, which suppress the thyroid. Cysteine is excitoxic, and tryptophan is the precursor
+ for serotonin. Presumably, their presence in, and stress-induced release from, the muscles is one of the
+ mechanisms that reduce metabolic activity during certain types of stress.
+
+
+ When pregnant animals are deprived of protein, the newborn animals have abnormally high levels of serotonin,
+ and the enzymes responsible for that excess tend to maintain the serotonin excess even when they are grown
+ and have adequate protein. This is analogous to the effect of excess estrogen early in life, which creates a
+ tendency to develop breast or prostate cancer in adulthood. It would be interesting to study the gestational
+ experience, e.g., length of gestation and birth weight, of the people who later develop MS.
+
+
+ Although people in the northern countries aren't normally protein-starved, they do tend to get a large part
+ of their protein from the muscle meats. In traditional cultures, all parts of the food animals were
+ eaten--chicken feet, heads, and necks, animals' ears and eyeballs, etc.--and so the amino acid balance was
+ favorable for maintaining a high metabolic rate and preventing stress.
+
+
+
+ The observation that multiple sclerosis is associated with the consumption of pork and horsemeat, but not
+ beef, lamb, or goat, is very interesting, since the fat of those animals is essentially like the fats of the
+ plant materials that they eat, meaning that it is extremely high in linoleic and linolenic acids. The rumen
+ of cows, sheep, and goats contains bacteria that convert the polyunsaturated fats into more saturated fats.
+ Unsaturated fats inhibit the enzymes that digest protein, and MS patients have been reported to have poor
+ digestion of meat (Gupta, et al., 1977).
+
+
+ The polyunsaturated fats are in themselves toxic to mitochondria, and suppress glucose oxidation, and
+ inhibit the thyroid function, with the same suppressive effect on the ability to oxidize glucose, but they
+ are also turned, enzymically, into the prostaglandins, and non-enzymically, by spontaneous lipid
+ peroxidation, into the toxic isoprostanes. The isoprostanes, and some of the prostaglandins, are elevated in
+ the brain and other tissues of people with MS.
+
+
+ Lipid peroxidation is very high in multiple sclerosis. Nitric oxide (whose synthesis is promoted by estrogen
+ in most parts of the brain) is a free radical that activates peroxidation.
+
+
+ Lipid peroxidation selectively destroys, naturally, the unstable polyunsaturated fats. In atherosclerosis,
+ the blood vessel plaques contain very little unsaturated fat. This is because they are peroxidized so
+ rapidly, but their high ratio of saturated to unsaturated fats has been used to argue that the
+ polyunsaturated oils are "heart protective." Similar arguments are often made in MS, though some studies
+ don't support the idea that there is a lack of any of the unsaturated fats. Since lipid peroxidation is very
+ high, it would be reasonable to assume that there was an abundance of polyunsaturated fats being peroxidized
+ through reactions with catalysts such as iron (S.M. LeVine, 1997) and nitric oxide and peroxynitrile.
+
+
+ I believe that an important aspect of the intolerance for heat so often reported in people with MS could be
+ the tendency of relative hyperthermia to release increased amounts of free fatty acids into the blood
+ stream. Women, because of estrogen's effects, usually have much higher levels of free fatty acids in the
+ blood than men do. Estrogen increases the release of free fatty acids from stored fat, and the unsaturated
+ fats synergize with both estrogen and prolactin, increasing their effects.
+
+
+ Temperature regulation apparently involves some nerve cells that sense temperature very accurately, and
+ change their activity accordingly. Water has a remarkably high heat capacity, meaning that it takes a
+ relatively large amount of heat to change its temperature. The "disappearing heat" is being consumed by
+ structural changes in the water. Proteins have the same sort of structural complexity as water, and together
+ they can make effective temperature transducers, "thermometers." (Other substances tend to undergo major
+ structural changes only as they melt or vaporize. The famous "liquid crystals" have a few distinct
+ structural phases, but cytoplasm is like a very subtle liquid crystal.) The "thermostat cells" are actually
+ responding to a degree of internal structure, not to the temperature in the abstract. So things that change
+ their internal structure will modify their temperature "set-point."
+
+
+
+ Increased estrogen causes an animal to lower its temperature, and it probably does this by increasing the
+ "structural temperature" of the thermostat cells, "melting" their internal structure. Progesterone causes
+ the animal to increase its temperature, and it apparently does this by increasing the structure/decreasing
+ the structural temperature of the thermostat cells. If you put ice in the thermostat, the room gets hot.
+
+
+ A cell's internal structure is equivalent to its readiness to work. Fatigue represents a slightly "melted"
+ state of the cell, in which structure appears to have been consumed along with the chemical energy reserves.
+ Experiments that demonstrated this effect were very clear, but they were ignored because they didn't fit
+ people's stereotyped idea of the cell. With a very sensitive thermometer, it's possible to measure the heat
+ produced by a nerve when it is stimulated. That's not surprising. But it's surprising that, when the nerve
+ is recovering from the stimulation, it absorbs heat from its environment, lowering the temperature locally.
+ That even violated some people's conception of "entropy," but it can easily be demonstrated that changing
+ the form of some materials changes their heat capacity, as when a rubber band is stretched (it gets hot), or
+ contracts (it gets cooler).
+
+
+ The excitants, estrogen and cortisol, slow the conduction of nerves, because they cause its internal
+ structure to be dissipated. They create a "pre-fatigued" state in the cell.
+
+
+ In experiments with rabbit hearts, Szent-Gyorgyi showed that estrogen decreased the heart's readiness to
+ work, and that progesterone increased its readiness to work, and he said it did this by "building
+ structure." He pointed out that, for a given drug or other stimulus, cells have a characteristic response,
+ becoming either more activated or more inhibited, but he showed that, outside the normal concentration or
+ intensity range of the stimulus, a cell's response is often reversed.
+
+
+ If this is the situation in the nerves in MS, it explains the strange behavior, in which warming the nerve
+ reduces its function. The implication is that internal structure (and energy) must be restored to the
+ nerves. In experiments that I have described in previous newsletters, increasing sodium, ATP, carbon
+ dioxide, and progesterone, and increasing the ratio of magnesium to calcium, have been found to increase
+ cellular energy and structure. The thyroid hormone is ultimately responsible for maintaining cells' energy
+ and structure, and responsiveness, but if it is increased suddenly without allowing all the other factors to
+ adjust, it will raise the temperature too suddenly. It needn't take a long time, but all the factors have to
+ be present at the same time.
+
+
+
+ Serotonin, melatonin, estrogen, and polyunsaturated fats all tend to lower body temperature. Since estrogen
+ and the unsaturated fats are cellular excitants, the actual decrease in body temperature helps to offset
+ their excitatory effects.
+
+
+ Both bright light and high altitude tend to reduce serotonin's effects. The tissue carbon dioxide retained
+ at high altitude reduces the incidence of many diseases, and multiple sclerosis might be affected as heart
+ disease and cancer are. It is known that carbon dioxide is involved in myelin's regulation of its own water
+ content. Hyperventilation, by causing a loss of carbon dioxide, releases both histamine and serotonin,
+ making blood more viscous, while making blood vessels more permeable, and causing them to constrict.
+
+
+ If people with MS have developed it through the interactions of excessive estrogen, serotonin, unsaturated
+ fats, iron, and water, and deficient thyroid, and deficient pregnenolone produced in the myelin-forming
+ cells (oligodendrocytes), there are many things that can be done to stop its progress, and possibly to
+ reverse it.
+
+
+ Since a sudden increase in temperature will release increased amounts of the pro-inflammatory fats, things
+ should be changed gradually. Increased salt is thermogenic, but increased magnesium is protective against
+ hyperthermia, so increased magnesium (epsom salts baths, for example, coffee, fruits, some vegetables and
+ meats) would be helpful. Magnesium is rapidly lost from cells in hypothyroidism. Sugar, when accompanied by
+ fats and minerals, as in milk, is needed to lower cortisol, and to maintain thyroid activity. Balanced
+ proteins, such as cheese, potatoes, eggs, and beef- or lamb-broth (for the gelatin and mineral content in
+ particular) will prevent the tryptophan excess that suppresses the thyroid and is potentially a nerve toxin.
+ Saturated fats, used regularly, reduce the immediate toxic antimetabolic effects of the stored unsaturated
+ fats, but it takes a long time to change the balance of stored fats.
+
+
+ Since aspirin lowers temperature, is antiinflammatory, in some situations antiestrogenic, and is a powerful
+ antioxidant, it is likely that it would alleviate symptoms and prevent progression of MS, as it does in
+ other degenerative diseases. Since platelet aggregation is likely to be involved in the focuses of
+ inflammation, aspirin might help to prevent the formation of new areas of damage.
+
+
+
+ While the glucocorticoids are useful for their antiinflammatory actions, cortisol is known to promote the
+ killing of brain cells by excitotoxicity. Since estrogen decreases GABA, and both estrogen and serotonin
+ activate the excitatory amino acid transmitters, the addition of synthetic glucocorticoids to the
+ pre-existing cortisol excess is likely to damage parts of the brain in addition to the inflamed areas.
+
+
+ The excess cortisol of depression, old age, and hyperestrogenism often comes down with use of a thyroid
+ supplement, but pregnenolone has a very direct action (in opposition to serotonin) that can quiet the
+ pituitary, reducing ACTH and cortisol. Progesterone has some similar effects, and is protective against
+ excess cortisol, and is a major factor in nerve and brain restoration. Thyroid, progesterone, and
+ pregnenolone are all involved in the formation of new myelin, and in the prevention of the edema that
+ damages it.
+
+
+ Since thyroid and progesterone decrease the formation of estrogen in inflamed tissue, while cortisol
+ stimulates its formation, it would seem wise to use thyroid and progesterone for their immediate
+ antiinflammatory effects, which include the inhibition of NO formation (Drew and Chavez, 2000), and their
+ lack of the excitotoxic, estrogen-stimulating effects of the glucocorticoids. While the glucocorticoids are
+ catabolic and liberate cysteine and tryptophan from muscles, thyroid and progesterone are not catabolic, and
+ protect against the toxic consequences of those amino acids.
+
+ REFERENCES
+
+ J Neurol Neurosurg Psychiatry 1988 Feb;51(2):260-5. Perivascular iron deposition and other vascular damage
+ in multiple sclerosis. Adams CW. "The multiple sclerosis cases showed venous intramural fibrinoid deposition
+ (7%), recent haemorrhages (17%), old haemorrhages revealed by haemosiderin deposition (30%), thrombosis (6%)
+ and thickened veins (19%). In all, 41% of all multiple sclerosis cases showed some evidence of vein damage."
+ "Haemosiderin deposition was common in the substantia nigra and other pigmented nuclei in all cases. It is
+ concluded that the cerebral vein wall in multiple sclerosis is subject to chronic inflammatory damage, which
+ promotes haemorrhage and increased permeability, and constitutes a form of vasculitis."
+
+
+
+ Am J Pathol 1985 Dec;121(3):531-51. Sex hormones, immune responses, and autoimmune diseases. Mechanisms of
+ sex hormone action. Ansar Ahmed S, Penhale WJ, Talal N. "Immune reactivity is greater in females than in
+ males. In both experimental animals and in man there is a greater preponderance of autoimmune diseases in
+ females, compared with males. Studies in many experimental models have established that the underlying basis
+ for this sex-related susceptibility is the marked effects of sex hormones. Sex hormones influence the onset
+ and severity of immune-mediated pathologic conditions by modulating lymphocytes at all stages of life,
+ prenatal, prepubertal, and postpubertal."
+
+
+ J Appl Physiol 1996 Feb;80(2):464-71. Effects of changes in dietary fatty acids on isolated skeletal muscle
+ functions in rats. Ayre KJ, Hulbert AJ The effects of manipulating dietary levels of essential
+ polyunsaturated fatty acids on the function of isolated skeletal muscles in male Wistar rats were examined.
+ Three isoenergetic diets were used: an essential fatty acid-deficient diet (EFAD), a diet high in essential
+ (n-6) fatty acids [High (n-6)], and a diet enriched with essential (n-3) fatty acids [High (n-3)]. After 9
+ wk, groups of rats on each test diet were fed a stock diet of laboratory chow for a further 6 wk. Muscle
+ function was examined by using a battery of five tests for soleus (slow twitch) and extensor digitorum
+ longus (EDL; fast twitch). Tests included single muscle twitches, sustained tetanic contractions,
+ posttetanic potentiation, sustained high-frequency stimulation, and intermittent low-frequency stimulation.
+ Results for muscles from the High (n-6) and High (n-3) groups were very similar. However, the EFAD diet
+ resulted in significantly lower muscular tensions and reduced response times compared with the High (n-6)
+ and High (n-3) diets. Peak twitch tension in soleus muscles was 16-21% less in the EFAD group than in the
+ High (n-6) and High (n-3) groups, respectively [analysis of variance (ANOVA), P < 0.01). During
+ high-frequency stimulation, EDL muscles from the EFAD rats fatigued 32% more quickly (ANOVA, P < 0.01)].
+ Also, twitch contraction and half-relaxation times were significantly 5-7% reduced in the EFAD group (ANOVA,
+ P < 0.01). During intermittent low-frequency stimulation, soleus muscles from the EFAD group generated
+ 25-28% less tension than did the other groups (ANOVA, P < 0.01), but in EDL muscles from the EFAD group,
+ endurance was 20% greater than in the High (n-6) group (ANOVA, P < 0.05). After 6 wk on the stock diet,
+ there were no longer any differences between the dietary groups. Manipulation of dietary fatty acids results
+ in significant, but reversible, effects in muscles of rats fed an EFAD diet.
+
+
+
+ Endocr Res 1999 May;25(2):207-14. Prolactin secretion is increased in patients with multiple sclerosis. Azar
+ ST, Yamout B
+
+
+ Acta Neurol Scand 1999 Feb;99(2):91-4. Correlation between sex hormones and magnetic resonance imaging
+ lesions in multiple sclerosis. Bansil S, Lee HJ, Jindal S, Holtz CR, Cook SD "Patients with high estradiol
+ and low progesterone levels had a significantly greater number of Gd enhancing lesions than those with low
+ levels of both these hormones. Patients with a high estrogen to progesterone ratio had a significantly
+ greater number of active MRI lesions than those with a low ratio."
+
+
+ J Neuroimmunol 1996 Mar;65(1):75-81. Circulating antibodies directed against conjugated fatty acids in sera
+ of patients with multiple sclerosis. Boullerne A, Petry KG, Geffard M "These results suggest that in MS and
+ RA, autoepitopes on cell membranes that are normally hidden from the immune system become immunogenic. This
+ may arise because of previous membrane disruption by oxidative processes."
+
+
+ J Neurosci Res 2000 Nov 15;62(4):503-9. Dehydroepiandrosterone inhibits microglial nitric oxide production
+ in a stimulus-specific manner. Barger SW, Chavis JA, Drew PD.
+
+
+ J Exp Med 1984 Nov 1;160(5):1532-43. Inhibition of autoimmune neuropathological process by treatment with an
+ iron-chelating agent. Bowern N, Ramshaw IA, Clark IA, Doherty PC "Iron is believed to influence both the
+ migration and function of immune effector cells. It can also act as a catalyst in the formation of free
+ radicals, which are highly toxic agents causing tissue damage in sites of inflammation."
+
+
+
+ J Neurol Neurosurg Psychiatry 1981 Apr;44(4):340-3. Rheological and fibrinolytic findings in multiple
+ sclerosis. Brunetti A, Ricchieri GL, Patrassi GM, Girolami A, Tavolato B. "The whole blood viscosity was
+ found to be increased in multiple sclerosis."
+
+
+ J Neurochem 1988 Apr;50(4):1185-93. Induction of intracellular superoxide radical formation by arachidonic
+ acid and by polyunsaturated fatty acids in primary astrocytic cultures. Chan PH, Chen SF, Yu AC "Other
+ PUFAs, including linoleic acid, linolenic acid, and docosahexaenoic acid, were also effective in stimulating
+ NBF formation in astrocytes, whereas saturated palmitic acid and monounsaturated oleic acid were
+ ineffective. Similar effects of these PUFAs were observed in malondialdehyde formation in cells and lactic
+ acid accumulation in incubation medium. These data indicate that both membrane integrity and cellular
+ metabolism were perturbed by arachidonic acid and by other PUFAs."
+
+
+ Ann Neurol 1983 Jun;13(6):625-32. Induction of brain edema following intracerebral injection of arachidonic
+ acid. Chan PH, Fishman RA, Caronna J, Schmidley JW, Prioleau G, Lee J "Intracerebral injection of
+ polyunsaturated fatty acids (PUFAs), including linolenic acid (18:3) and arachidonic acid (20:4), caused
+ significant increases in cerebral water and sodium content concomitant with decreases in potassium content
+ and Na+- and K+- dependent adenosine triphosphatase activity. There was gross and microscopic evidence of
+ edema. Saturated fatty acids and monounsaturated fatty acid were not effective in inducing brain edema. The
+ [125I]-bovine serum albumin spaces increased twofold and threefold at 24 hours with 18:3 and 20:4,
+ respectively, indicating vasogenic edema with increased permeability of brain endothelial cells" "These data
+ indicate that arachidonic acid and other PUFAs have the ability to induce vasogenic and cellular brain edema
+ and further support the hypothesis that the degradation of phospholipids and accumulation of PUFAs,
+ particularly arachidonic acid, initiate the development of brain edema in various disease states."
+
+
+ Med Sci Sports Exerc 1997 Jan;29(1):58-62. Effects of acute physical exercise on central serotonergic
+ systems. Chaouloff F "Works from the 1980's have established that acute running increases brain serotonin
+ (5-hydroxytryptamine: 5-HT) synthesis in two ways. Lipolysis-elicited release of free fatty acids in the
+ blood compartment displaces the binding of the essential amino acid tryptophan to albumin, thereby
+ increasing the concentration of the so-called "free tryptophan" portion, and because exercise increases the
+ ratio of circulating free tryptophan to the sum of the concentrations of the amino acids that compete with
+ tryptophan for uptake at the blood-brain barrier level, tryptophan enters markedly in the brain
+ compartment." "Indirect indices of 5-HT functions open the possibility that acute exercise-induced increases
+ in 5-HT biosynthesis are associated with (or lead to) increases in 5-HT release."
+
+
+
+ Med Hypotheses 1995 Nov;45(5):455-8. Melanin, melatonin, melanocyte-stimulating hormone, and the
+ susceptibility to autoimmune demyelination: a rationale for light therapy in multiple sclerosis.
+ Constantinescu CS "The hypothesis formulated here is based on the observation that resistance to multiple
+ sclerosis and experimental autoimmune encephalomyelitis is associated with dark skin pigmentation. While
+ this may signify a protective role for melanin against environmental factors producing oxidative damage, the
+ mechanism postulated here is that susceptibility to autoimmune demyelination is influenced by hormonal
+ factors, i.e. the neurohormones melatonin and melanocyte stimulating hormone, which have opposing effects on
+ immune functions and, the same time, are important determinants of the individual's production of melanin."
+
+
+ Neurosci Lett 1989 Nov 6;105(3):246-50. Presence of Schwann cells in neurodegenerative lesions of the
+ central nervous system. Dusart I, Isacson O, Nothias F, Gumpel M, Peschanski M Ultrastructural analysis of
+ neurodegenerative CNS lesions produced by an excitotoxic substance revealed that the majority of cells
+ ensheathing axons were not oligodendrocytes. By their morphology and the presence of both a basal lamina and
+ collagen fibers they were identified as Schwann cells. The presence of Schwann cells, whose growth-promoting
+ role in the peripheral nervous system has been largely documented, may account for the development of
+ regenerating growth cones which have been observed in the excitotoxically lesioned central nervous system.
+ Further support for this hypothesis came from the analysis of fetal neural transplants implanted into the
+ lesioned area. Schwann cells ensheathing axons were indeed numerous in the neuron-depleted area surrounding
+ the transplants, where neurite outgrowth of graft origin occurred.
+
+
+ J Neuroimmunol 2000 Nov 1;111(1-2):77-85. Female sex steroids: effects upon microglial cell activation. Drew
+ PD, Chavis JA.
+
+
+ Neurology 1999 Nov 10;53(8):1876-9 Cerebrospinal fluid isoprostane shows oxidative stress in patients with
+ multiple sclerosis. Greco A, Minghetti L, Sette G, Fieschi C, Levi G "The CSF level of the isoprostane
+ 8-epi-prostaglandin (PG)-F2alpha (a reliable marker of oxidative stress in vivo) was three times higher in
+ subjects with definite MS than in a benchmark group of subjects with other neurologic diseases."
+
+
+ J Intern Med 1989 Oct;226(4):241-4. Serum sex hormone and gonadotropin concentrations in premenopausal women
+ with multiple sclerosis. Grinsted L, Heltberg A, Hagen C, Djursing H.
+
+
+
+ Am J Gastroenterol 1977 Dec;68(6):560-5. Multiple sclerosis and malabsorption. Gupta JK, Ingegno AP, Cook
+ AW, Pertschuk LP.
+
+
+ Free Radic Res 1997 Apr;26(4):351-62. Toxicity of polyunsaturated fatty acid esters for human
+ monocyte-macrophages: the anomalous behaviour of cholesteryl linolenate. Hardwick SJ, Carpenter KL, Law NS,
+ Van Der Veen C, Marchant CE, Hird R, Mitchinson MJ. "The triglycerides showed a direct relationship between
+ toxicity and increasing unsaturation, which in turn correlated with increasing susceptibility to oxidation."
+ "Triarachidonin (20:4; omega-6), trieicosapentaenoin (20:5; omega-3) and tridocosahexaenoin (22:6; omega-3)
+ were profoundly and rapidly toxic. There was a similar relationship between toxicity and increasing
+ unsaturation for most of the cholesterol esters, but cholesteryl linolenate was apparently anomalous, being
+ non-toxic in spite of possessing three double bonds and being extensively oxidised." "The toxicity of
+ triglycerides suggests that polyunsaturated fatty acid peroxidation products are also toxic."
+
+
+ J Clin Invest 1990 Oct;86(4):1115-23. Essential fatty acid deficiency ameliorates acute renal dysfunction in
+ the rat after the administration of the aminonucleoside of puromycin. Harris KP, Lefkowith JB, Klahr S,
+ Schreiner GF.
+
+
+ Mikrobiyol Bul 1989 Oct;23(4):342-7. [Leukotrienes and neurological diseases]. [Article in Turkish] Irkec C,
+ Ercan S, Irkec M "LTC4 levels were found to be elevated in MS and Behcet patient in comparison with
+ controls. Augmentation of LTC4 levels underlines the fact that leukotrienes may be held responsible the
+ pathogenesis of these disorders."
+
+
+
+ Lancet 1982 Feb 13;1(8268):380-6. Evidence for subacute fat embolism as the cause of multiple sclerosis.
+ James PB "The neurological features of decompression sickness, which is thought to be due to gas embolism,
+ are similar to those of multiple sclerosis (MS). This similarity suggested the re-examination of a concept,
+ first proposed in 1882, that the demyelination in MS is due to venous thrombosis. Unfortunately, although
+ the plaques of MS are often perivenular, thromboses are not always present. Nevertheless, vascular theories
+ can explain the topography of the lesions in MS." "There is also evidence in man that fat may lodge in the
+ microcirculation of the nervous system and cause distal perivenous oedema with the loss of myelin from
+ axons."
+
+
+ J Clin Pathol 1979 Oct;32(10):1025-9. Antithrombin activities in childhood malnutrition. Jimenez RA, Jimenez
+ E, Ingram GI, Mora LA, Atmetlla F, Carrillo JM, Vargas W.
+
+
+ Arch Latinoam Nutr 1980 Dec;30(4):580-9. [Prethrombosis in child malnutrition]. Jimenez R, Jimenez E, Mora
+ LA, Vargas W, Atmetlla F, Carrillo JM
+
+
+ Stroke 1991 Nov;22(11):1448-51. Platelet secretory products may contribute to neuronal injury. Joseph R,
+ Tsering C, Grunfeld S, Welch KM "The view that certain endogenous substances, such as glutamate, may also
+ contribute to neuronal injury is now reasonably well established. Blood platelets are known to contain and
+ secrete a number of substances that have been associated with neuronal dysfunction. Therefore, we
+ hypothesize that a high concentration (approximately several thousand-fold higher than in plasma, in our
+ estimation) of locally released platelet secretory products derived from the causative thrombus may
+ contribute to neuronal injury and promote reactive gliosis." "We further observed that serotonin, a major
+ platelet product, has neurotoxic properties."
+
+
+
+ Zh Nevropatol Psikhiatr Im S S Korsakova 1985;85(2):198-206. [Role of disorders of the hemostatic system in
+ the pathogenesis of multiple sclerosis and ways of correcting them]. [Article in Russian] Karlov VA, Makarov
+ VA, Savina EB, Seleznev AN, Savin AA The changes in the hemostatic system were studied in 77 patients with
+ different patterns of disseminated sclerosis (DS). The studies demonstrated activation of both
+ vasculothrombocytic and coagulation components of hemostasis as well as of fibrinolytic blood properties.
+ The latent course of the disseminated intravascular coagulation was revealed in 20.7% of cases. The role of
+ hemostatic disorders in the pathogenetic mechanisms of DS is discussed. The patients with DS received
+ pathogenetic treatment including drugs eliminating hemostatic disorders, which was beneficial for most
+ patients.
+
+
+ Zh Nevropatol Psikhiatr Im S S Korsakova 1990;90(11):47-50. [Changes in rheological properties of blood in
+ multiple sclerosis and their correction]. [Article in Russian] Karlov VA, Savin AA, Smertina LP, Redchits
+ EG, Seleznev AN, Svetailo LI, Margosiuk NV, Stulin ID As many as 45 patients with multiple sclerosis were
+ examined for rheological blood properties. As compared to controls, the group under examination manifested
+ the rise of plasma viscosity, acceleration of red blood cell aggregation. 26.2% of patients demonstrated an
+ appreciable increase of blood viscosity. It is assumed that these changes contribute to the deterioration of
+ microcirculation and aggravate the demyelinating process. Correction of the rheological properties of the
+ blood by plasmapheresis coupled with other methods of pathogenetic therapy turned out effective.
+
+
+ Brain Res 1997 Jun 20;760(1-2):298-303 Iron deposits in multiple sclerosis and Alzheimer's disease brains.
+ LeVine SM "In summary, the localization of iron deposition in MS and AD brains indicates potential sites
+ where iron could promote oxidative damage in these disease states."
+
+
+ Circ Shock 1990 Jun;31(2):159-70. Resistance of essential fatty acid-deficient rats to endotoxin-induced
+ increases in vascular permeability. Li EJ, Cook JA, Spicer KM, Wise WC, Rokach J, Halushka PV.
+
+
+ FEBS Lett 1978 Nov 1;95(1):181-4. Selective inactivation of the NADH-ubiquinone segment of the respiratory
+ chain of submitochondrial particles by endogenous free fatty acids during hyperthermia. Ludwig P, Bartels M,
+ Schewe T, Rapoport S.
+
+
+
+ J Pain Symptom Manage 2000 Nov;20(5):388-91. Ondansetron in multiple sclerosis. Macleod AD. "Two young women
+ with chronic nausea and vertigo caused by multiple sclerosis responded to the introduction and maintenance
+ of the 5HT3 receptor antagonist, ondansetron."
+
+
+ Am J Phys Med Rehabil 1994 Jul-Aug;73(4):283-5. Intracranial venous thrombosis in a patient with multiple
+ sclerosis. A case report and review of contraceptive alternatives in patients with disabilities. Malanga GA,
+ Gangemi E.
+
+
+ Folia Biol (Praha) 1999;45(4):133-41. Essential fatty acids and related molecular and cellular mechanisms in
+ multiple sclerosis: new looks at old concepts. Mayer M.
+
+
+ J Clin Endocrinol Metab 1994 Sep;79(3):848-53. Multiple sclerosis is associated with alterations in
+ hypothalamic-pituitary-adrenal axis function. Michelson D, Stone L, Galliven E, Magiakou MA, Chrousos GP,
+ Sternberg EM, Gold PW "Compared to matched controls, patients with MS had significantly higher plasma
+ cortisol levels at baseline. Despite this hypercortisolism and in contrast to patients with depression who
+ had similar elevations in plasma cortisol levels, patients with MS showed normal, rather than blunted,
+ plasma ACTH responses to ovine CRH, suggesting that the pathophysiology of hypercortisolism in MS is
+ different from that in depression." "Taken together, these findings are compatible with data from studies of
+ experimental animals exposed to chronic inflammatory stress, which showed mild increased activation of the
+ HPA axis with increased relative activity of AVP in the regulation of the pituitary-adrenal axis."
+
+
+ Exp Neurol 1977 Oct;57(1):142-57. Tryptophan availability: relation to elevated brain serotonin in
+ developmentally protein-malnourished rats. Miller M, Leahy JP, Stern WC, Morgane PJ, Resnick O.
+
+
+
+ Am J Physiol 1989 Oct;257(4 Pt 2):H1192-9. Lung injury caused by cobra venom factor is reduced in rats
+ raised on an essential fatty acid-deficient diet. Morganroth ML, Schoeneich SO, Till GO, Pickett W, Ward PA.
+
+
+ Eur J Haematol 2000 Jul;65(1):82-3. More on the relationship between cystic fibrosis and venous thrombosis.
+ Mori PG, Acquila M, Bicocchi MP, Bottini F, Romano L. Letter
+
+
+ Acta Neurol Scand 1982 Oct;66(4):497-504, Platelet aggregation and multiple sclerosis. Neu IS, Prosiegel M,
+ Pfaffenrath V Measurements of blood platelet aggregation were carried out in 30 patients suffering from
+ multiple sclerosis (MS) and in 15 healthy individuals. Compared with the control group, the MS patients
+ showed an increase in both spontaneous and induced (ADP and serotonin) platelet aggregation. The possible
+ pathogenetic significance of these results is discussed.
+
+
+ Neurology 1975 Aug;25(8):713-6. Schwann cells and regenerated peripheral myelin in multiple sclerosis: an
+ ultrastructural study. Ogata J, Feigin I Tissue of a multiple sclerosis plaque in the brachium conjunctivum
+ of the pons known to contain peripheral myelin by light microscopic studies were removed from the paraffin
+ block and processed for electron microscopic studies. The cells related to the peripheral myelin possessed
+ the ultrastructural characteristics of Schwann cells, with basement membranes and associated collagen
+ fibers. No continuity was seen with the peripheral within the central nervous tissues by selective
+ maturation of multipotential primitive reticular cells, a phenomenon consistent with the view that Schwann
+ cells are mesenchymal in character.
+
+
+ Tohoku J Exp Med 1999 Dec;189(4):259-65. Elevated plasma level of plasminogen activator inhibitor-1 (PAI-1)
+ in patients with relapsing-remitting multiple sclerosis. Onodera H, Nakashima I, Fujihara K, Nagata T,
+ Itoyama Y "Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system
+ and one of the earliest changes in inflammatory focus involves the activation of vascular endothelial
+ cells." "The level of plasma PAI-1 was significantly higher in active MS cases when compared to stable MS
+ and controls." "These results suggested that PAI-1 plasma levels are associated with MS disease activity and
+ is a good marker for MS relapse."
+
+
+
+ J Mol Med 1997 Mar;75(3):174-86. The role of nitric oxide in multiple sclerosis. Parkinson JF, Mitrovic B,
+ Merrill JE "Elevated nitric oxide bio-synthesis has been associated with nonspecific immune-mediated
+ cellular cytotoxicity and the pathogenesis of chronic, inflammatory autoimmune diseases including rheumatoid
+ arthritis, insulin-dependent diabetes, inflammatory bowel disease, and multiple sclerosis."
+
+
+ Fed Proc 1987 Jan;46(1):91-6. Role of the clotting system in the pathogenesis of neuroimmunologic disease.
+ Paterson PY, Koh CS, Kwaan HC "Our studies of the clotting system and ensuing fibrinolysis implicate
+ coagulation and cleavage of fibrin within or on the luminal surface of the cerebrovasculature as events
+ initiating the inflammation characterizing EAE." "We postulate that the critical event precipitating EAE is
+ binding of circulating MBP-reactive immune effector cells to MBP immunodeterminants on the surface of
+ cerebrovascular endothelial cells. Coagulation and ensuing fibrinolysis occur at sites of binding of
+ effector cells to cerebrovascular endothelium. Release of biologically active peptides cleaved from fibrin
+ open the BBB, thereby setting the stage for the cascade of inflammatory events culminating in clinical
+ manifestations of EAE."
+
+
+ Neurotoxicology 1998 Aug-Oct;19 (4-5):599-603. In vitro effect of the cysteine metabolites homocysteic acid,
+ homocysteine and cysteic acid upon human neuronal cell lines. Parsons RB, Waring RH, Ramsden DB, Williams AC
+ "Cysteine (CYS) is a non-essential amino acid which elicits excitotoxic properties via the
+ N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor.. CYS levels are known to be elevated in
+ association with neurological disease such as Alzheimers Disease (AD) and Parkinsons Disease (PD)." "These
+ results show that toxic responses are cell-type specific for CYS and its metabolites and this may be
+ reflected in the patterns of neurodegeneration observed in such diseases as AD and PD."
+
+
+ WMJ 1983 Mar-Apr;55(2):146-50. [Effect of tryptophan excess in a diet on amino acid composition of skin
+ collagen and on an initial stage of protein biosynthesis in rat liver]. Pechenova TN, Sushkova VV, Solodova
+ EV, Gulyi MF Protein deficiency and tryptophane load against its background lead to the acid-soluble
+ collagen synthesis in the rat skin. The amino acid composition of the collagen differs from the norm. This
+ is accompanied by changes in the free amino acid pool of blood serum and liver, under tryptophane load the
+ free amino acids pool of the liver increasing twice as high. At the same time protein deficiency increases
+ and tryptophane load decreases the level of tRNA amino acylation with tryptophane in the animal liver. Thus,
+ protein deficiency and tryptophane load against its background cause deep changes in the protein
+ biosynthesis.
+
+
+
+ Fed Proc 1987 Jan;46(1):91-6. Role of the clotting system in the pathogenesis of neuroimmunologic disease.
+ Paterson PY, Koh CS, Kwaan HC "Our studies of the clotting system and ensuing fibrinolysis implicate
+ coagulation and cleavage of fibrin within or on the luminal surface of the cerebrovasculature as events
+ initiating the inflammation characterizing EAE." "We postulate that the critical event precipitating EAE is
+ binding of circulating MBP-reactive immune effector cells to MBP immunodeterminants on the surface of
+ cerebrovascular endothelial cells. Coagulation and ensuing fibrinolysis occur at sites of binding of
+ effector cells to cerebrovascular endothelium. Release of biologically active peptides cleaved from fibrin
+ open the BBB, thereby setting the stage for the cascade of inflammatory events culminating in clinical
+ manifestations of EAE."
+
+
+ Rev Esp Fisiol 1983 Mar;39(1):39-44. Intralipid and free plasmatic tryptophan in vitro. Pena JM, Aulesa C,
+ Vinas O, Bosch J, Farriol M, Schwartz S "In an attempt to investigate the role of the lipidic emulsion
+ Intralipid in the development of metabolic encephalopathy in a patient showing high free tryptophan levels,
+ the relationship between lipidic emulsion and free tryptophan was examined in in vitro experiments. The
+ addition of intralipid to normal serum produces an immediate increase in non-esterified fatty acids and a
+ parallel rise in free tryptophan. Moreover, when serum with intralipid is incubated at 37 degrees C, the
+ lipases release new non-esterified fatty acids and the free tryptophan increases proportionally." "It is
+ concluded that intralipid causes an increase in free tryptophan levels. It is known that in vivo free
+ tryptophan modulates 5-hydroxytryptamine synthesis and thus may be considered a possible causal agent for
+ encephalopathy."
+
+
+ Med Hypotheses 1980 May;6(5):545-557. Fatty acids, fibrinogen and blood flow: a general mechanism for
+ hyperfibrinogenemia and its pathologic consequences. Pickart LR, Thaler MM Plasma fibrinogen is elevated in
+ various stressful states and conditions in which active mobilization of free fatty acids (FFA) occurs.
+ Reduction of plasma FFA by an assortment of hypolipidemic drugs is consistently followed by a decrease in
+ the accompanying hyperfibrinogenemia. A direct link between FFA and fibrinogen has been demonstrated in
+ animals, and in experiments employing incubated liver slices. Based on these clinical and experimental
+ observations, we postulate that hepatic fibrinogen synthesis is stimulated by FFA. Since fibrinogen is a
+ major determinant of whole blood viscosity, erythrocyte aggregation, and sludging of red cells in terminal
+ and pre-terminal blood vessels, we propose that microcirculatory blood flow may be impaired in the presence
+ of chronically elevated plasma FFA levls. Consequently, hypolipidemic drugs may be effective in prevention
+ of circulatory complications associated with FFA-induced hyperfibrinogenemia.
+
+
+ Neurologia 1996 Aug-Sep;11(7):272. [Exacerbation of spasticity induced by serotonin reuptake inhibitors.
+ Letter]. del Real MA, Hernandez A, Vaamonde J, Gudin M
+
+
+
+ J Neurol Neurosurg Psychiatry 1997 Mar;62(3):282-4. Ondansetron, a 5-HT3 antagonist, improves cerebellar
+ tremor. Rice GP, Lesaux J, Vandervoort P, Macewan L, Ebers GC. "It has been previously shown that
+ ondansetron, a 5-HT3 antagonist, can ameliorate vertigo in patients with acute brainstem disorders. A
+ coincidental benefit was the improvement of cerebellar tremor in some patients with both vertigo and tremor.
+ To further evaluate this effect, a placebo controlled, double blind, crossover study was conducted of a
+ single dose of intravenous ondansetron in 20 patients with cerebellar tremor caused by multiple sclerosis,
+ cerebellar degeneration, or drug toxicity." "Thirteen of 19 patients were deemed to have improved spiral
+ copying after treatment with ondansetron when compared with baseline performance."
+
+
+ Neurologia 1993 Oct;8(8):252-5. [Retinal periphlebitis in multiple sclerosis. A prospective study]. Rio J,
+ Colin A, Salvador F, Tintore M, Viguera ML, Montalban J, Codina A "In three cases (12.5%) retinal
+ periphlebitis was observed." "Given the absence of myelin in the retina, the presence of retinal
+ periphlebitis suggests the existence of a vascular mechanism in the pathogenesis of multiple sclerosis."
+
+
+ Int J Neurosci 1995 Dec;83(3-4):187-98. Premenstrual exacerbation of symptoms in multiple sclerosis is
+ attenuated by treatment with weak electromagnetic fields. Sandyk R. "The present report concerns two women
+ with chronic progressive stage MS who experienced, coincident with increasing functional disability, regular
+ worsening of their symptoms beginning about a week before menstruation and abating with the onset of
+ menstruation. These symptoms resolved two months after the initiation of treatment with EMFs."
+
+
+
+ J Physiol Biochem 1998 Dec;54(4):229-37. The role of nitric oxide in the pathogenesis of multiple sclerosis.
+ Santiago E, Perez-Mediavilla LA, Lopez-Moratalla N "The inducible NOS (iNOS) is associated with the
+ development of a number of autoimmune diseases." "Induction of the enzyme is effected by proinflammatory
+ cytokines, immunomodulating peptides, and even beta-endorphin through a mechanism involving an increase in
+ cAMP. An excessive production of NO has been implicated in the severe lesions observed in multiple sclerosis
+ (MS)."
+
+
+ J Neurol 1980 Jan;222(3):177-82. Cerebrospinal fluid lipids in demyelinating disease. II. Linoleic acid as
+ an index of impaired blood-CSF barrier. Seidel D, Heipertz R, Weisner B "The linoleic acid content of
+ control CSF (1.6 +/- 0.8 nMol/ml) is considerably lower than the corresponding serum value (2.5--4.1
+ muMol/ml). Although CSF from MS patients contains a significantly higher linoleic acid concentration than
+ controls the close correlation between CSF linoleic acid and CSF albumin is maintained. The high CSF
+ concentration of cholesterol esters rich in linoleic acid, which are abundant in serum but represent only
+ traces in CNS lipids, points towards an impaired BBB function as the cause of CSF linoleic increase. We are
+ able to show that both albumin and linoleic acid are suitable as "serum markers...."
+
+
+ J Neurol Sci 1987 Feb;77(2-3):147-52. Chronic periphlebitis retinae in multiple sclerosis. A
+ histopathological study. Shaw PJ, Smith NM, Ince PG, Bates D Retinal periphlebitis in multiple sclerosis is
+ of particular interest in relation to our understanding of the pathogenesis of the demyelinating central
+ nervous system plaques. Previous studies have largely been clinical, and there is little detailed
+ histopathological information relating to this condition. We present the first detailed report in the
+ neurological literature on the histological findings in chronic periphlebitis retinae associated with
+ multiple sclerosis. The most significant abnormalities of the affected retinal veins were the presence of
+ thick laminated collagen in the wall, associated with a scanty infiltration of plasma cells.
+
+
+ Am Heart J 2000 Aug;140(2):212-8. Low intracellular magnesium levels promote platelet-dependent thrombosis
+ in patients with coronary artery disease. Shechter M, Merz CN, Rude RK, Paul Labrador MJ, Meisel SR, Shah
+ PK, Kaul S.
+
+
+
+ J Neurochem 1996 Mar;66(3):1157-66. Mast cell activation causes delayed neurodegeneration in mixed
+ hippocampal cultures via the nitric oxide pathway. Skaper SD, Facci L, Romanello S, Leon A. "Neurotoxicity
+ required a prolonged period (12 h) of mast cell incubation, and appeared to depend largely on elaboration of
+ the free radical nitric oxide by astrocytes." "Myelin basic protein and 17 beta-estradiol had a synergistic
+ action on the induction of mast cell-associated neuronal injury." "Further, palmitoylethanolamide, which has
+ been reported to reduce mast cell activation by a local autacoid mechanism, decreased neuron loss resulting
+ from mast cell stimulation in the mixed cultures but not that caused by direct cytokine induction of
+ astrocytic nitric oxide synthase." "These results support the notion that brain mast cells could participate
+ in the pathophysiology of chronic neurodegenerative and inflammatory diseases of the nervous system, and
+ suggest that down-modulation of mast cell activation in such conditions could be of therapeutic benefit."
+
+
+ International Journal of Microcirculation--Clinical and Experimental, 1996, Vol 16, Iss 5, pp 266-270.
+ Hyperventilation enhances transcapillary diffusion of sodium fluorescein. J Steurer, D Schiesser, C Stey, W
+ Vetter, MV Elzi, JP Barras, UK Franzeck. "Voluntary hyperventilation (HV) provokes hemoconcentration due to
+ a loss of fluid from the intravascular space." "The exact, mechanism of enhanced transcapillary diffusion of
+ Na fluorescein is not known, The distinct increase in FLI without a significant change in microvascular skin
+ flux suggests an HV-induced increase in capillary pressure or an enhancement in capillary permeability for
+ water and small solutes."
+
+
+ Kidney Int 1992 May;41(5):1245-53. Essential fatty acid deficiency normalizes function and histology in rat
+ nephrotoxic nephritis. Takahashi K, Kato T, Schreiner GF, Ebert J, Badr KF.
+
+
+
+ Arthritis Rheum 1981 Aug;24 (8):1054-6. Sex steroid hormones and systemic lupus erythematosus. Talal N.
+
+
+ Clin Rheum Dis 1982 Apr;8(1):23-8. Sex hormones and modulation of immune response in SLE. Talal N.
+
+
+ Ann N Y Acad Sci 1986;475:320-8. Hormonal approaches to immunotherapy of autoimmune disease. Talal N, Ahmed
+ SA, Dauphinee M.
+
+
+ Ann Nucl Med 1998 Apr;12(2):89-94. Clinical significance of reduced cerebral metabolism in multiple
+ sclerosis: a combined PET and MRI study. Sun X, Tanaka M, Kondo S, Okamoto K, Hirai S "The severity of
+ cerebral hypometabolism was also related to the number of relapses." "Our results suggest that measurement
+ of cerebral metabolism in MS has the potential to be an objective marker for monitoring disease activity and
+ to provide prognostic information."
+
+
+ Fed Proc 1987 Jan;46(1):118-26. Pathway to carrageenan-induced inflammation in the hind limb of the rat.
+ Vinegar R, Truax JF, Selph JL, Johnston PR, Venable AL, McKenzie KK "Antiserotonin agents inhibited the
+ hypoalgesia and part of the edema. These findings and histological observations suggested that dermal mast
+ cells were injured by C. The hyperalgesia and part of the edema were sensitive to arachidonate
+ cyclooxygenase inhibitors (AACOIs). It is speculated that injured mast cells metabolize arachidonic acid and
+ reactive intermediates, not prostaglandins, mediate the NPIR hyperalgesia and part of the edema."
+ "Arachidonic acid metabolism by neutrophils is speculated to produce the mediators of phagocytic
+ inflammatory (PI) edema and hyperalgesia."
+
+
+ © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
+
+