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    <head><title>Aging, estrogen, and progesterone</title></head>
    <body>
        <h1>
            Aging, estrogen, and progesterone
        </h1>

        <p>
            <em>"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.
            </em>
        </p>
        <em>
            <p>
                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.
            </p>
            <p>
                By the middle of the century, many toxic effects of the estrogens were known, and more are being
                discovered.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                Some hormones do decrease with aging, but others increase.
            </p>

            <p>
                All of the unpleasant consequences of estrogen excess happen to resemble some of the events of aging.
            </p>
            <p>
                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.
            </p>
            <p>
                Estrogen steals oxygen from mitochondria, shifting patterns of growth and adaptation.
            </p></em>

        <hr />

        <p>
            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.
        </p>
        <p>
            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 <strong><em>parabiosis</em></strong>, 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 &amp; 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.
        </p>

        <p>
            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).<strong><em>
                    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.
                </em></strong>
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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. <strong><em>
                    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.</em></strong> This shows a close association
            between the generalized atrophy of aging and the amount of estrogen in the tissues.
        </p>
        <p>
            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<strong>:</strong> 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.
        </p>

        <p>
            (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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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 <strong><em>increased</em></strong>
            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.
        </p>
        <p>
            <strong><em>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.</em></strong>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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)
        </p>
        <p>
            Estrogen, by creating an oxygen deficiency, stimulates first swelling, and then collagen synthesis. Collagen
            tends to accumulate with aging.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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]
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            In sleep, as in shock, hyperventilation is common, and it sometimes produces extreme vasoconstriction,
            because of the loss of carbon dioxide.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Progesterone is both an anticatabolic hormone and an antiestrogenic hormone, and in both cases, it protects
            the functional systems from atrophy.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p><h3>REFERENCES</h3></p>
        <p>
            Adv Shock Res 1978;1:19-27. <strong>Alterations in venous compliance in hemorrhagic shock.</strong> 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,<strong>
                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."</strong>
        </p>

        <p>
            Acta Physiol Scand 1990 Sep;140(1):85-94. <strong>Effects of hypertonic NaCl solution on microvascular
                haemodynamics in normo- and hypovolaemia.</strong> 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<strong>
                to haemorrhage, upon bleeding, arterioles larger than 40 microns constricted,</strong> 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."
        </p>
        <p>
            Medicina (B Aires) 1998;58(4):367-73. <strong>[Physiopathologic effects of nitric oxide and their
                relationship with oxidative stress].</strong> [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 <strong>essential for
                the development of hypertension, atherosclerosis, neurodegenerative diseases, viral infections,
                ischemia-reperfusion injury, and cancer.</strong>
        </p>

        <p>
            Stress 1998 Dec;2(4):281-7. <strong>Effects of major depression, aging and gender upon calculated diurnal
                free plasma cortisol concentrations: a re-evaluation study.</strong> Deuschle M, Weber B, Colla M,
            Depner M, Heuser I<strong>. "Depression, aging and female gender are associated with increased diurnal
                concentrations of total plasma cortisol."</strong> "This finding is in line with the observation that
            <strong>in both conditions medical problems triggered and/or maintained by glucocorticoids (e.g.
                osteoporosis) are frequently seen."</strong>
        </p>
        <p>
            Adv Exp Med Biol 1975;53:359-69. <strong>The effect of nutritional regimes upon collagen concentration and
                survival of rats.</strong> 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."<strong>
                "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</strong>

            (and perhaps organism)."
        </p>
        <p>
            Early Pregnancy 1996 Jun;2(2):113-20. <strong>Relationship of estradiol and progesterone levels to uterine
                blood flow during early pregnancy.</strong> Dickey RP, Hower JF. "After correction for gestational age,
            estradiol was negatively related to uterine artery flow volume (p &lt; 0.05), diameter (p &lt; 0.05),
            pulsatility index (p &lt; 0.05) and resistance index (p &lt; 0.01) for weeks 5-16 and to diameter (p &lt;
            0.05) after week 9. Progesterone was positively related <strong>to volume (p &lt; 0.05) and velocity (p &lt;
                0.01) for weeks 5-16 and to volume (p &lt; 0.05) for weeks 5 to 9. S</strong>piral artery indices of
            resistance were unrelated to hormone levels. These<strong>
                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."</strong>
        </p>
        <p>
            Ann Surg 1998 Jun;227(6):851-60. <strong>Microvascular changes explain the "two-hit" theory of multiple
                organ failure.</strong> Garrison RN, Spain DA, Wilson MA, Keelen PA, Harris PD "Acute bacteremia<strong>
                alone results in persistent intestinal vasoconstriction and mucosal hypoperfusion. Little experimental
                data exist to support the pathogenesis of</strong> vascular dysregulation during sequential physiologic
            insults." <strong>"Acute bacteremia, with or without prior hemorrhage, caused significant large-caliber A1
                arteriolar constriction with a concomitant decrease in blood flow. This</strong> 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 <strong>with enhanced constrictor forces in inflow
                vessels."</strong>
        </p>

        <p>
            Am J Physiol 1998 Jul;275(1 Pt 2):H292-300.<strong>
                Estrogen reduces myogenic tone through a nitric oxide-dependent mechanism in rat cerebral
                arteries.</strong>
            Geary GG, Krause DN, Duckles SP. <strong>"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.
            </strong>
            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."<strong> </strong>
        </p>
        <p>
            Free Radic Res 1999 Feb;30(2):105-17. <strong>Inactivation of myocardial dihydrolipoamide dehydrogenase by
                myeloperoxidase systems: effect of halides, nitrite and thiol compounds.</strong> Gutierrez-Correa J,
            Stoppani AO. "The summarized observations support the hypothesis that peroxidase-generated "reactive
            species" oxidize essential thiol groups at LADH catalytic site."
        </p>

        <p>
            Medicina (B Aires) 1998;58(2):171-8. <strong>[Myeloperoxidase as a factor of oxidative damage of the
                myocardium: inactivation of dihydrolipoamide dehydrogenase].</strong>
            Gutierrez Correa J, Stoppani AO. "Myocardial dihydrolipoamide dehydrogenase (LADH) is inactivated after
            incubation at 30 degree C, with myeloperoxidase (MPO)-dependent systems."
        </p>
        <p>
            J Natl Cancer Inst 1981 Aug;67(2):455-9. <strong>Synergism of estrogens and X-rays in mammary carcinogenesis
                in female ACI rats.</strong> Holtzman S, Stone JP, Shellabarger CJ.
        </p>
        <p>
            Br J Exp Pathol 1988 Apr;69(2):157-67. <strong>Effect of the anti-oestrogen tamoxifen on the development of
                renal cortical necrosis induced by oestrone + vasopressin administration in rats.
            </strong>
            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<strong>. The results suggest that oestrogen receptors in
                the kidney are involved in the induction of renal cortical necrosis by vasopressin.</strong>
        </p>

        <p>
            Br J Exp Pathol 1987 Feb;68(1):35-43.<strong>
                Histochemical and ultrastructural study of renal cortical necrosis in rats treated with oestrone +
                vasopressin, and its prevention with a vasopressin antagonist.</strong> Kocsis J, Karacsony G, Karcsu S,
            Laszlo FA. <strong>Renal cortical necrosis was induced by the administration of vasopressin to
                oestrogen-pretreated rats.</strong> 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.
        </p>
        <p>
            Invest Radiol 1979 Jul-Aug;14(4):295-9. <strong>Serioangiographic study of renal cortical necrosis induced
                by administration of estrin and vasopressin in rats.</strong> 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.
        </p>

        <p>
            Contrib Nephrol 1981;28:1-216.<strong>
                Renal cortical necrosis. Experimental induction by hormones.</strong> Laszlo FA.
        </p>
        <p>
            Morphol Igazsagugyi Orv Sz 1974 Jan;14(1):8-12 <strong>[The effect os estrogen, ACTH and cortisone
                administration, as well as hypophysectomy on histological changes in unilateral renal hilus
                ligation].</strong> [Article in Hungarian] Laszlo F, Monus Z.
        </p>
        <p>
            Eur J Neurosci 1997 Feb;9(2):271-9. <strong>Positive correlations between cerebral protein synthesis rates
                and deep sleep in Macaca mulatta.</strong> 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.
        </p>

        <p>
            Can J Physiol Pharmacol 2000 Oct;78(10):757-65. <strong>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.</strong> 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%. <strong>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%.</strong> 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."
        </p>
        <p>
            Physiol Behav 1990 Nov;48(5):749-53. <strong>Rates of cerebral protein synthesis are linked to slow wave
                sleep in the rat.</strong> 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
            <strong>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.</strong> 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.
        </p>

        <p>
            Surgery 1991 Oct;110(4):685-8; discussion 688-90. <strong>The effect of hypertonic saline resuscitation on
                bacterial translocation after hemorrhagic shock in rats.</strong> 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<strong>
                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."</strong>
        </p>
        <p>
            Am J Physiol 1999 Feb;276(2 Pt 2):H563-71. <strong>Changes in resistance vessels during hemorrhagic shock
                and resuscitation in conscious hamster model.</strong>
            Sakai H, Hara H, Tsai AG, Tsuchida E, Johnson PC, Intaglietta M. "The unanesthetized hamster dorsal skinfold
            preparation was used to monitor<strong>
                diameters and blood flow rates in resistance arteries (small arteries, A0: diameter, 156</strong> +/- 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. <strong>A0 and V0 vessels constricted
                significantly to 52 and 70% of the basal values,
            </strong>

            respectively, whereas precapillary arterioles (A1-A4, 8-60 micrometers) and collecting venules (VC-VL, 26-80
            micrometers) did not change or tended to dilate. <strong>Blood flow rates in the microvessels declined to
                &lt;20% of the basal values."</strong>
        </p>
        <p>
            Horm Behav 1998 Feb;33(1):58-74. <strong>Suppression of cortisol levels in subordinate female marmosets:
                reproductive and social contributions.</strong> 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,<strong>
                as well as higher estradiol and estrone levels and lower progesterone and luteinizing hormone (LH)
                levels</strong>."
        </p>
        <p>
            Zh Evol Biokhim Fiziol 1989 Jan-Feb;25(1):52-9. <strong>[Seasonal characteristics of the functioning of the
                hypophysis-gonad system in the suslik Citellus parryi].</strong> 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." <strong
            >"Estradiol secretion was noted in hibernating females, whereas progesterone</strong> was found in the blood
            only in May."
        </p>

        <p>
            Maturitas 1984 Nov;6(3):269-78. <strong>Spontaneous skin flushing episodes in the aging female rat.</strong>
            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<strong>. 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.</strong> 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.
        </p>
        <p>
            Carcinogenesis 1994 Nov;15(11):2637-43. <strong>The metabolism of 17 beta-estradiol by lactoperoxidase: a
                possible source of oxidative stress in breast cancer.</strong> Sipe HJ Jr, Jordan SJ, Hanna PM, Mason
            RP. Electron spin resonance (ESR) spectroscopy and <strong>oxygen consumption measurements using a
                Clark-type oxygen electrode have been used to study the metabolism of the estrogen 17 beta-estradiol by
                lactoperoxidase.</strong> 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,<strong>
                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.</strong>
            <strong>The NAD. radical is not spin trapped by DMPO, but instead reduces molecular oxygen to the superoxide
                radical,</strong> which is then spin-trapped by DMPO. The superoxide generated may either spontaneously
            dismutate to form hydrogen peroxide <strong>or react with another NADH to form NAD., thus propagating a
                chain reaction leading to oxygen consumption and hydrogen peroxide accumulation.</strong> 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. <strong>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.</strong> The accumulation of
            intracellular hydrogen peroxide could explain the hydroxyl radical-induced DNA base lesions recently
            reported for female breast cancer tissue.
        </p>

        <p>
            Endocrinol Metab Clin North Am 1995 Sep;24(3):531-47<strong>. Idiopathic edema. Pathogenesis, clinical
                features, and treatment.
            </strong>
            Streeten DH. "Idiopathic edema is usually orthostatic." "It occurs almost exclusively in post-pubertal
            women. . . ."
        </p>
        <p>
            Carcinogenesis 1995 Apr;16(4):891-5. <strong>Mitochondrial enzyme-catalyzed oxidation and reduction
                reactions of stilbene estrogen.</strong> 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."
        </p>
        <p>
            J Clin Endocrinol Metab 2000 Apr;85(4):1382-7. <strong>Regulation of protein metabolism in middle-aged,
                premenopausal women: roles of adiposity and estradiol.</strong> Toth MJ, Tchernof A, Rosen CJ, Matthews
            DE, Poehlman ET. <strong>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</strong>
            <hr />
        </p>

        <p>
            J Korean Med Sci 1999 Jun;14(3):277-85. <strong>The metabolic effects of estriol in female rat
                liver.</strong> Yang JM, Kim SS, Kim JI, Ahn BM, Choi SW, Kim JK, Lee CD, Chung KW, Sun HS, Park DH,
            Thurman RG. <strong>"Basal oxygen consumption of perfused liver increased significantly in estriol or
                ethanol-treated rats."</strong>
            <strong>"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."</strong>
        </p>
        <p>
            Bone 1996 May;18(5):443-50.<strong>
                Ovariectomy-induced high turnover in cortical bone is dependent on pituitary hormone in rats.
            </strong>
            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."
        </p>
        <p>© Ray Peat 2006. All Rights Reserved. www.RayPeat.com</p>
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    <head><title>Aging Eyes, Infant Eyes, and Excitable Tissues</title></head>
    <body>
        <h1>
            Aging Eyes, Infant Eyes, and Excitable Tissues
        </h1>

        <em>
            <p>
                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.
            </p>
            <p>
                For 60 years there have been controversies about the cause of retinopathy of prematurity, which has
                blinded tens of thousands of people.
            </p>
            <p>
                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.
            </p>

            <p>
                Melatonin and prolactin are induced by stress, and darkness is a stress because it impairs mitochondrial
                energy production.
            </p>
            <p>
                The polyunsaturated fats which accumulate in the brain and retina damage mitochondria.
            </p>
            <p>
                Iron, which accumulates prenatally, and then again with aging, reacts with unsaturated fats during
                stress to destroy cells.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>

            <p>
                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.
            </p></em>
        <hr />

        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            (Chemically, the meaning of "a pigment" is that it"s a chemical which selectively absorbs radiation. <strong
            >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.
            </strong>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.)
        </p>
        <p>
            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."
        </p>
        <p>
            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. <strong>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.</strong
            > This is the sort of culture that imbued research on the biology of light cycles.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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<strong>;</strong> 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.
        </p>

        <p>
            Almost any kind of stress increases the formation of melatonin.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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<strong>;</strong> the substitution of polyunsaturated fats lowers its activity. Mitochonrial
            function in general is poisoned by the unsaturated fats, especially arachidonic acid and DHA.
        </p>

        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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 <strong><em>
                    prenatally</em></strong> 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.
        </p>
        <p>
            Apparently, it doesn"t occur to many people that administering the glucocorticoid triggers premature birth,
            creating the problem they are intending to treat.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            <strong>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.<em>
                    But all organs are subject to the same kinds of damage.
                </em></strong>
            Medical treatments for respiratory distress and macular degeneration in old people are often the same as
            those used so inappropriately for babies.<strong><em>
                    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.</em></strong>
        </p>

        <p>
            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.
        </p>
        <p><strong><h3>REFERENCES</h3></strong></p>
        <p>
            Eksp Klin Farmakol 1999 Mar-Apr; 62(2):58-60.<strong>
                [Melatonin lowers the threshold of light sensitivity of the human retina]</strong>
            ; 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.
        </p>
        <p>
            Cochrane Database Syst Rev 2001;4:CD001077. <strong>Restricted versus liberal oxygen exposure for preventing
                morbidity and mortality in preterm or low birth weight infants</strong> (Cochrane Review). Askie LM,
            Henderson-Smart DJ.
        </p>
        <p>
            Prog Clin Biol Res 1989;312:95-112. <strong>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.</strong> Bazan NG.
        </p>
        <p>
            Biull Eksp Biol Med 1976 Oct;82(10):1181-3. <strong>[Role of the biological activity of serotonin in the
                production of the "shock lung" syndrome.] ;</strong> Bazarevich GI, Deviataev AM, Likhtenshtein AO,
            Natsvlishvili BP, Sadeko MK.
        </p>
        <p>
            Invest Ophthalmol Vis Sci 1993 Sep;34(10):2878-80. <strong>
                An elevated hematogenous photosensitizer in the preterm neonate.</strong> Bynoe LA, Gottsch JD, Sadda
            SR, Panton RW, Haller EM, Gleason CA.
        </p>
        <p>
            Eur J Endocrinol 1995 Dec;133(6):691-5. <strong>Melatonin enhances cortisol levels in aged but not young
                women.</strong> Cagnacci A, Soldani R, Yen SS
        </p>

        <p>
            Am J Psychiatry 1976 Oct;133(10):1181-6. <strong>Negative effects of melatonin on depression.</strong>
            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. <strong>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</strong> in three of four patients studied. The authors discuss the implications of this
            finding.
        </p>
        <p>
            Neuroendocrinol Lett 2001 Dec;22(6):432-4. <strong>Melatonin shortens the survival rate of Ehrlich
                ascites-inoculated mice.</strong> Catrina SB, Curca E, Catrina AI, Radu C, Coculescu M. Dept.
            Endocrinology II, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania. <a
                href="mailto:sergiu-bogdan.catrina@molmed.ki.se"
                target="_blank"
            >sergiu-bogdan.catrina@molmed.ki.se</a>
            <hr />
        </p>
        <p>
            J Neurochem 1988 Apr;50(4):1185-93. <strong>Induction of intracellular superoxide radical formation by
                arachidonic acid and by polyunsaturated fatty acids in primary astrocytic cultures.</strong> Chan PH,
            Chen SF, Yu AC.
        </p>
        <p>
            Graefes Arch Clin Exp Ophthalmol 1993 Jul;231(7):416-23. <strong>Inhibition of cytochrome oxidase and
                blue-light damage in rat retina.</strong> Chen E. St. Erik's Eye Hospital, Karolinska Institute,
            Stockholm, Sweden.<strong>
                The activity of cytochrome oxidase, outer nuclear layer thickness, and edema were quantitatively
                evaluated in the blue-light exposed rat retina.</strong>
            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.
        </p>

        <p>
            Acta Ophthalmol Suppl 1993;(208):1-50. <strong>Inhibition of enzymes by short-wave optical radiation and its
                effect on the retina.</strong> 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." <strong>"Blue light inhibited cytochrome
            </strong>
            <strong>oxidase</strong>
            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. <strong>These findings support the hypothesis that inhibition of cytochrome oxidase is one of the
                causes of blue-light retinal damage.</strong>"
        </p>
        <p>
            Aust N Z J Ophthalmol 1997 May;25 Suppl 1:S73-5. <strong>Retinal control of scleral precursor
                synthesis.</strong> Devadas M, Morgan
        </p>

        <p>
            Eur J Pharmacol 1990 Jul 3;182(2):313-25. <strong>Antidepressant-like activity of the melatonin receptor
                antagonist, luzindole (N-0774), in the mouse behavioral despair test.</strong> Dubocovich ML, Mogilnicka
            E, Areso PM.
        </p>
        <p>
            J Pharmacol Exp Ther 1988 Sep;246(3):902-10. <strong>Luzindole (N-0774): a novel melatonin</strong>
            <strong>
                receptor antagonist.</strong> Dubocovich ML.
        </p>
        <p>
            Exp Eye Res 1985 Oct;41(4):497-507. <strong>The diurnal susceptibility of rat retinal photoreceptors to
                light-induced damage.</strong> 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. <strong>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.</strong> 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.
        </p>

        <p>
            Nature 1983 Dec 22-1984 Jan 4;306(5945):782-4. <strong>Melatonin is a potent modulator of dopamine release
                in the retina.</strong> Dubocovich ML.
        </p>
        <p>
            Semin Perinatol 2000 Aug;24(4):291-8. <strong>Environmental light and the preterm infant.
            </strong>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.
        </p>
        <p>
            Pediatrics 1992 Apr;89(4 Pt 1):648-53. <strong>
                Light and retinopathy of prematurity: does retinal location offer a clue?</strong> 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<strong>
                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</strong> 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.
        </p>

        <p>
            N Engl J Med 1985 Aug 15;313(7):401-4. <strong>Effect of bright light in the hospital nursery on the
                incidence of retinopathy of prematurity.</strong> 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). <strong>There was a higher incidence of retinopathy of prematurity in the group of infants who had
                been exposed to the brighter nursery lights,</strong> 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.
        </p>
        <p>
            Doc Ophthalmol 1990 Mar;74(3):195-203. <strong>Light and the developing retina.
            </strong>Glass P. George Washington University School of Medicine &amp; Health Sciences, Washington, DC.
            <strong>"Retinopathy of prematurity (ROP) has increased in the United States in the past decade.</strong>"
        </p>

        <p>
            Pediatr Res 1987 Oct;22(4):414-6. Calcemic responses to photic and pharmacologic manipulation of serum
            melatonin. Hakanson DO, Penny R, Bergstrom WH.
        </p>
        <p>
            Pediatr Res 1990 Jun;27(6):571-3. <strong>Pineal and adrenal effects on calcium homeostasis in the
                rat.</strong> Hakanson DO, Bergstrom WH.
        </p>
        <p>
            Science 1981 Nov 13;214(4522):807-9. <strong>Phototherapy-induced hypocalcemia in newborn rats: prevention
                by melatonin.</strong> Hakanson DO, Bergstrom WH.
        </p>
        <p>
            Doc Ophthalmol 1992;79(2):141-50. <strong>Diurnal variations in the electroretinographic c-wave and retinal
                melatonin content in rats with inherited retinal dystrophy.</strong> Hawlina M, Jenkins HG, Ikeda H.
        </p>

        <p>
            <strong>J.A.M.A. 90:353 (Feb. 25) 1928. The Prevention and Treatment of Asphyxia in the New-Born, Henderson,
                Yandell.</strong>
        </p>
        <p>
            Neuroendocrinology 2001 Feb;73(2):111-22. <strong>Estrogen modulates alpha(1)/beta-adrenoceptor- induced
                signaling and melatonin production in female rat pinealocytes.</strong> Hernandez-Diaz FJ, Sanchez JJ,
            Abreu P, Lopez-Coviella I, Tabares L, Prieto L, Alonso R.
        </p>
        <p>
            J Neurosci Res 1989 Oct;24(2):247-50. <strong>Brain mitochondrial swelling induced by arachidonic acid and
                other long chain free fatty acids.</strong> Hillered L, Chan PH.
        </p>
        <p>
            J Neurosci Res 1988;19(1):94-100. <strong>Effects of arachidonic acid on respiratory activities in isolated
                brain mitochondria.</strong>

            Hillered L, Chan PH.
        </p>
        <p>
            J Neurosci Res 1988 Aug;20(4):451-6. <strong>Role of arachidonic acid and other free fatty acids in
                mitochondrial dysfunction in brain ischemia.</strong> Hillered L, Chan PH.
        </p>
        <p>
            J Neurosci Res 1989 Oct;24(2):247-50. <strong>
                Brain mitochondrial swelling induced by arachidonic acid and other long chain free fatty acids.</strong>
            Hillered L, Chan PH.
        </p>
        <p>
            J Clin Epidemiol 1992 Nov;45(11):1265-87. <strong>Oxygen as a cause of blindness in premature infants:
                "autopsy" of a decade of errors in clinical epidemiologic research.</strong> 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<strong>
                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.
            </strong>The autopsy revealed a museum of diverse intellectual pathology."
        </p>

        <p>
            Curr Eye Res 2001 Jul;23(1):11-9. <strong>Rod outer segments mediate mitochondrial DNA damage and apoptosis
                in human retinal pigment epithelium.
            </strong>
            Jin GF, Hurst JS, Godley BF.
        </p>
        <p>
            Endocrinol Exp 1976 Jun;10(2):131-7. <strong>Diurnal variation in the effect of melatonin on plasma and
                muscle free fatty acid levels in the pigeon.</strong>
            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<strong>
                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</strong> 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<strong>
                in both plasma as well as muscle FFA levels was obtained at 90 min</strong> 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.
        </p>

        <p>
            Arch Int Physiol Biochim 1983 Jul;91(2):115-20. <strong>Diurnal impact of locomotory activity and melatonin
                and N-acetylserotonin treatment on blood metabolite levels in the rainbow trout.</strong> 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<strong>
                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</strong> 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.
        </p>
        <p>
            J Neural Transm 1977;40(2):87-97. <strong>The adrenal medulla may mediate the increase in pineal melatonin
                synthesis induced by stress, but not that caused by exposure to darkness.</strong> Lynch HJ, Ho M,
            Wurtman RJ.
        </p>
        <p>
            Bull Acad Natl Med 2000;184(2):415-28; discussion 428-30. <strong>[Pulmonary toxicity of oxygen]</strong>
            [Article in French] Mantz JM, Stoeckel ME.
        </p>

        <p>
            Br J Pharmacol 1977 Dec;61(4):607-14. <strong>The action of melatonin on single amphibian pigment cells in
                tissue culture.</strong> Messenger EA, Warner AE.
        </p>
        <p>
            Oftalmol Zh 1989;(8):469-73. <strong>[The early diagnosis, evaluation of treatment results and modelling of
                certain aspects of the pathogenesis of retinal dystrophy]</strong>
            ; 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.
            <strong>Melatonin in 10(-3) M concentration leads to development of dystrophic changes</strong> 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) <strong>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</strong>
            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.
        </p>
        <p>
            J Clin Endocrinol Metab 1977 Oct;45(4):768-74. <strong>The effects of oral melatonin on skin color and on
                the release of pituitary hormones.</strong>
            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."
        </p>
        <p>
            Invest Ophthalmol 1976 Oct;15(10):869-72. <strong>Hormonal influences on photoreceptor damage: the pituitary
                gland and ovaries.</strong> 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.
        </p>
        <p>
            Invest Ophthalmol Vis Sci 1996 Oct;37(11):2243-57. <strong>Retinal light damage in rats with altered levels
                of rod outer segment docosahexaenoate. Organisciak DT, Darrow RM, Jiang YL, Blanks JC.</strong>

            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: <strong
            >Rats maintained for 7 to 12 weeks on the linolenic acid-deficient diet had significantly lower levels of
                DHA</strong> 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<strong>
                exhibited protection against retinal damage from either intermittent or hyperthermic light exposure.
                However, the unsaturated fatty acid content of ROS</strong> 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.
        </p>
        <p>
            Exp Neurol 1970 May;27(2):194-205.<strong>
                Retinal and optic nerve serotonin and retinal degeneration as influenced by photoperiod.</strong>
            O'Steen WK.
        </p>
        <p>
            Invest Ophthalmol Vis Sci 1982 Jan;22(1):1-7. <strong>Antagonistic effects of adrenalectomy and
                ether/surgical stress on light-induced photoreceptor damage.</strong> 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. <strong>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.</strong>
        </p>

        <p>
            Brain Res 1990 Nov 26;534(1-2):99-105. <strong>Water deprivation protects photoreceptors against light
                damage.</strong> 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."
        </p>
        <p>
            Brain Res 1985 Oct 7;344(2):231-9. <strong>Neuronal damage in the rat retina after chronic stress.</strong>
            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: <strong>input of the sensory
                stimulus, light, to the retina of stressed rats augmented neuronal damage and might be required for its
                initiation;</strong> and hormones and/or neurotransmitters associated with long-term chronic stress
            might be related to increased neuronal cell death in the mammalian retina.
        </p>
        <p>
            Invest Ophthalmol Vis Sci 1977 Oct;16(10):940-6. <strong>Effects of hypophysectomy, pituitary gland
                homogenates and transplants, and prolactin on photoreceptor destruction.</strong> 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. <strong>Hypophysectomized rats treated with prolactin had more severe retinal damage than
                untreated, hypophysectomized rats."</strong> "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."
        </p>
        <p>
            Life Sci 1985 Nov 4;37(18):1743-6. <strong>Stress-induced synthesis of melatonin: possible involvement of
                the endogenous monoamine oxidase inhibitor (tribulin).</strong> Oxenkrug GF, McIntyre IM.
        </p>
        <p>
            Mech Ageing Dev 2000 Jan 10;112(3):169-83. <strong>Double bond content of phospholipids and lipid
                peroxidation negatively correlate with maximum longevity in the heart of mammals.</strong> Pamplona R,
            Portero-Otin M, Ruiz C, Gredilla R, Herrero A, Barja G.
        </p>

        <p>
            Prostaglandins Leukot Essent Fatty Acids 2001 Feb;64(2):75-80. <strong>Comparative studies on lipid
                peroxidation of microsomes and mitochondria obtained from different rat tissues: effect of retinyl
                palmitate.</strong> Piergiacomi VA, Palacios A, Catala A.
        </p>
        <p>
            Curr Eye Res 1992 Oct;11(10):939-53. <strong>Oxygen-induced retinopathy in the rat: hemorrhages and
                dysplasias may lead to retinal detachment.</strong> Penn JS, Tolman BL, Lowery LA, Koutz CA.
        </p>
        <p>
            Vision Res 1995 May;35(9):1247-64. <strong>Studies on the role of the retinal dopamine/melatonin system in
                experimental refractive errors in chickens.</strong>

            Schaeffel F, Bartmann M, Hagel G, Zrenner E.
        </p>
        <p>
            Exp Clin Endocrinol Diabetes 1997;105(2): 109-12. <strong>Melatonin</strong>
            <strong>
                and serotonin regulate the release of insulin-like growth factor-I, oxytocin and progesterone by
                cultured human granulosa cells.</strong> Schaeffer HJ, Sirotkin AV.
        </p>
        <p>
            Zh Evol Biokhim Fiziol 1989 Jan-Feb;25(1):52-9. <strong>[Seasonal characteristics of the functioning of the
                hypophysis-gonad system in the suslik</strong> Citellus parryi] Shvareva NV, Nevretdinova ZG. "In
            females, FSH was found in the blood in October, being absent from November to<strong>
                January; beginning from February, it may be found both in sleeping and active</strong> animals." <strong
            >"Estradiol secretion was noted in hibernating females, whereas progesterone was found in the blood only in
                May."</strong>
        </p>

        <p>
            J Pineal Res 1985;2(1):39-49. <strong>Melatonin and N-acetylserotonin stress responses: effects of type of
                stimulation and housing conditions.</strong> Seggie J, Campbell L, Brown GM, Grota LJ.
        </p>
        <p>
            Acta Ophthalmol Scand 2001 Aug;79(4):428-30. <strong>Presumed sertraline maculopathy.</strong> Sener EC,
            Kiratli H.
        </p>
        <p>
            Paediatr Perinat Epidemiol 1999 Apr;13(2):128-30. <strong>Effects of premature exposure to light: a
                credibility struggle.</strong> Silverman WA.
        </p>

        <p>
            J Pineal Res 1994 Oct;17(3):112-7. <strong>Direct influence of melatonin on steroid, nonapeptide hormones,
                and cyclic nucleotide secretion by granulosa cells isolated from porcine ovaries.</strong> Sirotkin AV.
            <strong>
                "It was found that melatonin is able to inhibit progesterone and stimulate estradiol secretion."</strong
            > "The present observations suggest a direct effect of melatonin on the steroid, nonapeptide hormone, and
            cyclic nucleotide release from porcine ovarian cells."
        </p>
        <p>
            J Pineal Res 1994 Oct;17(3):112-7. <strong>Direct influence of melatonin on steroid, nonapeptide hormones,
                and cyclic nucleotide secretion by granulosa cells isolated from porcine ovaries.</strong> Sirotkin AV.
        </p>
        <p>
            Prog Clin Biol Res 1989;312:229-49. <strong>Inhibitors of the arachidonic acid cascade in the management of
                ocular inflammation.</strong>

            Srinivasan BD, Kulkarni PS.
        </p>
        <p>
            J Nutr 2000 Dec;130(12):3028-33. <strong>Polyunsaturated (n-3) fatty acids susceptible to peroxidation are
                increased in plasma and tissue lipids of rats fed docosahexaenoic acid-containing oils.</strong> Song
            JH, Fujimoto K, Miyazawa T.<strong>
                "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</strong>
            susceptibility of membranes to lipid peroxidation and by disrupting the antioxidant system."
        </p>
        <p>
            Acta Ophthalmol (Copenh) 1992 Feb;70(1):115-22. <strong>Effects of steady electric fields on human retinal
                pigment epithelial cell orientation and migration in culture.</strong> Sulik GL, Soong HK, Chang PC,
            Parkinson WC, Elner SG, Elner VM
        </p>

        <p>
            Ned Tijdschr Geneeskd 2001 Dec 29;145(52):2521-5. <strong>[Administration of glucocorticosteroids to
                premature infants: increasing evidence of adverse effects]</strong> [Article in Dutch] van Bel F.
            <strong>"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.</strong>"
        </p>
        <p>
            Brain Res 1984 Feb 27;294(1):166-8. <strong>Pineal methoxyindoles depress calcium uptake by rat brain
                synaptosomes.</strong> Vacas MI, Keller Sarmiento MI, Cardinali DP.
        </p>
        <p>
            Ann N Y Acad Sci 1994 Nov 17;738:408-18. <strong>Serotonin binding proteins: an in vitro model system for
                monoamine-related neurotoxicity.</strong> Vauquelin G, Del Rio MJ, Pardo CV.
        </p>

        <p>
            J Hypertens Suppl 1985 Dec;3 Suppl 3:S107-9. <strong>Seasonal variation in the development of stress-induced
                systolic hypertension in the rat.</strong>
            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."
            <strong>
                "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,
            </strong>
            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<strong>
                sympathetic pressor activity by stress hormones, adrenaline, corticosterone and prolactin, under the
                influence of melatonin."</strong>
        </p>
        <p>
            Invest Ophthalmol Vis Sci 1992 May;33(6):1894-902. <strong>Melatonin increases photoreceptor susceptibility
                to light-induced damage.</strong> Wiechmann AF, O'Steen WK. <strong>"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.</strong>" "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."
        </p>

        <p>
            J Neurochem 1986 Oct;47(4):1181-9. <strong>Effects of arachidonic acid on glutamate and gamma-aminobutyric
                acid uptake in primary cultures of rat cerebral cortical astrocytes and neurons.</strong> Yu AC, Chan
            PH, Fishman RA.
        </p>

        <p>
            © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
        </p>
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    <head><title>Altitude and Mortality</title></head>
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        <h1>
            Altitude and Mortality
        </h1>

        <p></p>
        <p>
            <em>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.</em>
        </p>
        <p>
            <strong><em>Stress, shock, inflammation, aging, and organ failure are, in important ways, respiratory
                    problems.</em></strong>
        </p>

        Definitions <strong>
            Haldane effect:
        </strong>Oxygen displaces carbon dioxide from hemoglobin, in proportion to its partial (specific) pressure.
        <strong>
            Bohr effect:</strong> Carbon dioxide (or acidity) displaces oxygen from hemoglobin. <strong>
            Lactic acidemia:
        </strong>The presence of lactic acid in the blood. <strong>
            Alkalosis:</strong> A pH of the blood above 7.4. <strong>
            Acidosis:
        </strong>A blood pH below 7.4. <strong>
            Lactate paradox:</strong> 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.<p></p>
        <p>
            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 <strong><em>perceptions and intuitions
                </em></strong>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"<strong>:</strong> A pathological retention of water. The swollen heart beats poorly, the swollen
            lens turns milky, other cells divide rapidly as a result of swelling.
        </p>
        <p>
            People who live at very high altitudes live significantly longer<strong>;</strong> 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.
        </p>

        <p>
            "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.
        </p>
        <p>
            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,<strong>
                periods of higher pressure correspond to an increased incidence of death</strong>
            from heart disease and strokes.
        </p>
        <p>
            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.
        </p>
        <p>
            Hyperventilation, breathing excessively and causing too much carbon dioxide to be lost, is similar to being
            in the presence of too much oxygen<strong>;</strong> 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.
        </p>

        <p>
            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.
        </p>
        <p>
            Breathing too much oxygen displaces too much carbon dioxide, provoking an increase in lactic acid<strong
            >;</strong> too much lactate displaces both oxygen and carbon dioxide. Lactate itself tends to suppress
            respiration.
        </p>
        <p>
            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..
        </p>
        <p>
            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..
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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. <strong>
                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.
            </strong>
            Besides<strong> </strong>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.
        </p>
        <p>
            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.
        </p>

        <p>
            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, <strong>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.</strong>
        </p>
        <p>
            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. <strong>This is very similar to the "multiple organ failure" that occurs in
                inflammatory conditions, bacteremia, congestive heart failure, cancer, and trauma.</strong>
        </p>
        <p>
            <strong>Otto Warburg established that lactic acid production even in the presence of oxygen is a fundamental
                property of cancer.</strong> 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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.<strong> </strong>
            (Carbon dioxide itself directly reduces tissue edema, as can be seen in studies of the cornea.)<strong>
                Thyroid, progesterone, magnesium, glucose, and saturated fatty acids are among the central protective
                elements.</strong>
        </p>

        <p>
            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.
        </p>
        <p>
            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..
        </p>
        <p>
            When the ideas of "stress," "respiratory defect," and "hyperventilation" are considered together, they seem
            practically interchangeable.
        </p>
        <p>
            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. <strong>The mere presence of lactic acid can make cells more
                susceptible to the transformation into cancer cells.
            </strong>(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.
        </p>
        <p>
            Blocking the production of lactic acid can make cells more resistant (Seymour and Mothersill, 1988)<strong
            >;</strong>

            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.
        </p>
        <p>
            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<strong>;</strong> 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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            There are many little cliches in the medical culture that prevent serious thought about integral
            therapy<strong>:</strong> "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.
        </p>
        <p><h3>REFERENCES</h3></p>
        <p>
            Cell Biol Int Rep 1983 Nov;7(11):971-80.<strong>
                Lactate-mediated changes in growth morphology and transformation frequency of irradiated C3H 10T1/2
                cells.</strong> 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 <strong>both high lactate levels and high glycolytic metabolism in
                tumours</strong> 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 <strong>
                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.
            </strong>
            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.
        </p>
        <p>
            <strong>Radiat Environ Biophys 1988;27(1):49-57. The effect of glycolysis</strong>
            <strong>
                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.
            </strong>
        </p>
        <p>
            Crit Care Med 1999 Aug;27(8):1517-23. <strong>Protective effect of poly(ADP-ribose) synthetase inhibition on
                multiple organ failure after zymosan-induced peritonitis in the rat.</strong> Cuzzocrea S, Zingarelli B,
            Costantino G, Sottile A, Teti D, Caputi AP
        </p>
        <p>
            Eur J Cancer 1975 May;11(5):365-371. <strong>Cancer and altitude. Does intracellular pH regulate cell
                division?</strong> Burton AC.<strong> </strong>
        </p>

        <p>
            <strong>Monaldi Arch Chest Dis 1999 Aug;54(4):365-72. The pathophysiology of hyperventilation syndrome.
                Folgering H.</strong> Dept Pulmonology Dekkerswald, University of Nijmegen, Groesbeek, The Netherlands..
            <strong>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.</strong> 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<strong>
                increased sympathetic adrenergic tone.</strong> 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.
        </p>
        <p>
            N Engl J Med 1977 Mar 17;296(11):581-585.<strong>
                Reduction in mortality from coronary heart disease in men residing at high altitude.</strong> 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 <strong>were 98, 90, 86 and 72 per cent of that for the county group below 1220-m altitude (P less
                than 0.0001).</strong> 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.
        </p>

        <p>
            Br Med J 1980 Jan 5;280(6206):5. Cardiovascular mortality and altitude.
        </p>
        <p>
            Radiat Res 1987 Nov;112(2):381-390. <strong>Altitude, radiation, and mortality from cancer and heart
                disease.</strong> 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 <strong>negative correlations with background radiation</strong> seen for <strong>mortality
                from arteriosclerotic heart disease and cancers of the lung, the intestine, and the breast</strong>
            disappeared or became positive once altitude was included in the models. <strong>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.
            </strong>
        </p>
        <p>
            Biull Eksp Biol Med 1993 Jun;115(6):576-578. <strong>[The effect of high-altitude ecological and
                experimental stresses on the thrombocyte-vascular wall system].</strong> [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<strong
            >
                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.
            </strong>
        </p>

        <p>
            Diabetologia 1982 Jun;22(6):493. <strong>Measurement of glycosylated haemoglobin at high altitudes.</strong>
            Paisey R, Valles V, Arredondo G, Wong B, Lozano-Castaneda O.
        </p>
        <p>
            <strong>[Change in the ultrastructure of rat myocardium under the influence of 12-months' adaptation to high
                altitude]</strong> 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.<strong>
                Hyperplasia and hypertrophy of individual organellae, particularly mitochondria</strong>, 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.
        </p>
        <p>
            <strong>[Morphologic characteristics of the hearts of argali continuously dwelling at high mountain
                altitudes]</strong>, Zhaparov B; Kamitov SKh; Mirrakhimov MM, Biull Eksp Biol Med, 1980 Apr, 89<strong
            >:</strong>4, 498-501 The hearts of argali [wild sheep] living at 3800-5000 m above the sea level were
            examined.<strong>
                Macroscopy showed complete absence of fatty tissue under the epicardium.</strong> 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<strong>
                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.
            </strong>
        </p>

        <p>
            J Dev Physiol 1990 Sep;14(3):139-46. <strong>Effect of lactate and beta-hydroxybutyrate infusions on brain
                metabolism in the fetal sheep.</strong>
            <hr />
            <strong>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</strong> concentrations during the butyrate infusions. Both substrates
            have metabolic actions that may inhibit brain glucose uptake. <strong>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.</strong>
        </p>
        <p>
            Hypertens 1995 Feb;9(2):119-22. <strong>
                Pressor effect of hyperventilation in healthy subjects.</strong> 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<strong>
                observation. Hyperventilation significantly increased SBP by 8.9 mm Hg (95% CI 3.8-13.8, P &lt; 0.01),
                diastolic blood pressure by 8.2 mm Hg (95% CI 1.7-14.7, P &lt; 0.05), mean arterial pressure by 10.0 mm
                Hg (95% CI 3.3-16.7, P &lt; 0.01) and heart rate by 36 beats/min (95% CI 31-44, P &lt; 0.01). The
                changes in diastolic and mean arterial pressure correlated significantly with the total</strong>
            <hr />
            <strong>
                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</strong>
            min.
        </p>

        <p>
            Respiration 1986;49(3):187-94. <strong>Role of hypocapnia in the alveolar surfactant increase induced by
                free fatty acid intravenous infusion in the rabbit.</strong>
            Oyarzun MJ, Donoso P, Quijada D<strong>. 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</strong>
            <hr />
        </p>
        <p>
            Farmakol Toksikol 1977. Sep-Oct; 40(5):620-3..<strong>
                [Effect of combinations of apressin, obsidan, diprazin, adenosine, NAD and nicotinamide on the
                resistance of rats to hypoxia and on carbohydrate metabolic indices].</strong> [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, <strong>brings down the excess lactate level and raises the
                redoz potential of the system lactic-acid-pyruvic</strong> acid in the brain of rats exposed to the
            effects of rarefied atmosphere.
        </p>

        <p>
            Schweiz Med Wochenschr 1977 Nov 5;107(44):1585-6. <strong>[Protective effect of pyridoxilate on the hypoxic
                myocardium. Experimental studies].</strong> [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. <strong>The mechanisms of action of
                piridoxilate are probably fairly similar to those of Na dichloracetate</strong>.
        </p>
        <p>
            J. Appl Physiol 1991 Apr;70(4):1720-30. .<strong>Metabolic and work efficiencies during exercise in Andean
                natives.</strong> Hochachka PW, Stanley C, Matheson GO, McKenzie DC, Allen PS, Parkhouse WS Department
            of Zoology, University of British Columbia, Vancouver, Canada. <strong>
                Maximum O2 and CO2 fluxes during exercise were less perturbed by hypoxia in Quechua natives</strong>
            from the Andes than in lowlanders. In exploring how this was achieved, we found that, <strong>for a given
                work rate, Quechua highlanders at 4,200 m accumulated substantially less lactate
            </strong>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 <strong>efficiency advantage of aerobic metabolism (high ATP yield
                per mol of substrate metabolized) compared with anaerobic glycolysis.</strong> 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);<strong>
                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).</strong> 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.
        </p>

        <p>
            Br J Anaesth 1975 Jun;47(6):669-78. <strong>Effect of CO2 on myocardial contractility and aortic input
                impedance during anaesthesia.</strong> 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<strong>
                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).
            </strong>
        </p>
        <p>
            J Appl Physiol 1991 May;70(5):1963-76.<strong>
                Skeletal muscle metabolism and work capacity: a 31P-NMR study of Andean natives and lowlanders.</strong>
            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 <strong>maximal O2 consumption (VO2max) paradox (higher work
                rates following acclimatization without increases in VO2max)
            </strong>and the lactate paradox (progressive reductions in muscle and blood lactate with exercise at
            increasing altitude). To
        </p>

        <p>
            J Hum Hypertens 1995 Feb;9(2):119-22.<strong>
                Pressor effect of hyperventilation in healthy subjects.</strong>Todd GP, Chadwick IG, Yeo WW, Jackson
            PR, Ramsay LE.
        </p>
        <p>
            J Infect Dis 1998 May;177(5):1418-21.<strong>The effect of lactic acid on mononuclear cell secretion of
                proinflammatory cytokines in response to group B streptococci.</strong>
            Steele PM, Augustine NH, Hill HR Department of Pathology, University of Utah School of Medicine, Salt Lake
            City 84132, USA.<strong><hr /></strong>
        </p>
        <p>
            J Appl Physiol 1994 Apr;76(4):1462-7<strong>.</strong> Lactic acidosis as a facilitator of oxyhemoglobin
            dissociation during exercise. Stringer W, Wasserman K, Casaburi R, Porszasz J, Maehara K, French W.
        </p>

        <p>
            <strong>Involvement of nitric oxide and N-methyl- D-aspartate in acute hypoxic altitude convulsion in mice.
            </strong>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." <strong>"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."</strong>
            "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."<strong> </strong>
        </p>
        <p>
            <strong>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.
            </strong>
            Said SI; Berisha HI; Pakbaz H. Proc Natl Acad Sci U S A, 1996 May 14, 93:10, 4688-92. <strong>"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."</strong>
            The injury was prevented by competitive NMDA receptor antagonists or by channel-blocker MK-801, and <strong
            >was reduced in the presence of Mg2+.</strong> As with NMDA toxicity to central neurons, the lung injury was
            nitric oxide (NO) dependent: it <strong>required L-arginine, was associated with increased production of
                NO,</strong> and was attenuated by either of two NO synthase inhibitors. The neuropeptide<strong>
            </strong>vasoactive intestinal peptide and<strong>
                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.
            </strong>

            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.
        </p>
        <p>
            <strong>Adenosine modulates N-methyl-D- aspartate- stimulated hippocampal nitric oxide production in vivo.
            </strong>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."
        </p>
        <p>
            Anesthesiology 1993 Jan;78(1):91-9.<strong>
                Hypocapnia worsens arterial blood oxygenation and increases VA/Q heterogeneity in canine pulmonary
                edema.</strong> 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."
        </p>

        <p>
            <strong>Acta Anaesthesiol Scand 1996 Jan;40(1):133-4 Hyperlactatemia associated with hypocarbic
                hyperventilation. Cheung PY</strong>
        </p>
        <p>
            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. <strong>
                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.</strong>
            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 &lt; 0.05). Moreover in red muscles, both
            GLUT-4 mRNA (-30% in red quadriceps and -60% in soleus; P &lt; 0.025) and protein (-40% in red quadriceps; P
            &lt; 0.05) were decreased, whereas the (E1alpha)pyruvate dehydrogenase (PDH) mRNA was increased (+40% in red
            quadriceps; P &lt; 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 <strong>chronic
                hyperlactatemia</strong> reduces glucose uptake by affecting the expression of genes involved in glucose
            metabolism in muscle, suggesting a role for lactate in t<strong>he development of insulin
                resistance.</strong>
        </p>

        <p>
            Radiat Res 1993 Apr;134(1):79-85 <strong>Effects of in vivo heart irradiation on myocardial energy
                metabolism in rats.</strong>
            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<strong>
                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
            </strong>
            <hr />
            <strong>changes in energy supplies provide a mechanism to explain impaired contractility after local heart
                irradiation.
            </strong>
        </p>
        <p>
            J Radiat Res (Tokyo) 1993 Sep;34(3):195-203.<strong>
                Radiosensitization of human lung fibroblasts by chemical that decrease ATP levels.
            </strong>Kumar A, Kimura H, Aoyama T.<strong>
                "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.
            </strong>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.<strong>
                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."</strong>
        </p>
        <p>
            J Exp Med 1993 May 1;177(5):1391-8. <strong>Enhancement of experimental metastasis by tumor necrosis
                factor.</strong> 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 <strong>
                more metastatic foci and augmented proliferative activity of the tumor cells after
            </strong>
            <strong>rmTNF pretreatment of mice.</strong> However, no direct effect of rmTNF on the proliferation rate of
            tumor cells was seen in vitro."
        </p>
        <p>
            Nippon Geka Gakkai Zasshi 1996 Sep;97(9):726-32.<strong>
                [Energy substrate metabolism during stress].
            </strong> Sugimoto H. Department of Traumatology and Critical Care Medicine, Osaka University School of
            Medicine, Suita, Japan.<strong>
                "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."</strong>
        </p>
        <p>
            <em>Clin Physiol 1995 Nov;15(6):581-95.
            </em>
            <strong><em>Effects of lactate infusion on hepatic gluconeogenesis and glycogenolysis.</em></strong>
            <em>
                Haesler E, Schneiter P, Temler E, Jequier E, Tappy L.</em>
        </p>
        <p>
            <em>Cancer Res 1993 Apr. 15;53(8):1939-44..
            </em>
            <strong><em>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.</em
                ></strong>
            <em>
                Wu S, Boyer CM, Whitaker RS, Berchuck A, Wiener JR, Weinberg JB, Bast RC Jr.</em>
        </p>
        <p>
            Klin Med (Mosk) 1989 May;67(5):38-41<strong>. ["Dry" carbon dioxide baths in treating patients with
                myocardial infarction at the sanatorium stage of rehabilitation].
            </strong>

            [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.
        </p>
        <p>
            J Dev Physiol 1989 Nov;12(5):283-6. <strong>Haemodynamic effects of respiratory alkalosis independent of
                changes in airway pressure in anaesthetized newborn dogs.</strong> Reuter JH, Donovan EF, Kotagal U.R.
            <strong>"We have recently reported a decrease in cardiac output in newborn dogs during respiratory alkalosis
                which is independent of changes in airway pressure."</strong>
        </p>
        <p>
            Undersea Hyperb Med 1994 Jun;21(2):169-83. <strong>Influence of hyperbaric oxygen on left ventricular
                contractility, total coronary blood flow, and myocardial oxygen consumption in the conscious dog.
            </strong>
            Savitt MA, Rankin JS, Elberry JR, Owen CH, Camporesi E.M. <strong>"It is known that hyperbaric oxygenation
                (HBO) decreases total coronary blood flow (TCBF) and cardiac output (CO)."</strong>
        </p>
        <p>
            <strong><em>Heart rhythm disturbances in the inhabitants of mountainous regions.</em></strong>
            <em>
                Mirrakhimov MM; Meimanaliev TS Cor Vasa, 1981, 23:5, 359-65.
            </em>
            <strong><em>"During exercise heart arrhythmias</em></strong>
            <strong><em>
                    appeared conspicuously less frequently in the high mountain than in the low altitude inhabitants."
                </em></strong>
        </p>
        <p>© Ray Peat 2006. All Rights Reserved. www.RayPeat.com</p>
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    <head><title>The problem of Alzheimer's disease as a clue to immortality - Part&nbsp;1</title></head>
    <body>
        <h1>
            The problem of Alzheimer's disease as a clue to immortality - Part&nbsp;1
        </h1>

        <p>
            I. INTRODUCTION
        </p>
        <p>
            II. COMMON FACTORS IN INJURY DURING GROWTH AND AGING
        </p>
        <p>
            III. A VIEW OF ENTROPY--RENEWAL OF THE BRAIN
        </p>
        <p>
            IV. FALSE SIGNALS FROM THE ENVIRONMENT
        </p>
        <p>
            A. EDUCATION, DIET AND MEDICINE INTERACT
        </p>

        <p>
            B. SIGNALS IN THE ABSTRACT
        </p>
        <p>
            V. HORMONE IMBALANCE, LEADING TO FAILURE OF PROTECTIVE INHIBITION AND ALZHEIMER'S DISEASE
        </p>
        <p>
            A. THE FUNCTION OF ENERGY
        </p>
        <p>
            B. EFFECTS OF ESTROGEN AND UNSATURATED FATTY ACIDS
        </p>
        <p>
            C. VITAMIN A AND STEROIDS
        </p>

        <p>
            D. THE NATURE OF ALZHEIMER'S DISEASE
        </p>
        <p>
            E. AN EXAMPLE; DIET AFFECTS HORMONES WHICH AFFECT STRUCTURE AND LEAD TO APPARENT SELF- DESTRUCTION
        </p>
        <p>
            VI. STRUCTURE AS A REGULATORY SYSTEM--AN EMERGING VISION OF PERVASIVE EPIGENESIS
        </p>
        <p>
            <strong>I. INTRODUCTION</strong>
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            <strong>II. COMMON FACTORS IN BRAIN INJURY DURING GROWTH AND AGING
            </strong>
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            <strong>III. A VIEW OF ENTROPY: RENEWAL OF THE BRAIN
            </strong>
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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).
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p><strong>IV. FALSE SIGNALS FROM THE ENVIRONMENT</strong></p>
        <p>
            The environment can be supportive, but it can also divert development from an optimal course.
        </p>
        <p>
            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.
        </p>
        <p>
            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.)
        </p>

        <p>
            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..
        </p>
        <p>
            (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.)
        </p>
        <p>
            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.
        </p>

        <p>
            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."
        </p>
        <p>
            <strong>SIGNALS IN THE ABSTRACT</strong>
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            These have metabolic links with each other, with ammonia, and with stress and energy metabolism.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Endotoxin: Antimitochondrial action, causes elevation of estrogen. It synergizes with unsaturated fats, and
            naloxone opposes some of its toxic effects.
        </p>

        <p>
            Urea, cholesterol: Structural stability of proteins and lipid-protein complexes.
        </p>
        <p>
            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.
        </p>

        <p>
            <a href="http://raypeat.com/articles/articles/alzheimers2.shtml"><strong>Article continued in Part 2 - click
                    here</strong></a>
        </p>

        <p>
            Raymond Peat, Ph.D.
        </p>
        <p>
            Copyright 1997
        </p>

        <p>
            <strong><h3>SELECTED REFERENCES</h3></strong>
        </p>
        <p>
            S. Rose, "Genuine genetics or conceited convenience?" Trends in Neuro. Sci. 17(3), 105, 1994.
        </p>

        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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."]
        </p>
        <p>
            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."
        </p>
        <p>
            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 &amp; 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."
        </p>
        <p>
            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."
        </p>

        <p>
            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."
        </p>
        <p>
            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."
        </p>
        <p>
            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...."
        </p>
        <p>
            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."
        </p>

        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>

        <p>
            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>
        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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."
        </p>
        <p>
            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."
        </p>

        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>

        <p>
            T. Gunther and V. Hollriegl, "Increased protein oxidation by magnesium deficiency and vitamin E depletion,"
            Magnesium-Bull. 16(3), 101-103, 1994.
        </p>
        <p>
            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...."
        </p>

        <p>
            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."
        </p>
        <p>
            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>

        <p>
            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."
        </p>
        <p>
            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.
        </p>

        <p>
            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."
        </p>
        <p>
            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."
        </p>

        <p>
            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.
        </p>
        <p>
            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.)]
        </p>
        <p>
            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>
        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>

        <p>
            <a href="http://raypeat.com/articles/articles/alzheimers2.shtml"><strong>Article continued in Part 2 - click
                    here</strong></a>
        </p>
        <strong>
            <p>
                © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
            </p>
        </strong>
        <strong> </strong>
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    <head><title>Aspirin, brain, and cancer</title></head>
    <body>
        <h1>
            Aspirin, brain, and cancer
        </h1>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Early in the 20th century, people were told that fevers were very bad, and that aspirin should be used
            whenever there is a fever.
        </p>
        <p>
            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)
        </p>
        <p>
            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.
        </p>

        <p>
            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.)
        </p>

        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Aspirin, like progesterone or vitamin E, can improve fertility, by suppressing a prostaglandin, and
            improving uterine circulation.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

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        </p>

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        </p>
        <p>
            Int J Cancer 2001 Aug 15;93(4):497-506.<strong>
                Cyclooxygenase inhibitors retard murine mammary tumor progression by reducing tumor cell migration,
                invasiveness and angiogenesis.</strong> Rozic JG, Chakraborty C, Lala PK.
        </p>
        <p>
            Res Commun Mol Pathol Pharmacol 1998 Sep;101(3):259-68. <strong>Protective ability of acetylsalicylic acid
                (aspirin) to scavenge radiation induced free radicals in J774A.1 macrophage cells.</strong> Saini T,
            Bagchi M, Bagchi D, Jaeger S, Hosoyama S, Stohs SJ.
        </p>

        <p>
            Mol Cell Biochem 1999 Sep;199(1-2):93-102. <strong>
                Antioxidant properties of aspirin: characterization of the ability of aspirin to inhibit silica-induced
                lipid peroxidation, DNA damage, NF-kappaB activation, and TNF-alpha production.</strong> Shi X, Ding M,
            Dong Z, Chen F, Ye J, Wang S, Leonard SS, Castranova V, Vallyathan V
        </p>
        <p>
            J Physiol Paris 2001 Jan-Dec;95(1-6):51-7. <strong>Protection by aspirin of indomethacin-induced small
                intestinal damage in rats: mediation by salicylic acid.</strong> 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."
        </p>

        <p>
            FASEB J 2001 Oct;15(12):2057-72. <strong>Cyclooxygenase-independent actions of cyclooxygenase</strong>
            <strong>
                inhibitors.</strong> Tegeder I, Pfeilschifter J, Geisslinger G.
        </p>
        <p>
            J Indian Med Assoc 1997 Feb;95(2):43-4, 47. <strong>Role of low dose aspirin in prevention of pregnancy
                induced hypertension.</strong> Tewari S, Kaushish R, Sharma S, Gulati N
        </p>
        <p>
            J Chromatogr B Biomed Appl 1995 Jul 21;669(2):404-7. <strong>Aspirin inhibits collagen-induced platelet
                serotonin release, as measured by microbore high-performance liquid chromatography with electrochemical
                detection.</strong> Tsai TH, Tsai WJ, Chen CF.
        </p>

        <p>
            Clin Exp Immunol 1991 Nov;86(2):315-21. <strong>Piroxicam, indomethacin</strong>
            <strong>
                and aspirin action on a murine fibrosarcoma.</strong> 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)."
        </p>
        <p>
            Int J Radiat Biol 1995 May;67(5):587-96. <strong>Amelioration of radiation nephropathy by acetylsalicylic
                acid.</strong> Verheij M, Stewart FA, Oussoren Y, Weening JJ, Dewit L.
        </p>

        <p>
            Semin Perinatol 1986 Oct;10(4):334-55. <strong>The role of arachidonic acid metabolites in
                preeclampsia.</strong> Walsh SW, Parisi VM.
        </p>
        <p>
            Proc Natl Acad Sci U S A 1999 Apr 27;96(9):5292-7. <strong>Suppression of inducible cyclooxygenase 2 gene
                transcription by aspirin and sodium salicylate.</strong> 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."
        </p>
        <p>
            Hum Reprod 1994 Oct;9(10):1954-7. <strong>The benefits of low-dose aspirin therapy in women with impaired
                uterine perfusion during assisted conception.</strong>

            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."
        </p>
        <p>
            J Ethnopharmacol 1991 Sep;34(2-3):215-9. <strong>Radiation-protective and platelet aggregation inhibitory
                effects of five traditional Chinese drugs and acetylsalicylic acid following high-dose
                gamma-irradiation.</strong>
            Wang HF, Li XD, Chen YM, Yuan LB, Foye WO.
        </p>
        <p>
            Fertil Steril 1997 Nov;68(5):927-30. <strong>Low-dose aspirin for oocyte donation recipients with a thin
                endometrium: prospective, randomized study.</strong> 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."
        </p>

        <p>
            Dermatologica 1978;156(2):89-96. <strong>Effect of topical salicylic acid on animal epidermopoiesis.</strong
            > 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%.
        </p>
        <p>
            Arch Exp Veterinarmed 1981;35(3):465-70. <strong>[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]</strong> 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)."
        </p>
        <p>
            Biomed Pharmacother 1999 Aug;53(7):315-8. <strong>Aspirin induced apoptosis in gastric cancer cells.</strong
            > Wong BC, Zhu GH, Lam SK
        </p>

        <p>
            Scand J Immunol 2000 Oct;52(4):393-400. <strong>Tamoxifen decreases renal inflammation and alleviates
                disease severity in autoimmune NZB/W F1 mice.</strong> 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."
        </p>
        <p>
            Science 2001 Aug 31;293(5535):1673-7. <strong>Reversal of obesity- and diet-induced insulin resistance with
                salicylates or targeted disruption of Ikkbeta.</strong> Yuan M, Konstantopoulos N, Lee J, Hansen L, Li
            ZW, Karin M, Shoelson SE.
        </p>
        <p></p>
        <hr />
        <p>
            <strong><em>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.</em></strong>
        </p>
        <p>
            <strong><em>It protects against the harmful effects of estrogen, prolactin, serotonin, cortisol, histamine,
                    and radiation (u.v., x-rays, gamma rays).</em></strong>
        </p>

        <p>
            <strong><em>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.</em></strong>
        </p>
        <p>
            <strong><em>It protects the brain, and can improve learning. It's an antioxidant, prevents cataracts, and
                    protects against glycation in diabetes.
                </em></strong>
        </p>
        <p>
            <strong><em>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.</em></strong>
        </p>
        <p>
            <strong><em>Although aspirin protects against uncontrolled cell proliferation, as in cancer and psoriasis,
                    salicylic acid increases normal cell division in the skin.</em></strong>
        </p>
        <p>
            <strong><em>Aspirin protects against many forms of shock and stess, and corrects imbalances in the nervous
                    system.</em></strong>
        </p>
        <p><strong><em>It protects against several kinds of toxins involved in brain degeneration.</em></strong></p>

        <p>
            <strong><em>"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."</em></strong>
        </p>
        <p>
            <strong><em>
                    De Cristobal, et al., 2002</em></strong>
        </p>
        <p>
            <strong><em>"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</em></strong>
        </p>

        <p>© Ray Peat 2006. All Rights Reserved. www.RayPeat.com</p>
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        <h1>
            Academic authoritarians, language, metaphor, animals, and science
        </h1>

        <p></p>
        <h1><strong>Academic authoritarians, language, metaphor, animals, &amp; science</strong></h1>

        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<strong> </strong>
        a greater susceptibility of children to cultural conventions." (Horner and Whiten, 2005; Whiten, et al.,
        2004).<p></p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Around the same time, I found that some people dream in vivid images, while others describe dreams as
            "listening to someone tell a story."
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            There have been various studies that have investigated the number of words understood by children at
            different ages.
        </p>
        <p>
            The Virginia Polytechnic Institute website says that
        </p>
        <p>
            By age 4 a person probably knows 5,600 words
        </p>
        <p>
            By age 5 a person probably knows 9,600 words
        </p>
        <p>
            By age 6 a person probably knows 14,700 words
        </p>
        <p>
            By age 7 a person probably knows 21,200 words
        </p>

        <p>
            By age 8 a person probably knows 26,300 words
        </p>
        <p>
            By age 9 a person probably knows 29,300 words
        </p>
        <p>
            By age 10 a person probably knows 34,300 words
        </p>
        <p>
            By age 20 a college sophomore probably knows 120,000 words
        </p>
        <p>
            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.
        </p>

        <p>
            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".
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            "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.
        </p>
        <p>
            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.
        </p>
        <p>
            A name for "a thing" is a name for a pattern, a set of relationships.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Learning of this sort is always a system of closed compartments, though one system might occasionally be
            exchanged for another, in a "conversion experience."
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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, <em>The Authoritarians</em> (2006) is available on the internet.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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?"
        </p>
        <p>
            "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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p><h3>REFERENCES</h3></p>
        <p>
            New Yorker,<strong> </strong>April 16, 2007<strong>, "The Interpreter: Has a remote Amazonian tribe upended
                our understanding of language?"
            </strong>
            by John Colapinto. "Dan Everett believes that Pirah" undermines Noam Chomsky's idea of a universal grammar."
        </p>

        <p>
            Language &amp; Communication Volume 23, Issue 1, January 2003, Pages 1-43. <strong>
                "Remarks on the origins of morphophonemics in American structuralist linguistics,"
            </strong>E. F. K. Koerner. Chomsky has led the public to believe that he originated things which he borrowed
            from earlier linguists.
        </p>
        <p>
            Science. 2008 Feb 1;319(5863):569; author reply 569. <strong>Comparing social skills of children and
                apes.</strong> De Waal FB, Boesch C, Horner V, Whiten A. Letter
        </p>
        <p>
            Curr Biol. 2007 Jun 19;17(12):1038-43. Epub 2007 Jun 7.<strong>
                Transmission of multiple traditions within and between chimpanzee groups.</strong> 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 href="mailto:A.whiten@st-andrews.ac.uk" target="_blank">A.whiten@st-andrews.ac.uk</a>
            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.
        </p>

        <p>
            J Comp Psychol. 2007 Feb;121(1):12-21. <strong>Learning from others' mistakes? limits on understanding a
                trap-tube task by young chimpanzees (Pan troglodytes) and children (Homo sapiens).
            </strong>Horner V, Whiten A. Centre for Social Learning and Cognitive Evolution, School of Psychology,
            University of St Andrews, Fife, Scotland, UK. <a href="mailto:Vhorner@rmy.emory.edu" target="_blank"
            >Vhorner@rmy.emory.edu</a> 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.
        </p>
        <p>
            Proc Biol Sci. 2007 Feb 7;274(1608):367-72. <strong>Spread of arbitrary conventions among chimpanzees: a
                controlled experiment.</strong> Bonnie KE, Horner V, Whiten A, de Waal FB. Living Links, Yerkes National
            Primate Research Center, Atlanta, GA 30329, USA. <a href="mailto:Kebonni@emory.edu" target="_blank"
            >Kebonni@emory.edu</a> 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.
        </p>

        <p>
            Proc Natl Acad Sci U S A. 2006 Sep 12;103(37):13878-83. <strong>Faithful replication of foraging techniques
                along cultural transmission chains by chimpanzees and children.</strong> 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.
        </p>
        <p>
            Nature. 2005 Sep 29;437(7059):737-40. <strong>Conformity to cultural norms of tool use in
                chimpanzees.</strong> 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
                href="mailto:A.whiten@st-and.ac.uk"
                target="_blank"
            >A.whiten@st-and.ac.uk</a> 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.
        </p>

        <p>
            Anim Cogn. 2005 Jul;8(3):164-81. <strong>Causal knowledge and imitation/emulation switching in chimpanzees
                (Pan troglodytes) and children (Homo sapiens).</strong>
            Horner V, Whiten A. Centre for Social Learning and Cognitive Evolution, School of Psychology, University of
            St Andrews, St Andrews, KY16 9JU, UK. <a href="mailto:Vkh1@st-andrews.ac.uk" target="_blank"
            >Vkh1@st-andrews.ac.uk</a> 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 <strong>more comprehensive copy of an observed action. In contrast to the chimpanzees,
                children employed imitation</strong> 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<strong>
                a greater susceptibility of children to cultural conventions,</strong> perhaps combined with a
            differential focus on the results, actions and goals of the demonstrator.
        </p>
        <p>
            Learn Behav. 2004 Feb;32(1):36-52. <strong>How do apes ape?</strong> 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
                href="mailto:A.whiten@st-and.ac.uk"
                target="_blank"
            >A.whiten@st-and.ac.uk</a>

            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 <strong>flexibly adaptive
                ways,</strong> in conjunction with nonsocial learning. We conclude by sketching the kind of decision
            tree that appears to underlie the deployment of these alternatives.
        </p>
        <p>
            <a href="http://www.ucc.vt.edu/stdysk/vocabula.html" target="_blank"><strong><u
                    >http://www.ucc.vt.edu/stdysk/vocabula.html</u></strong></a>
        </p>

        © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
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    <head><title>Bleeding, clotting, cancer</title></head>
    <body>
        <h1>
            Bleeding, clotting, cancer
        </h1>

        <p>
            <em>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.</em>
        </p>
        <em>
            <p>
                Mental stress, exercise, estrogen, and serotonin activate both the formation and dissolution of clots.
            </p>
            <p>
                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.
            </p>

            <p>
                Disordered clotting contributes to maladaptive inflammation and to the "diseases" of aging and
                degeneration.
            </p>
            <p>
                Metabolic energy is the basic defense against the stress reactions that disrupt circulation, healing,
                and growth.
            </p>
            <p>
                "It is commonly known that the ESR (red cell sedimentation rate) of cancer patients is always high."
            </p>
        </em>
        <p>
            <em>
                "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.<strong>, 1947</strong>)</em>
        </p>

        <hr />
        <p>
            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.
        </p>

        <p>
            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. <strong>Selye observed that stress causes
                internal bleeding (in lungs, adrenals, thymus, intestine, salivary and tear glands, etc.),</strong>
            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<strong>; </strong>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            <strong>"Consumption coagulopathy" refers to the bleeding that follows excessive activation of the clotting
                system,</strong> 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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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<strong>; </strong>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.)
        </p>
        <p>
            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<strong>;</strong> in toxemic pregnancies this isn"t sufficient to
            maintain normal viscosity and perfusion.
        </p>
        <p>
            In the brain, hyperviscosity contributes to dementia. In the lung, to edema and reduced oxygenation ("shock
            lung," "wet lung," respiratory distress<strong>; </strong>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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Heparin, a natural anticoagulant, is currently being tested as an anticancer agent.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            <strong>Things to reduce the stress-related coagulopathies:</strong> 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.
        </p>
        <p>
            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.
        </p>
        <hr />
        <p><strong><h3>REFERENCES</h3></strong></p>

        <p>
            Vet Rec. 1988 Apr 2;122(14):329-32. <strong>Relationships between the erythrocyte sedimentation rate, plasma
                proteins and viscosity, and leucocyte counts in thoroughbred racehorses.</strong> 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<strong>
                was correlated inversely with the haematocrit,</strong>
            <strong>
                but directly with fibrinogen, plasma viscosity and serum total globulins.
            </strong>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<strong>
                haematocrit which accounted for the inverse correlation found between albumin and ESR.
            </strong>
            <hr />
        </p>
        <p>
            Ann N Y Acad Sci. 1976;275:28-46. <strong>Metabolic influences in experimental thrombosis.</strong>
            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. <strong>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.</strong>
            <strong>Glucose injection in fasted rats and insulin injection in diabetic rats reversed their
                susceptibility to thrombosis.</strong> 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.
        </p>

        <p>
            Cardiologia. 1997 Jul;42(7):729-35.<strong>
                [Circadian variation of sudden cardiac death in young people with and without coronary disease]</strong>
            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 &lt; 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 &lt; 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<strong>
                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</strong> system as a trigger able to produce the
            event."
        </p>
        <p>
            An R Acad Nac Med (Madr). 2002;119(1):163-73; discussion 173-4. <strong>[HELLP syndrome and hemorrhagic
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            Wales, died on an unknown condition with uteroplacental hemorrhage <strong>
                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
            </strong>
            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.
        </p>
        <p>
            Thromb Haemost. 1987 Aug 4;58(2):698-704. <strong>The basement membrane underlying the vascular endothelium
                is not thrombogenic: in vivo and in vitro studies with rabbit and human tissue.</strong> Buchanan MR,
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        </p>
        <p>
            Am J Physiol Heart Circ Physiol. 2003 Mar;284(3):H1028-34. Epub 2002 Nov 21. <strong>Endotoxemia stimulates
                skeletal muscle Na+-K+-ATPase and raises blood lactate under aerobic conditions in humans.</strong>
            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.
        </p>
        <p>
            Thromb Haemost. 2001 Jul;86(1):334-45.<strong>
                Tissue factor--a</strong>
            <strong>
                receptor involved in the control of cellular properties, including angiogenesis.</strong> Chen J,
            Bierhaus A, Schiekofer S, Andrassy M, Chen B, Stern DM, Nawroth PP. <strong>"Tissue factor (TF), the major
                initiator of blood coagulation, serves as a regulator of angiogenesis, tumor growth and
                metastasis.</strong>"
        </p>

        <p>
            Thromb Res Suppl. 1983;5:105-45. <strong>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.</strong> Copley AL. "The author's theory of the <strong
            >endoendothelial fibrin lining (EEFL) . . .
            </strong>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 <strong>fibrinogen gel clotting without
                thrombin action or 'fibrinogenin' formation in vivo.</strong>" "The EEFL of the vessel-blood organ is
            considered by the author as the crucial critical interface between the blood and the vessel wall. <strong>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,</strong> 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."
        </p>
        <p>
            Am J Obstet Gynecol. 1995 Apr;172(4 Pt 1):1291-8. <strong>Blindness associated with preeclampsia and
                eclampsia.</strong> Cunningham FG, Fernandez CO, Hernandez C.
        </p>

        <p>
            East Afr Med J. 2002 Apr;79(4):181-3<strong>. Haemorheological changes during the menstrual cycle.</strong>
            Dapper DV, Didia BC.
        </p>
        <p>
            Cancer Res. 2001 Feb 1;61(3):795-8. <strong>
                Tumor hypoxia,</strong>
            <strong>
                the physiological link between Trousseau's syndrome (carcinoma-induced coagulopathy) and
                metastasis.</strong> Denko NC, Giaccia AJ.
        </p>
        <p>
            Lab Invest 1998 Jun;78(6):657-68. <strong>Development of porous defects in plasma membranes of adenosine
                triphosphate-depleted Madin-Darby canine kidney cells and its inhibition by glycine.</strong> Dong Z,
            Patel Y, Saikumar P, Weinberg JM, Venkatachalam MA
        </p>

        <p>
            Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):2692-7. <strong>Seasonal variations of rheological and
                hemostatic parameters and acute-phase reactants in young, healthy subjects.</strong> Frohlich M, Sund M,
            Russ S, Hoffmeister A, Fischer HG, Hombach V, Koenig W.
        </p>
        <p>
            Respir Physiol Neurobiol. 2003 Oct 16;138(1):37-44. <strong>Lactate as a modulator of hypoxia-induced
                hyperventilation.</strong>Gargaglioni LH, Bicego KC, Steiner AA, Branco LG.
        </p>
        <p>
            Am J Vet Res. 1994 Jun;55(6):854-61.<strong>
                Hemorheologic</strong>
            <strong>
                alterations induced by incremental treadmill exercise in Thoroughbreds.
            </strong>

            Geor RJ, Weiss DJ, Smith CM.
        </p>
        <p>
            Vopr Pitan. 1995;(1):7-11. <strong>[Effects of dietary fat on permeability of the protective intestinal
                barrier to</strong>
        </p>
        <p><strong>macromolecules in experimental anaphylaxis]</strong>[Article in Russian]</p>
        <p>
            Gmoshinskii IV, Ermekpaeva RA, Lysikov IuA, Kulakova SN, Mazo VK, Morozov IA.
        </p>
        <p>
            Am J Physiol Cell Physiol 2000 Nov;279(5):C1495-505. <strong>Calcium regulates estrogen increase in
                permeability of cultured CaSki epithelium by eNOS-dependent mechanism.</strong> Gorodeski GI.
        </p>

        <p>
            J Reprod Med. 2002 Dec;47(12):1021-4. <strong>Documentation of amniotic fluid embolism via lung
                histopathology. Fact or Fiction?
            </strong>
            Hankins GD, Snyder R, Dinh T, Van Hook J, Clark S, Vandelan A.
        </p>
        <p>
            Klin Wochenschr. 1990 Jun 5;68(11):559-64. <strong>
                [Hemodynamic and hemorheologic findings in patients with pregnancy-induced hypertension: comparison of
                pre-eclampsia and chronic hypertension]</strong>
            Heilmann L, Schmid-Schonbein H.
        </p>
        <p>
            Zentralbl Gynakol. 1986;108(7):393-402. <strong>
                [Changes in flow properties of the blood in pregnancy]</strong> Heilmann L.
        </p>
        <p>
            Eur J Vasc Surg. 1992 Jan;6(1):36-40. <strong>Claudication induces systemic capillary endothelial
                swelling.</strong> Hickey NC, Hudlicka O, Simms MH.
        </p>
        <p>
            Blood. 2001 Mar 15;97(6):1697-702.<strong>
                Serotonin induces the expression of tissue factor and plasminogen activator inhibitor-1 in cultured rat
                aortic endothelial cells.</strong> 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.
        </p>

        <p>
            Br Med J (Clin Res Ed). 1984 Nov 24;289(6456):1405-8.<strong>
                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.</strong> Keatinge WR,
            Coleshaw SR, Cotter F, Mattock M, Murphy M, Chelliah R.<strong>
                "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</strong> from 126/69 to 138/87 mm
            Hg."
        </p>
        <p>
            Acta Chir Scand. 1976;142(1):20-5. <strong>Induction of endogenous fibrinolysis inhibition in the dog.
                Effect of intravascular coagulation and release of free fatty acids.</strong> 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 <strong>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.</strong>

            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."
        </p>
        <p>
            Matrix Biol. 2002 Jan;21(1):31-7. <strong>Inhibitors of the hyaluronidases.</strong> Mio K, Stern R.
            "Because of increased interest in hyaluronidases and their hyaluronan substrate, a study of these inhibitors
            was undertaken recently. <strong>The predominant serum inhibitor is magnesium-dependent....</strong>"
        </p>
        <p>
            Vopr Onkol. 1991;37(9-10):992-7. <strong>[Blood coagulation disorders and tumor growth]</strong>[Article in
            Russian] Mkrtchian LN, Shukurian SG, Sarkisian OM, Magakian AG, Khachaturova TS, Ambartsumian AM.
        </p>
        <p>
            Usp Fiziol Nauk. 1989 Oct-Dec;20(4):94-109. <strong>[The physiologic coagulation fibrinolytic system of the
                body and
            </strong>
            <strong>thrombohemorrhagic theory in oncology]</strong> [Article in <strong>Russian</strong>] Nadiradze ISh,
            Machabeli MS.
        </p>

        <p>
            Arch Gynecol Obstet. 2002 Nov;267(1):7-10. <strong>Sex hormones, hemostasis and early pregnancy
                loss.</strong> 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
            <strong>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.</strong>"
        </p>
        <p>
            Toxicol Pathol. 1992;20(1):71-80. <strong>
                Pathogenesis of blood-filled cavities in estrogen-induced anterior pituitary tumors in male
                Sprague-Dawley rats.</strong> van Nesselrooij JH, Hendriksen GJ, Feron VJ, Bosland MC.
        </p>
        <p>
            Arch Int Physiol Biochim. 1983 Jul;91(2):81-5. <strong>Effects of the administration of progesterone and
                adrenal medullectomy on the plasma fibrinogen levels in rats with surgical injury (laparotomy).</strong>
            Palma JA, Gavotto AC, Villagra SB.
        </p>

        <p>
            Pediatr Crit Care Med. 2000 Jul;1(1):65-71. <strong>Administration of autologous fetal membranes: Effects on
                the coagulation in pregnant mini-pigs.</strong>
            Petroianu GA, Toomes LM, Maleck WM, Friedberg C, Bergler WF, Rufer R. "<strong>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.</strong>" "Animals received 2 g FM [fetal
            membranes] (shredded and suspended in lactated Ringer's solution) via an ear vein. <strong>
                However, the full clinical picture of amniotic fluid embolism and disseminated intravascular coagulation
                could not be elicited despite the high dose of FM used.</strong>"
        </p>
        <p>
            Am J Physiol. 1976 Apr;230(4):996-1002. <strong>Free fatty acids and albumin as mediators of
                thrombin-stimulated fibrinogen synthesis.</strong>

            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."
        </p>
        <p>
            Thromb Haemost. 1995 Jul;74(1):391-5. <strong>Tissue factor expression in human leukocytes and tumor
                cells.</strong> Rickles FR, Hair GA, Zeff RA, Lee E, Bona RD. <strong>"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."</strong> "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."
        </p>
        <p>
            Nature 138: 32 (1936). Selye, H. <strong>A Syndrome produced by diverse nocuous agents.</strong>
        </p>

        <p>
            Int J Microcirc Clin Exp. 1996 Sep-Oct;16(5):266-70. <strong>Hyperventilation enhances transcapillary
                diffusion of sodium fluorescein.</strong> Steurer J, Schiesser D, Stey C, Vetter W, Elzi MV, Barras JP,
            Franzeck UK.
        </p>
        <p>
            Lancet. 1991 Jul 6;338(8758):9-13. <strong>Seasonal variations in fibrinogen concentrations among elderly
                people.</strong> 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."
        </p>
        <p>
            Akush Ginekol (Mosk). 1989 Jan;(1):43-6. <strong>[Coagulative activity of the amniotic fluid]</strong>
            [Article in <strong>Russian</strong>] 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).<strong>
                Its AF level shows no correlation to the rate of intrapartum or early postpartum thrombohemorrhagic
                complications...."</strong>
        </p>
        <p>
            Metabolism. 1989 May;38(5):471-8. <strong>
                Effects of hypothyroidism on vascular 125I-albumin permeation and blood flow in Rats.</strong> 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, <strong>125I-albumin permeation was increased significantly
                in the kidney, aorta, eye (anterior uvea, choroid, retina), skin, and new granulation tissue</strong
            >...."
        </p>
        <p>
            Clin Nutr. 2001 Aug;20(4):351-9. <strong>Effect of eicosapentaenoic acid (EPA) on tight junction
                permeability in intestinal monolayer cells.</strong> Usami M, Muraki K, Iwamoto M, Ohata A, Matsushita
            E, Miki A.
        </p>

        <p>
            Carcinogenesis. 2003 Jun;24(6):1009-13. Epub 2003 Mar 28. <strong>Tissue factor signal
            </strong>
            <strong>transduction in angiogenesis.</strong> Versteeg HH, Peppelenbosch MP, Spek CA. <strong>Tissue factor
                (TF), a 47-kDa transmembrane glycoprotein, is a principal regulator of oncogenic neoangiogenesis and
                controls therefore the cancerous process.
            </strong>
            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.
        </p>
        <p>
            Semin Thromb Hemost. 2003 Jun;29(3):317-20. <strong>Occurrence of components of fibrinolytic pathways in
                situ in laryngeal cancer.</strong>
            Wojtukiewicz MZ, Sierko E, Zacharski LR, Rozanska-Kudelska M, Zimnoch L.
        </p>
        <p>
            Semin Thromb Hemost. 2003 Jun;29(3):239-46. <strong>Malignancy as a solid-phase coagulopathy: implications
                for the etiology, pathogenesis, and treatment of cancer.</strong> Zacharski LR.
        </p>

        <p>
            Thromb Res. 2003 Jun 1;110(4):213-4. <strong>Heparin treatment of malignancy: the case for clinical trials
                in colon cancer.</strong> Zacharski LR.
        </p>
        <p>
            Anticancer Res. 2003 May-Jun;23(3C):2789-93. <strong>Low-molecular-weight heparin in oncology.</strong>
            Zacharski LR, Loynes JT.
        </p>
        <p>
            Cancer Lett. 2002 Dec 1;186(1):1-9. <strong>
                Anticoagulants in cancer treatment: malignancy as a solid phase coagulopathy.</strong> Zacharski LR.
        </p>

        <p>© Ray Peat 2006. All Rights Reserved. www.RayPeat.com</p>
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    <head><title>Bone Density: First Do No Harm</title></head>
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        <h1>
            Bone Density: First Do No Harm
        </h1>

        <article class="posted">
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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]
            </p>
            <p>
                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]
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                Ultrasound devices can do an extremely good job of evaluating both bone density and strength [14-16],
                rather than just density.
            </p>
            <p>Ultrasound stimulates bone repair.</p>
            <p>X-rays accelerate the rate of bone loss.</p>
            <p>X-rays do their harm at any dose; there is no threshold at which the harm begins.</p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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<strong
                >;</strong> 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..
            </p>
            <p>
                Gofman has said<strong>: "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.
                </strong>
            </p>
            <p>
                <strong>
                    "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]
                </strong>
            </p>
            <p>
                <strong>
                    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]
                </strong>
            </p>
            <p>
                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.<strong></strong>
            </p>
            <p>
                <strong>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.
                </strong>
            </p>
            <p>
                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.
            </p>
            <p>
                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 “<strong><em>metabolic</em></strong> alkalosis,” with <strong><em>increased</em></strong>
                bicarbonate, calcium is retained more efficiently and bone formation is stimulated, and its dissolution
                is suppressed.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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]
            </p>
            <p>
                The same diet that protects against osteoporosis, i.e., plenty of protein and calcium, etc., also
                protects against kidney stones and other abnormal calcificatons.
            </p>
            <p>&nbsp;</p>
            <p><strong><h3>REFERENCES</h3></strong></p>
            <p>
                1. Proc Assoc Am Physicians 1996 Mar;108(2):155-64 <strong>Potential mechanism of estrogen-mediated
                    decrease in bone formation: estrogen increases production of inhibitory insulin-like growth
                    factor-binding protein-4.</strong> Kassem M, Okazaki R, De Leon D, Harris SA, Robinson JA, Spelsberg
                TC, Conover CA, Riggs BL.
            </p>
            <p>
                <strong> 2.</strong> Am J Phys Anthropol 1990 Dec;83(4):467-76. <strong>Stature loss among an older
                    United States population and its relation to bone mineral status.</strong> 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. <strong>This contrasts to
                    the much slower rates predicted from earlier populations (Trotter and Gleser: American Journal of
                    Physical Anthropology 9:311-324, 1951).
                </strong>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.”
            </p>
            <p>
                <strong> 3.</strong> Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1994 Mar;160(3):260-5. <strong
                >[The quantitative determination of bone mineral content--a system comparison of similarly built
                    computed tomographs].</strong> [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.
            </p>
            <p>
                <strong> 4.</strong> Osteoporos Int 1990 Oct;1(1):23-9. <strong>Vertebral bone mineral density measured
                    laterally by dual-energy X-ray absorptiometry.</strong> 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<strong> after repositioning was 2.8%.”</strong>
            </p>
            <p>
                <strong> 5.</strong> Eur J Nucl Med 1990;17(1-2):3-9.<strong>
                    Comparative study of the performances of X-ray and gadolinium 153 bone densitometers at the level of
                    the spine, femoral neck and femoral shaft.</strong> Slosman DO, Rizzoli R, Buchs B, Piana F, Donath
                A, Bonjour JP. “In vivo, at the spine level, with DPA, mean<strong>
                    CV of BMD measured 6 times after repositioning in 6 healthy volunteers was 3.8% +/- 1.9% and 2.1%
                    +/- 0.7% . . . .”
                </strong>
            </p>
            <p><strong> &nbsp;</strong></p>
            <p>
                <strong> 6. </strong> Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 1995 Apr;162(4):269-73. <strong
                >[Experimental studies of the visualization of the vertebral body spongiosa by high-resolution computed
                    tomography].</strong> Henschel MG, Freyschmidt J, Holland BR. “The measured lower limit of<strong>
                    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.”
                </strong>
            </p>
            <p>
                7. J Comput Tomogr 1984 Apr;8(2):91-7. <strong>Quantitative computed tomography assessment of spinal
                    trabecular bone. I. Age-related regression in normal men and women.</strong> Firooznia H, Golimbu C,
                Rafii M, Schwartz MS, Alterman ER. “Computed tomography, <strong>utilized in conjunction with a
                    calibrated phantom containing a set of reference densities</strong> (K2HPO4 and water), is capable
                of determining the mineral content of the trabecular bone of the spine with an<strong>
                    accuracy of about 6%</strong> of the ash weight of the vertebrae scanned (specimen studies).”
            </p>
            <p>
                8. Calcif Tissue Int 1991 Sep;49(3):174-8. <strong>Precision and stability of dual-energy X-ray
                    absorptiometry measurements.</strong>
                <hr />
                <strong></strong>
            </p>
            <p>
                <strong> 9.</strong> J Comput Assist Tomogr 1993 Nov-Dec;17(6):945-51. <strong>Influence of temperature
                    on QCT: implications for mineral densitometry.</strong> 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<strong>
                    fat error associated with single energy QCT for trabecular bone mineral densitometry was 20% less
                    for specimens at room temperature than at body temperature.”</strong> “The fat error of
                single<strong>
                    energy QCT for mineral densitometry may have been underestimated in previous in vitro studies using
                    vertebral specimens scanned at room temperature.”</strong>
            </p>
            <p>
                <strong> 10.</strong> Phys Med Biol 1986 Jan;31(1):55-63. <strong>Quantitative CT measurements: the
                    effect of scatter acceptance and filter characteristics on the EMI 7070.</strong> Merritt RB,
                Chenery SG “Non-linearities in projection values on computed tomography (CT) scanners <strong>cause
                    corresponding errors in derived Hounsfield unit attenuation measurements. Existing commercial
                    machines have been refined for clinical usefulness but not necessarily for quantitative
                    accuracy.”</strong>
                <strong>“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.”</strong>
            </p>
            <p>
                <strong> 11.</strong> Skeletal Radiol 1986;15(5):347-9. <strong>Observer variation in the detection of
                    osteopenia.</strong> 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. <strong>The individual observers were not able to
                    give consistent readings on the same film on different days</strong>
                <hr />
                <strong>additional factors of repeat films</strong>
                <hr />
                <strong>or separate observers</strong>
                <hr />
                <strong>agreement was even worse.</strong>
                <strong>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.</strong>
            </p>
            <p>
                <strong> 12.</strong> P. Schneider and C. Reiners, Letter, JAMA 277(1), 23, Jan. 1, 1997. <strong>"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."</strong>
            </p>
            <p>
                <strong> 13.</strong> Calcif Tissue Int 1990 Apr;46(4):280-1. <strong>Effect of radiographic
                    abnormalities on rate of bone loss from the spine.</strong> Dawson-Hughes B, Dallal GE. <strong
                >“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.”
                </strong>
            </p>
            <p>
                <strong> 14.</strong> Przegl Lek 2000;57(2):93-9. [No title available]. Jaworski M, Lorenc RS. <strong
                >“. . .</strong>Dual Energy X-ray Absorptiometry (DEXA) method is a reference method to diagnose
                osteoporosis. This method allows to <strong>measure bone density and bone mass, however bone quality can
                    not be estimated. Quantitative ultrasound (QUS)</strong>
                <strong>method provides information about bone structure.”</strong>
            </p>
            <p>
                <strong> 15.</strong> Osteoporos Int 2000;11(4):354-60.<strong>
                    Assessment of a new quantitative ultrasound calcaneus measurement: precision and discrimination of
                    hip fractures in elderly women compared with dual X-ray absorptiometry.</strong> He YQ, Fan B, Hans
                D, Li J, Wu CY, Njeh CF, Zhao S, Lu Y, Tsuda-Futami E, Fuerst T, Genant HK.
            </p>
            <p>
                <strong> 16.</strong> Cas Lek Cesk 2000 Apr 26;139(8):231-6 <strong>[X-ray densitometry and
                    ultrasonography of the heel bone--sensitivity and comparison with densitometry of the axial
                    skeleton].</strong> [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.”
            </p>
            <p>
                <strong>17.</strong> John Gofman, M.D. (biographical chapter. pages 401-412.) In Studs Terkel's book
                <strong><em>Coming of Age. The Story of our Century by Those Who Lived It.</em></strong> The New Press.
                NY. 1995.
            </p>
            <p>
                <strong>18.</strong> Gofman, J.W. <strong>An irreverent, illustrated view of nuclear power.</strong>
                Committee for Nuclear Responsibility. San Francisco, CA. pp. 227-228, 1979.
            </p>
            <p>
                <strong> 19.</strong> Kidney Int 1992 Sep;42(3):727-34. <strong>Chronic respiratory alkalosis induces
                    renal PTH-resistance, hyperphosphatemia and hypocalcemia in humans.</strong> Krapf R, Jaeger P,
                Hulter HN Department of Medicine, Insel University Hospital, Berne, Switzerland. <strong>“The effects of
                    chronic respiratory alkalosis on divalent ion homeostasis have not been reported in any
                    species.”</strong> “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) <strong>associated with increased fractional
                    excretion of Ca++ . . .”
                </strong>
            </p>
            <p>
                <strong> 20.</strong> J Clin Endocrinol Metab 1999 Jun;84(6):1997-2001 <strong>Hormone replacement
                    therapy causes a respiratory alkalosis in normal postmenopausal women.</strong>
                <hr />
                <strong>partial pressure of carbon dioxide. . . .”</strong>
                <strong>“Accompanying changes in blood pH were apparent in the estrogen plus MPA group, where there was
                    an upward trend at 1 week</strong>
                <hr />
            </p>
            <p>
                <strong> 21.</strong> Wien Klin Wochenschr 1979 Apr 27;91(9):304-7 <strong>[Investigations on the
                    pathogenesis of distal renal tubular acidosis].</strong> Schabel F, Zieglauer H. <strong
                >“Bicarbonate loading is followed by a lowering of calcium excretion to within the normal range and a
                    decrease in the uncharacteristic renal hyperaminoaciduria.”
                </strong>
            </p>
            <p>
                <strong> 22.</strong> Calcif Tissue Int 1984 Sep;36(5):604-7. <strong>Respiratory alkalosis and reduced
                    plasmatic concentration of ionized calcium in rats treated with 1,25
                    dihydroxycholecalciferol.</strong> 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<strong>
                    phenomenon was found associated with increased urinary excretion of cAMP, soft tissue calcium
                    content,</strong> and polyuria with hypostenuria, all known effects of parathyroid hormone.”
            </p>
            <p>
                <strong> 23.</strong> Am J Physiol 1996 Jul;271(1 Pt 2):F216-22. <strong>Metabolic alkalosis decreases
                    bone calcium efflux by suppressing osteoclasts and stimulating osteoblasts.</strong> Bushinsky
                DA.<strong>
                    “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.</strong>
                <strong>The additional urinary calcium is almost certainly derived from bone mineral.”</strong> “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,<strong> [HCO3-] approximately equal to 24</strong>), medium simulating mild alkalosis (pH
                approximately equal to 7.5, [HCO3-] approximately equal to 31), or severe alkalosis (pH approximately
                equal to 7.6,<strong> [HCO3-] approximately equal to 39) </strong>and measured JCa+ and the release of
                osteoclastic beta-glucuronidase and osteoblastic collagen synthesis. Compared with control, metabolic
                alkalosis caused a <strong>progressive decrease in JCa+</strong>, which was correlated inversely with
                initial medium pH (pHi). Alkalosis caused <strong>a decrease in osteoclastic beta-glucuronidase
                    release,</strong> 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.”
            </p>
            <p>
                <strong> 24.</strong> Am J Physiol 1997 Nov;273(5 Pt 2):F698-705 <strong>The effects of respiratory
                    alkalosis and acidosis on net bicarbonate flux along the rat loop of Henle in vivo.</strong> Unwin
                R, Stidwell R, Taylor S, Capasso G.
            </p>
            <p>
                <strong>25.</strong> Can J Anaesth 1999 Feb;46(2):185-9. <strong>Acute respiratory alkalosis associated
                    with low minute ventilation in a patient with severe hypothyroidism.</strong> Lee HT, Levine M.
                <strong>“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.”</strong>
            </p>
            <p>
                <strong>26.</strong> Am J Epidemiol 1991 Apr 1;133(7):649-60.<strong>
                    A prospective study of bone mineral content and fracture in communities with differential fluoride
                    exposure.</strong> Sowers MF, Clark MK, Jannausch ML, Wallace RB. “Residence in the higher-fluoride
                community was associated with a <strong>significantly lower radial bone mass</strong> 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, <strong>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.</strong>
                <strong>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).</strong> Estimates of risk were adjusted for age and body size.”
            </p>
            <p>
                <strong>27.</strong> J Nutr 2000 Dec;130(12):2889-96.<strong>
                    Long-term high protein intake does not increase oxidative stress in rats.</strong> Petzke KJ, Elsner
                A, Proll J, Thielecke F, Metges CC. <strong></strong>
            </p>
            <p>
                <strong>28.</strong> Med Hypotheses 1995 Sep;45(3):241-6.<strong>
                    Anabolic effects of insulin on bone suggest a role for chromium picolinate in preservation of bone
                    density.</strong> 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.” <strong>[I
                    think chromium is too toxic to use as a supplement.]</strong>
            </p>
            <p>&nbsp;</p>
            <p>
                29: Anesthesiology 1998 Dec;89(6):1389-400. <strong>Effects of hyperventilation and
                    hypocapnic/normocapnic hypoxemia on renal function and lithium clearance in humans.</strong>
                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 increased<strong
                ></strong>slightly during hypocapnic and normocapnic hypoxemia, hyperventilation, and normocapnic
                normoxemia with but not without the face mask. CONCLUSIONS:<strong></strong>The results indicate
                that<strong>
                    (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</strong>
                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.
            </p>
            <p>
                31: Wien Klin Wochenschr 1979 Apr 27;91(9):304-7. <strong>[Investigations on the pathogenesis of distal
                    renal tubular acidosis].</strong> [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. <strong>Under conditions of
                    bicarbonate-induced systemic alkalosis urinary the pCO2 exceeds blood pCO2 in normal
                    subjects.</strong> 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. <strong>Bicarbonate loading is
                    followed by a lowering of calcium excretion to within the normal range</strong> and a decrease in
                the uncharacteristic renal hyperaminoaciduria.
            </p>
            <p>&nbsp;</p>
            <p>&nbsp;</p>
            <p></p>
        </article>
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        <h1>
            Breast Cancer
        </h1>

        <article class="posted">
            <p>
                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.
            </p>
            <p>
                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 <strong><em>decreasing</em></strong> one half percent (0.5%) per year.
            </p>
            <p>
                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.
            </p>
            <p>
                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. <strong
                >This, despite the population distortion caused by the baby boom,</strong> causing a scarcity of people
                in the age groups with the highest rates of cancer mortality.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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, <strong>they say mortality from other cancers
                    has been declining since 1950! (“The fifty-year decline of cancer in America,”</strong> 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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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, <strong
                >then the use of biopsy specimens as the basis for determining whether a person needs treatment has no
                    scientific basis.</strong>
            </p>
            <p>
                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.
            </p>
            <p>
                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 <strong>only if we know that similar signs aren’t present in perfectly healthy
                    people.</strong> 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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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 <strong><em>in situ</em></strong>” 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, <strong><em>but the increased treatments and early diagnosis haven’t produced any visible
                        change in the death rate.
                    </em></strong>
            </p>
            <p>
                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 <strong>single defective
                    cell.</strong> 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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                The clonal-goblin theory of cancer leads logically to the conclusion that the cancer clone must be
                exorcised by surgery, chemotherapy, and/or radiation.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                <strong>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.
                </strong>
            </p>
            <p>
                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.)
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                Prenatal or early life exposure to estrogens, including phytoestrogens, or to irradiation, or to
                polyunsaturated oils, increases the incidence of mammary cancers in adulthood.
            </p>
            <p>
                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.
            </p>
            <p>
                Prenatal protein deficiency and excess unsaturated oils predispose to a developmental pattern involving
                hypothyroidism and hyperestrogenism<strong>;</strong> 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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <hr />
            <p><strong><h3>REFERENCES</h3></strong></p>
            <p>
                Radiat Res 1998 Sep;150(3):330-48 <strong>Mortality in beagles irradiated during prenatal and postnatal
                    development. II. Contribution of benign and malignant neoplasia.</strong> 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 (&lt;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.
            </p>
            <p>
                Int J Cancer 1999 Nov 26;83(5):585-90. <strong>Fatty-acid composition in serum phospholipids and risk of
                    breast cancer: an incident case-control study in Sweden.</strong> Chajes V, Hulten K, Van Kappel AL,
                Winkvist A, Kaaks R, Hallmans G, Lenner P, Riboli E. “. . . women in the<strong><hr /></strong>”
            </p>
            <p>
                Tumori 2000 Jan-Feb;86(1):12-6 <strong>Factors of risk for breast cancer influencing post-menopausal
                    long-term hormone replacement therapy.</strong> Chiechi LM, Secreto G. <strong>“. . . 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 . . . .”
                </strong>“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. <strong>Our
                    analysis suggests that HRT could increase the risk of breast cancer and useless in preventing
                    coronary heart disease and osteoporotic fractures</strong> when administered in women with
                positivity for one or more of these markers.”
            </p>
            <p>
                Cancer 1996 Nov 15;78(10):2045-8. <strong>Declining cancer mortality in the United States.</strong> Cole
                P, Rodu B.
            </p>
            <p>
                <strong><em>Preventing Breast Cancer:</em></strong>
                <strong><em>The story of a Major, Proven, Preventable Cause of This Disease.</em></strong> 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.”
            </p>
            <p>
                Am J Public Health 1998 Mar;88(3):458-60. <strong>Geographic variations in breast cancer mortality: do
                    higher rates imply elevated incidence or poorer survival?</strong> Goodwin JS, Freeman JL, Freeman
                D, Nattinger AB. <strong>“Mortality rates from breast cancer are approximately 25% higher for women in
                    the northeastern United States than for women in the South or West.</strong> 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<strong><hr
                    /></strong>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.”
            </p>
            <p>
                Nutrition 1999 May;15(5):392-401 <strong>The influence of maternal diet on breast cancer risk among
                    female offspring.</strong> 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<strong>
                    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</strong> 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.
            </p>
            <p>
                Mol Cell Biochem 1998 Nov;188(1-2):5-12 <strong>Timing of dietary fat exposure and mammary
                    tumorigenesis: role of estrogen receptor and protein kinase C activity.</strong> 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,
                <strong>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.</strong> 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. <strong>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.</strong> 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<strong>
                    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.
                </strong>
            </p>
            <p>
                Proc Natl Acad Sci U S A 1997 Aug 19;94(17):9372-7. <strong>A maternal diet high in n - 6
                    polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among
                    female rat offspring.</strong> Hilakivi-Clarke L, Clarke R, Onojafe I, Raygada M, Cho E, Lippman M.
                <strong>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%</strong> or 46% (high fat) of calories from corn oil, which primarily contains the
                n - 6 polyunsaturated fatty acid (PUFA) linoleic acid, throughout pregnancy. The<strong>
                    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 to</strong>7,12-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,<strong>
                    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.
                </strong>
            </p>
            <p>
                Oncol Rep 1998 May-Jun;5(3):609-16 <strong>Maternal genistein exposure mimics the effects of estrogen on
                    mammary gland development in female mouse offspring.</strong> 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.
            </p>
            <p>
                Am J Public Health 1991 Apr;81(4):462-5 <strong>Does increased detection account for the rising
                    incidence of breast cancer?</strong> 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.”
            </p>
            <p>
                J Clin Oncol 2001 Jan 1;19(1):239-41. <strong>The fifty-year decline of cancer in america.</strong> 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: <strong>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.</strong>
                <strong><em>CONCLUSION: The long-term decline is likely due primarily to improvements in medical care,
                        including screening, diagnosis, and treatment.</em></strong>
            </p>
            <p>&nbsp;</p>
            <p>
                J Mammary Gland Biol Neoplasia 1998 Jan;3(1):49-61 <strong>Role of hormones in mammary cancer initiation
                    and progression.</strong> 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.”
            </p>
            <p>&nbsp;</p>
            <p>
                Hum Reprod 1999 Aug;14(8):2155-61<strong>
                    Tryptophan ingestion by pregnant rats induces pituitary and mammary tumours in the adult female
                    offspring.
                </strong>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.”
            </p>
            <p>&nbsp;</p>
            <p>
                JAMA 1977 Feb 21;237(8):789-90. <strong>Breast cancer induced by radiation. Relation to mammography and
                    treatment of acne.</strong> Simon N.<strong></strong>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.<strong>
                    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.</strong>
            </p>
            <p>&nbsp;</p>
            <p>
                Rev Interam Radiol 1977 Oct;2(4):199-203. <strong>Cancer of the breast--induction by radiation and role
                    of mammography.</strong> Simon N.
            </p>
            <p>&nbsp;</p>
            <p>
                Eur J Clin Nutr 1999 Feb;53(2):83-7. <strong>Western nutrition and the insulin resistance syndrome: a
                    link to breast cancer.</strong> 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.”
            </p>
            <p>&nbsp;</p>
            <p>
                Strong, Leonell C, <strong><em>Biological Aspects of Cancer and Aging,</em></strong> Oxford, Pergamon
                Press, 1968.
            </p>
            <p>&nbsp;</p>
            <p>
                Ethn Dis 1999 Spring-Summer;9(2):181-9. <strong>Secular trend of earlier onset of menarche with
                    increasing obesity in black and white girls: the Bogalusa Heart Study.</strong>
                <hr />
                <strong>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</strong> (P&lt;0.001).” <strong>“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.”</strong>
            </p>
            <p>&nbsp;</p>
        </article>
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    <head><title>Caffeine: A vitamin-like nutrient, or adaptogen</title></head>
    <body>
        <h1>
            Caffeine: A vitamin-like nutrient, or adaptogen
        </h1>
        <p>
            <strong>
                Questions about tea and coffee, cancer and other degenerative diseases, and the hormones.</strong>
        </p>
        <p></p>
        <p>
            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.
        </p>
        <p>
            I think it would be good to reconsider coffee"s place in the diet and in health care.
        </p>
        <p>
            <strong>Coffee drinkers have a lower incidence of thyroid disease, including cancer,
                thannon-drinkers.</strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>
        <p>
            <strong>Caffeine protects against cancer caused by radiation, chemical carcinogens, viruses, and
                estrogens.</strong>
        </p>
        <p>
            <strong>Caffeine synergizes with progesterone, and increases its concentration in blood and tissues.</strong
            >
        </p>

        <p>
            <strong>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.</strong>
        </p>
        <p>
            <strong>Coffee provides very significant quantities of magnesium, as well as other nutrients including
                vitamin B1.</strong>
        </p>
        <p><strong>Caffeine "improves efficiency of fuel use" and performance: JC Wagner 1989.</strong></p>
        <p><strong>Coffee drinkers have a low incidence of suicide.</strong></p>
        <p><strong>Caffeine supports serotonin uptake in nerves, and inhibits blood platelet aggregation.</strong></p>
        <p>
            <strong>Coffee drinkers have been found to have lower cadmium in tissues; coffee making removes heavy metals
                from water.</strong>
        </p>

        <p><strong>Coffee inhibits iron absorption if taken with meals, helping to prevent iron overload.</strong></p>
        <p>
            <strong>Caffeine, like niacin, inhibits apoptosis, protecting against stress-induced cell death, without
                interfering with normal cell turnover.</strong>
        </p>
        <p><strong>Caffeine can prevent nerve cell death.</strong></p>
        <p><strong>Coffee (or caffeine) prevents Parkinson"s Disease (Ross, et al., 2000).</strong></p>
        <p>
            <strong>The prenatal growth retardation that can be caused by feeding large amounts of caffeine is prevented
                by supplementing the diet with sugar.</strong>
        </p>
        <p>
            <strong>Caffeine stops production of free radicals by inhibiting xanthine oxidase, an important factor in
                tissue stress.
            </strong>
        </p>

        <p>
            <strong>Caffeine lowers serum potassium following exercise; stabilizes platelets, reducing thromboxane
                production.</strong>
        </p>
        <p>
            One definition of a vitamin is that it is an organic chemical found in foods, the lack of which <strong><em
                >causes</em></strong> a specific <strong><em>disease,</em></strong>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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..
        </p>
        <p>
            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.
        </p>
        <p>
            Definitions have rarely distinguished clearly between nutrients and drugs, and new commercial motives are
            helping to further blur the distinctions.
        </p>
        <p>
            <strong>Essential nutrients, defensive (detoxifying, antistress) nutrients, hormone-modulating nutrients,
                self-actualization nutrients, growth regulating nutrients, structure modifiers, life extension agents,
                transgenerationally active (imprinting)</strong>
            <strong>nutrients--</strong>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.
        </p>

        <p>
            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.
        </p>
        <p>
            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. <strong>We still
                have to determine basic things such as the optimal rate of growth, and the optimal size.</strong>
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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 <em>increasing</em> 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.
        </p>
        <p>
            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.
        </p>
        <p>
            To talk about caffeine, it"s necessary to talk about uric acid. <strong>
                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.
            </strong>
            A deficiency of uric acid is a serious problem. Caffeine and uric acid are in the group of chemicals called
            purines.
        </p>
        <p>
            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.
        </p>
        <p>
            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 (CH<sub>3</sub>) 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<strong>;</strong> for example, when babies are given theophylline, they can convert
            it into caffeine.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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<strong>;</strong> that
            is, they don"t produce tumors by preventing the death of cells that aren"t needed.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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
            <em>lowers</em> uric acid levels, nevertheless appeared to be much more strongly protective against
            Parkinson"s disease than uric acid.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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 <em>uptake</em> (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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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 <em>locally</em> 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.
        </p>
        <p>
            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.
        </p>
        <p>
            <strong><h3>REFERENCES</h3></strong>
        </p>
        <p>
            Fiziol Zh SSSR Im I M Sechenova 1975 Oct;61(10):1531-8. <strong>[Changes in the resistance and capacity of
                the cerebral vascular bed under the influence of vasoactive substances].</strong> [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 <strong>CVR</strong>
            <strong>
                could be reduced by isopropilnoradrenaline, acetylcholine, histamine, and caffeine.</strong>
            <strong>CBV was decreased after isopropilnoradrenaline, acetycholine, histamine injections and increased by
                caffeine.
            </strong>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.
        </p>

        <p>
            Proc Soc Exp Biol Med 1999 Apr;220(4):244-8. <strong>The prevention of lung cancer induced by a
                tobacco-specific carcinogen in rodents by green and black Tea.</strong> 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 <strong>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</strong>
            <strong>
                caffeine as potential preventive agents against lung cancer, suggesting that a closer examination of the
                roles of tea and caffeine on lung cancer</strong>
            in smokers may be warranted."
        </p>
        <p>
            Pharmacol Biochem Behav 2000 May;66(1):39-45. <strong>Caffeine-induced increases in the brain and plasma
                concentrations of neuroactive steroids in the rat.</strong> 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<strong>
                concentrations of pregnenolone and progesterone with a dose-response relation similar to that observed
                in the brain . . ."
            </strong>

            "Moreover, the brain and plasma concentrations of pregnenolone, progesterone, and allopregnanolone were not
            affected by caffeine in adrenalectomized-orchiectomized rats."
        </p>
        <p>
            Cancer Res 1998 Sep 15;58(18):4096-101. <strong>Inhibition of</strong>
            <strong>lung carcinogenesis by black tea in Fischer rats treated with a tobacco-specific carcinogen:
                caffeine as an important constituent.</strong> 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 <strong>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</strong> induced by NNK from 34% in the group given only deionized water to 12%." <strong>"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</strong> 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, <strong>and this effect appears to be attributed, to a significant extent, to caffeine as an active
                ingredient of tea."</strong>
        </p>

        <p>
            Cancer Lett 1991 Mar;56(3):245-50.<strong>
                Inhibition by caffeine of ovarian hormone-induced mammary gland tumorigenesis in female GR mice.</strong
            > 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."
        </p>
        <p>
            Breast Cancer Res Treat 1991 Nov;19(3):269-75.<strong>
                Caffeine inhibits development of benign mammary gland tumors in carcinogen-treated female Sprague-Dawley
                rats.</strong> Wolfrom DM, Rao AR, Welsch CW.
        </p>
        <p>
            Cancer 1985 Oct 15;56(8):1977-81.<strong>
                The inhibitory effect of caffeine on hormone-induced rat breast cancer.</strong> 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."
        </p>

        <p>
            Nutr Cancer 1998;30(1):21-4.<strong>
                Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex
                hormone-binding globulin in premenopausal Japanese women.</strong> Nagata C, Kabuto M, Shimizu H.
            "Although the <strong>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."</strong>
        </p>
        <p>
            J Environ Pathol Toxicol Oncol 1992; 11(3):177-89.<strong>
                Caffeine, theophylline, theobromine, and developmental growth of the mouse mammary gland.</strong>
            VanderPloeg LC, Wolfrom DM, Rao AR, Braselton WE, Welsch CW. <strong>"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
            </strong>

            in female Balb/c mice, an effect that appears not to be manifested via a direct action of the
            methylxanthines on the mammary gland."
        </p>
        <p>
            J Environ Pathol Toxicol Oncol 1994;13(2):81-8.<strong>
                Enhancement by caffeine of mammary gland lobulo-alveolar development in mice: a function of increased
                corticosterone.</strong> Welsch CW, VanderPloeg LC. Previously we have reported that the stimulatory
            effect of caffeine on<strong>
                lobulo-alveolar development
            </strong>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 &lt; 0.001)
            enhancement of lobulo-alveolar development in the mammary glands of the hormone-treated mice, compared with
            hormone treated control mice, was observed."
        </p>
        <p>
            Am J Clin Nutr 1997 Jun;65(6):1826-30. <strong>Dietary caffeine intake and bone status of postmenopausal
                women.</strong> Lloyd T, Rollings N, Eggli DF, Kieselhorst K, Chinchilli VM.
        </p>

        <p>
            Eur J Epidemiol 1993 May;9(3):293-7. <strong>Unexpected effects of coffee consumption on liver
                enzymes.</strong> 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.
        </p>
        <p>
            Anticancer Res 1996 Jan-Feb;16(1):151-3<strong>
                Suppression by coffee cherry of the growth of spontaneous mammary tumours in SHN mice.</strong> 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<strong>
                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
            </strong>
            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.
        </p>
        <p>
            Yakugaku Zasshi 1997 Jul;117(7):448-54. <strong>[Effect of tea extracts, catechin and caffeine against
                type-I allergic reaction].</strong> [Article in Japanese] Shiozaki T, Sugiyama K, Nakazato K, Takeo
            T.<strong>
                "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."
            </strong>
        </p>

        <p>
            Acta Chir Scand 1989 Jun-Jul;155(6-7):317-20. <strong>Does coffee consumption protect against thyroid
                disease?</strong> Linos A, Linos DA, Vgotza N, Souvatzoglou A, Koutras DA
        </p>
        <p>
            Br J Nutr 1999 Aug;82(2):125-30.<strong>
                Inverse association between coffee drinking and serum uric acid concentrations in middle-aged Japanese
                males.</strong> Kiyohara C, Kono S, Honjo S, Todoroki I, Sakurai Y, Nishiwaki M, Hamada H, Nishikawa H,
            Koga H, Ogawa S, Nakagawa K
        </p>
        <p>
            Cancer Res 1997 Jul 1;57(13):2623-9. <strong>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</strong>. Huang MT, Xie JG, Wang ZY, Ho CT, Lou YR, Wang CX, Hard GC,
            Conney A.H.
        </p>

        <p>
            Mutat Res 1981 Jun;89(2):161-77. <strong>Non-mutagenicity of urine from coffee drinkers compared with that
                from cigarette smokers.</strong> Aeschbacher HU, Chappuis C.
        </p>
        <p>
            Biol Neonate 1981;40(3-4):196-8. <strong>The effects of maternal carbohydrate (sucrose) supplementation on
                the growth of offspring of pregnancies with habitual caffeine consumption.</strong> 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."
        </p>
        <p>
            Biochim Biophys Acta 1992 Dec 15;1175(1):114-22. <strong>Caffeine promotes survival of cultured sympathetic
                neurons deprived of nerve growth factor through a cAMP-dependent mechanism.</strong> Tanaka S, Koike T.
        </p>

        <p>
            JAMA 2000 May 24-31;283(20):2674-9. <strong>Association of coffee and caffeine intake with the risk of
                Parkinson disease.</strong> Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, Tanner
            CM, Masaki KH, Blanchette PL, Curb JD, Popper JS, White LR.
        </p>
        <p>
            Farmakol Toksikol 1983 Sep-Oct;46(5):107-11 <strong>[Use of the swimming test for demonstrating
                antidepressive activity of drugs during single and repeated administration].</strong> [Article in
            Russian] Rusakov DIu, Val'dman AV. <strong>
                "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</strong> 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.<strong>
                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."</strong>
        </p>
        <p>
            Gen Pharmacol 1996 Jan;27(1):167-70 <strong>The influence of antagonists of poly(ADP-ribose) metabolism on
                acetaminophen hepatotoxicity.</strong> Kroger H, Ehrlich W, Klewer M, Gratz R, Dietrich A, Miesel R.
        </p>
        <p>
            Ann Clin Lab Sci 1977 Jan-Feb;7(1):68-72. <strong>Effects of drugs on platelet function.</strong> Morse EE.
        </p>
        <p>
            Thromb Haemost 1982 Apr 30;47(2):90-5. <strong>Effect of cAMP phosphodiesterase inhibitors on ADP-induced
                shape change, cAMP and nucleoside diphosphokinase activity of rabbit platelets.
            </strong>

            Lam SC, Guccione MA, Packham MA, Mustard JF.
        </p>
        <p>
            Carcinogenesis 1998 Aug;19(8):1369-75.<strong>
                The coffee-specific diterpenes cafestol and kahweol protect against aflatoxin B1-induced genotoxicity
                through a dual mechanism.</strong> Cavin C, Holzhauser D, Constable A, Huggett AC, Schilter B.
        </p>
        <p>
            Am J Epidemiol 1994 Apr 1;139(7):723-7.<strong>
                Coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan.</strong>
            Kono S, Shinchi K, Imanishi K, Todoroki I, Hatsuse K.
        </p>
        <p>
            Carcinogenesis 1996 Nov;17(11):2377-84<strong>
                Placental glutathione S-transferase (GST-P) induction as a potential mechanism for the anti-carcinogenic
                effect of the coffee-specific components cafestol and kahweol</strong>. Schilter B, Perrin I, Cavin C,
            Huggett AC
        </p>

        <p>
            J Nutr 1999 Jul;129(7):1361-7.<strong>
                Teas and other beverages suppress D-galactosamine-induced liver injury in rats.</strong> Sugiyama K, He
            P, Wada S, Saeki S
        </p>
        <p>
            Nutr Cancer 1999;33(2):146-53.<strong>
                Effects of oral administration of tea,</strong>
            <strong>decaffeinated tea, and caffeine on the formation and growth of tumors in high-risk SKH-1 mice
                previously treated</strong> with ultraviolet B light. Lou YR, Lu YP, Xie JG, Huang MT, Conney AH.
        </p>
        <p>
            Ind Health 2000 Jan;38(1):99-102. <strong>Effects of coffee consumption against the development of liver
                dysfunction: a 4-year follow-up study of middle-aged Japanese male office workers.
            </strong>Nakanishi N, Nakamura K, Suzuki K, Tatara K.
        </p>

        <p>
            Ind Health 2000 Jan;38(1):99-102. <strong>Effects of coffee consumption against the development of liver
                dysfunction: a 4-year follow-up study of middle-aged Japanese male office workers.
            </strong>Nakanishi N, Nakamura K, Suzuki K, Tatara K. .
        </p>
        <p>
            Biochim Biophys Acta 1992 Dec 15; 1175(1):114-22. <strong>Caffeine promotes survival of cultured sympathetic
                neurons deprived of nerve growth factor through a cAMP-dependent mechanism.</strong> Tanaka S, Koike T.
        </p>
        <p>
            Int J Epidemiol 1998 Jun;27(3):438-43. <strong>Coffee consumption and decreased serum
                gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers.</strong> Tanaka
            K, Tokunaga S, Kono S, Tokudome S, Akamatsu T, Moriyama T, Zakouji H. <strong>
                ". . . recent epidemiological studies have suggested unexpected, possibly beneficial effects of coffee
                against the occurrence of alcoholic liver cirrhosis</strong> and upon serum liver enzyme levels."
            "Increased coffee consumption was strongly and independently associated with decreased GGT activity among
            males (P trend &lt; 0.0001); the inverse association between coffee and serum GGT was more evident among
            heavier alcohol consumers (P &lt; 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."
        </p>
        <p>
            Am J Hosp Pharm 1989 Oct;46(10):2059-67. <strong>Abuse of drugs used to enhance athletic performance.
            </strong>Wagner JC.
        </p>
        <p>
            © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
        </p>
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    <head>
        <title>Calcium and Disease: Hypertension, organ calcification, &amp; shock, vs. respiratory energy</title>
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    <body>
        <h1>
            Calcium and Disease: Hypertension, organ calcification, &amp; shock, vs. respiratory energy
        </h1>

        <p>
            <em>
                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.
            </em>
            <hr />
            It is extremely important to realize that calcium deposits in soft tissues become worse when the diet is <em
            >low in calcium.</em> 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,<em>
                Lets Eat Right to Keep Fit,</em> Adelle Davis, Signet, 1970.

            <hr />

            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 <em>ad
                hoc</em> 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.,
            <em>International J. of Cardiology, </em>
            Dec., 2002) are still promoting the idea that eating too much calcium causes hardening of the arteries and
            other diseases of calcification.

            <h3>REFERENCES</h3>
        </p>
        <p>
            <strong>
                J Am Soc Nephrol 1994 Apr;4(10):1814-9. A role of parathyroid hormone for the activation of cardiac
                fibroblasts in Uremia.</strong> 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.
        </p>
        <p>
            Clin Endocrinol (Oxf) 1976 May;5(3):291-3. Recurrent hormone dependent chorea: effects of oestrogens and
            progestogens. Barber PV, Arnold AG, Evans G.
        </p>
        <p>
            Biochem Biophys Res Commun 2001 Feb 23;281(2):277-81. <strong>17 beta-estradiol increases Ca(2+) influx and
                down regulates interleukin-2 receptor in mouse thymocytes.</strong> Azenabor AA, Hoffman-Goetz L.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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).
        </p>
        <p>
            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 &lt; 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 &lt; 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 &lt; 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.
        </p>

        <p>
            Mov Disord 1991;6(4):355-7. An unusual cause of recurrent chorea. Caviness JN, Muenter MD. Lee Silverman
        </p>
        <p>
            Bone 2000 Jan;26(1):79-85. <strong>
                Correlation of estradiol, parathyroid hormone, interleukin-6, and soluble interleukin-6 receptor during
                the normal menstrual cycle.</strong> Chiu KM, Arnaud CD, Ju J, Mayes D, Bacchetti P, Weitz S, Keller ET.
            <strong><hr /></strong>
            <hr />
            <strong>These data demonstrate that IL-6 and PTH fluctuate with E2, and serum II-6 is associated with PTH
                levels during the menstrual cycle.
            </strong>
        </p>
        <p>
            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.
        </p>
        <p>
            Adv Neurol 1979;26:123-33. Ovarian steroid hormones and cerebral function. Cogen PH, Zimmerman EA.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            J Maine Med Assoc 1977 Oct;68(10):370-1 Quadriparesis as an unusual manifestation of hypercalcemia. Dyro FM.
        </p>
        <p><hr /></p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            J Nutr Sci Vitaminol (Tokyo) 1985 Dec;31 Suppl:S15-9. <strong>Aging and calcium as an environmental
                factor.</strong>
            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, <strong>amyotrophic
                lateral sclerosis and senile dementia due to calcium deposition
            </strong>in the central nervous system, <strong>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)
            </strong>
        </p>
        <p>
            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.
        </p>

        <p>
            Contrib Nephrol 1991;90:206-11. <strong>
                Calcium, parathyroids and aging.
            </strong>
            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<strong>
                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</strong> progressive aggravation of calcium deficiency, such blunting
            also progresses with aging. The dysfunction, damage and death of cells occurring in all diseases<strong>
                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</strong>
            hormone secretion and the normalization of a such blunting <strong>of intercompartmental distribution of
                calcium examples in hypertension and diabetes mellitus with evident improvement of clinical
                manifestations and laboratory tests.
            </strong>
        </p>
        <p>
            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.
        </p>
        <p>
            Mol Med 1996 Mar;2(2):204-10. <strong>
                Parathyroid hormone-related protein is induced during lethal endotoxemia and contributes to
                endotoxin-induced mortality in rodents.</strong> 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<strong>
                results suggest that PTHrP belongs to the cascade of pro-inflammatory cytokines induced during lethal
                endotoxemia that is responsible for the toxic effects of</strong> LPS.
        </p>
        <p><hr /></p>
        <p>
            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.
        </p>

        <p>
            Proc Soc Exp Biol Med 1986 Mar;181(3):438-42. <strong>Forskolin-induced bone resorption in neonatal mouse
                calvaria in vitro.</strong> Gunasekaran S, Hall GE, Kenny AD <strong>Lactic acid release was increased
                during the 96 hr of incubation in proportion to the calcium release in the media.</strong>

            J Endocrinol 2000 Feb;164(2):129-38. <strong>Estrogen mediates the sex difference in post-burn
                immunosuppression.</strong> 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,<strong>
                in part, by increased production of interleukin-6 (IL-6).
            </strong>
            Increased circulating<strong>
                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
            </strong>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 <strong>treatment with E(2) suppressed splenocyte proliferation in a macrophage-dependent
                manner and enhanced macrophage production of IL-6.</strong>
        </p>

        <p>
            Calcif Tissue Int 1990 May;46(5):294-9. Effective therapy of glucocorticoid-induced osteoporosis with
            medroxyprogesterone acetate. Grecu EO, Weinshelbaum A, Simmons R.
        </p>
        <p>
            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.
        </p>
        <p>
            Fortschr Med 1985 Mar 28;103(12):328-30. <strong>
                [Antiallergic effect of oral calcium.</strong> A clinico-experimental study] [Article in German] Haas
            PJ. Randomized Controlled Trial
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            Calcif Tissue Res 1977 Oct 20;23(3):241-4.<strong>
                Proliferation of osteoclasts in rat bone following bleeding and femoral fractures.</strong> 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. <strong>Modulation of IL-6 production during the
                menstrual cycle in vivo and in vitro.</strong> 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. <strong><hr /></strong>
            <hr />

            Kidney Int Suppl 1983 Dec;16:S204-7. <strong>Pathogenesis of the anemia of uremia: role of secondary
                hyperparathyroidism.</strong> Massry SG PTH may participate in the genesis of the anemia of uremia
            through at least<strong>
                three pathways. These include inhibition of erythropoiesis, shortening survival of RBCs and inducing
                fibrosis of bone marrow cavity.
            </strong>
        </p>
        <p>
            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.
        </p>
        <p>
            Am J Clin Nutr 2000 Jul;72(1):168-73. <strong>
                A threshold for low-protein-diet-induced elevations in parathyroid hormone.</strong>

            Kerstetter JE, Svastisalee CM, Caseria DM, Mitnick ME, Insogna KL. <strong>
                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.</strong>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            J Clin Invest 1995 Apr;95(4):1933-40. <strong>
                The diurnal rhythm of bone resorption in the rat. Effect of feeding habits and pharmacological
                inhibitors.</strong> Muhlbauer RC, Fleisch H. This paper shows that, in rats, bone mass can be<strong>
                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 ....
            </strong>

            Whether bone mass in humans is also under the control of dietary habits is not known. <strong>If so, an
                increased meal frequency may be used to prevent osteoporosis.
            </strong>Nephron 2001 Dec;89(4):384-90. <strong>Prolonged dietary calcium restriction: a diagnostic approach
                in idiopathic Hypercalciuria.</strong> Muller D, Eggert P.
        </p>
        <p><hr /></p>

        <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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            Nippon Ronen Igakkai Zasshi 1989 May;26(3):216-22. <strong>[Calcium and magnesium metabolism in the
                aged]</strong>
            [Article in Japanese] Ouchi Y, Orimo H Although serum calcium concentration remains constant during ageing,
            the plasma<strong>
                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.</strong> On the other hand, the
            incidence of <strong>soft tissue calcification is known to increase with ageing.
            </strong>
        </p>
        <p>
            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.
        </p>
        <p>
            Muscle Nerve 1982 Jan;5(1):26-32. <strong>
                Hereditary polymyopathy and cardiomyopathy in the Syrian hamster. II. Development of heart necrotic
                changes in relation to defective mitochondrial function.</strong> Proschek L, Jasmin G <strong>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.</strong>

            Eur J Endocrinol 1998 Oct;139(4):433-7. <strong>Changes in cytochrome oxidase activity in brown adipose
                tissue during oestrous cycle in the rat.</strong>
            Puerta M, Rocha M, Gonzalez-Covaleda S, McBennett SM, Andrews JF. <strong>
                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.
            </strong>
        </p>
        <p>
            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.
        </p>
        <p>
            Arthritis Rheum 2001 Oct;44(10):2338-41. <strong>
                Association of osteoporosis and cardiovascular disease in women with systemic lupus
                erythematosus.</strong> 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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            J Allergy Clin Immunol 1990 Dec;86(6 Pt 1):881-5 <strong>1,25-Dihydroxyvitamin D3 potentiates the decreased
                response of lymphocytes from atopic subjects to agents that increase intracellular cyclic adenosine
                monophosphate.</strong> Ravid A, Tamir R, Liberman UA, Rotem C, Pick AI, Novogrodsky A, Koren R. Eur J
            Endocrinol 2002 May;146(5):635-42. <strong>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.</strong> Rejnmark L, Lauridsen AL, Vestergaard P, Heickendorff L, Andreasen F,
            Mosekilde L. <strong>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.
            </strong>
        </p>

        <p>
            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.
        </p>
        <p>
            Schweiz Med Wochenschr 1994 Jun 25;124(25):1122-8. <strong>[Hypercalcemia]</strong> Schmid C. <strong>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);
            </strong>
            the latter, in turn, aggravate hypercalcemia via decreased fluid intake, mobility, and renal calcium
            clearance.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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...
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            MMW Munch Med Wochenschr 1976 Oct 22;118(43):1395-8. <strong>[Oral application of calcium and vitamin D2 in
                allergic bronchial asthma</strong>] 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. <strong>It is concluded that calcium, given orally in combination
                with calciferol, causes a decrease of airway obstruction in patients with allergic bronchial asthma.
            </strong>J Urol 1994 Oct;152(4):1226-8. <strong>Urinary incontinence due to idiopathic hypercalciuria in
                children.
            </strong>Vachvanichsanong P, Malagon M, Moore ES. In addition to being the most common cause of
            microhematuria in children, our study demonstrates that idiopathic<strong>
                hypercalciuria is also frequently associated with urinary incontinence of all types.
            </strong>Magnes Trace Elem 1991-92;10(2-4):281-6. <strong>Relation of magnesium to osteoporosis and calcium
                urolithiasis.</strong> 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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Cas Lek Cesk 1997 Jul 30;136(15):459-63. <strong>
                [New drugs with positive effects on bones]
            </strong>

            [Article in Czech] Zofkova I, Kanceva RL. Magnesium influences bone in different ways. <strong>It activates
                osteoblasts, increases bone mineralization, and enhances the sensitivity of target tissues (incl. bone)
                to PTH and 1,25(OH)2 vitamin D3,</strong> 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. <strong>
                Bicarbonates are also favourable for bone. NaHCO3 together with potassium citrate stimulates osteoblasts
                and enhances bone mineralisation.</strong>

            © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
        </p>
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        © Ray Peat Ph.D. 2014. All Rights Reserved. www.RayPeat.com
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    <head><title>Food-junk and some mystery ailments: Fatigue, Alzheimer's, Colitis, Immunodeficiency.</title></head>
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        <h1>
            Food-junk and some mystery ailments: Fatigue, Alzheimer's, Colitis, Immunodeficiency.
        </h1>

        <article class="posted">
            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.<p>
                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."
            </p>
            <p>
                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.
            </p>
            <p>
                I think a similar situation exists now in relation to the effects of carrageenan.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.”
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p></p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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."
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                A few months ago I had a questionnaire circulated in a “fibromyositis” discussion group on the internet,
                and the consistency of responses was interesting.
            </p>
            <p>
                The questions were: 1) Have you noticed that any of your symptoms are worse premenstrually?
            </p>
            <p>
                2) Have you noticed that any symptom is less severe premenstrually?
            </p>
            <p>
                3) Do any symptoms seem to be worse periodically, but without being associated with the premenstrual
                time?
            </p>
            <p>
                4) Did your symptoms appear after use of oral contraceptives or IUD?
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p></p>
            <hr />
            <p><h3>REFERENCES</h3></p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p><hr /></p>
            <p><hr /></p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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. “
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                J Hyg Epidemiol Microbiol Immunol 1990;34(4):343-348 “Increasing trend of hyperbilirubinemia incidence
                in the blood donors population,” Pintera J.
            </p>
            <p>
                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.”
            </p>
            <p>
                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).”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                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.”
            </p>
            <p>
                Z Arztl Fortbild (Jena) 1993 Mar 12;87(3):217-221 [The phenomenon of persorption--history and
                facts].[Article in German] Volkheimer G.
            </p>
            <p>
                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 &lt;
                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.”
            </p>
            <p>R.F.V. Pulvertaft, PHA in relation to Burkitt's tumour, Lancet sept 12, pp 552-554, 1964.</p>
            <p>K.M. Stevens, The aetiology of SLE, Lancet, Sept. 5, 506-508, 1964.</p>
            <p><hr /></p>

            <p>Ray Peat's Newsletter</p>
            <p>
                Not for republication without written permission PO Box 5764, Eugene, OR 97405 Raymond PeatJuly, 1995
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                “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....”
            </p>
            <p></p>
        </article>
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        <p>
            <strong>
                Cascara, energy, cancer and the FDA's laxative abuse</strong>
        </p>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, <strong>breast cancer, attempted suicide, </strong>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." <em>"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.</em>"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 Q<sub>10</sub>,
        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 coQ<sub
        >10</sub> 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 coQ<sub>10</sub>.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<strong>: </strong>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 &amp;
        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 Q<sub>10</sub>, 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<strong>;</strong> 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 Q<sub>10</sub> 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
        <a href="http://www.gilbertling.org" target="_blank">www.gilbertling.org</a>.)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. <span style="white-space: pre-wrap"> </span>
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        <strong>Enzymatic and molecular modelling studies.</strong> Tarasiuk J, Mazerski J, Tkaczyk-Gobis K, Borowski E.
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        >Inhibition of hind-paw edema and cutaneous vascular plasma extravasation in mice by acetylshikonin.
        </strong>Wang JP, Raung SL, Chang LC, Kuo SC.Yao Xue Xue Bao. 2004 Apr;39(4):254-8. <strong>Inhibitory effects
            of emodin on angiogenesis.
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            of guinea pig ileitis.</strong> Wu TF, Carati CJ, Macnaughton WK, von der Weid PY.Mem Inst Oswaldo Cruz.
        2005 Mar;100 Suppl 1:107-10. <strong>Lymphatic vessel contractile activity and intestinal inflammation.</strong>
        Wu TF, MacNaughton WK, von der Weid PY.Life Sci. 2007 Oct 13;81(17-18):1332-8. <strong>Emodin-mediated
            protection from acute myocardial infarction via inhibition of inflammation and apoptosis in local ischemic
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        </strong>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. <strong>[Effects of emodin on hepatic fibrosis in rats]
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        Jul;115(7):1035-8. <strong>Effect of emodin on proliferation and differentiation of 3T3-L1 preadipocyte and FAS
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            inhibitor emodin.</strong>Zhang L, Hung MC.Clin Cancer Res. 1999 Feb;5(2):343-53. <strong>Tyrosine kinase
            inhibitor emodin suppresses growth of HER-2/neu-overexpressing breast cancer cells in athymic mice and
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            Effects of emodin on Ca2+ signal transduction of smooth muscle cells in multiple organ dysfunction
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        <p>
            © Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com
        </p>
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            <strong><strong>Cataracts: water, energy, light, and aging</strong>&nbsp;</strong>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).&nbsp;
        </p>
        <p>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.</span>
            <span>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).&nbsp;</span>
            <span>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).&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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).&nbsp;</span>
            <span>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.&nbsp;&nbsp; "… 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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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).&nbsp;</span>
            <span>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&nbsp;</span>
            <em>in vitro&nbsp;</em>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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).&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.&nbsp;</span>
            <span>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.</span>
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            <span>Invest Ophthalmol Vis Sci. 1981 Nov;21(5):700-13. Organophosphates of the crystalline lens: a nuclear
                magnetic resonance spectroscopic study. Greiner JV, Kopp SJ, Sanders DR, Glonek T.</span>
            <span>Acta Ophthalmol (Copenh). 1976 Aug;54(4):445-55. Effects of phospholine iodide on the metabolites of
                the glycolytic, pentose phosphate and sorbitol pathways in the rabbit lens. Harkonen M, Tarkkanen
                A.</span>
            <span>Exp Eye Res. 2008 Apr;86(4):701-3. The stiffness of human cataract lenses is a function of both age
                and the type of cataract. Heys KR, Truscott RJ.</span>
            <span>Arch Ophthalmol. 1977 Jul;95(7):1262-8. Atropine inhibition of echothiophate cataractogenesis in
                monkeys. Kaufman PL, Axelsson U, Barany EH.</span>
            <span>Vestn Oftalmol. 2010 Jan-Feb;126(1):32-5. [The bioamine profile of the lens during the development of
                different types of human age-related cataract].[Article in Russian]Korsakova NV, Sergeeva VE.</span>
            <span>American Journal of Psychiatry, 1953;110(4):281-289. Patterns of behavior disturbance following
                cataract extraction. Linn L, Kahn RL, Coles R, Cohen J, Marshall D, Weinstein EA.</span>
            <span>Arch Ophthalmol. 1967 Jun;77(6):804-8. Cholinesterase in the lens. Michon J Jr, Kinoshita JH.</span>
            <span>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.</span>
            <span>Indian J Ophthalmol. 1997 Dec;45(4):227-31. Possible role of lens collagen in cataractogenesis. Mishra
                G, Das GB, Behera HN.</span>
            <span>Nihon Ganka Gakkai Zasshi. 1993 Oct;97(10):1157-64. [Magnetic resonance imaging study on rat sugar
                cataract]. Mori K.</span>
            <span>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.</span>
            <span>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.</span>
            <span>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.</span>
            <span>Exp Eye Res. 2004 Mar;78(3):689-98. The lens: local transport and global transparency. Mathias RT, Rae
                JL.</span>
            <span>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.</span>
            <span>Exp Eye Res. 1985 Oct;41(4):569-75. Protein synthesis in bovine and human nuclear fiber cells.</span>
            <span>Ozaki L, Jap P, Bloemendal H.</span>
            <span>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.</span>
            <span>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.</span>
            <span>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.</span>
            <span>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.</span>
            <span>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.</span>
            <span>Mol Vis. 2013;19:463-75. Carbon turnover in the water-soluble protein of the adult human lens.</span>
            <span>Stewart DN, Lango J, Nambiar KP, Falso MJ, FitzGerald PG, Rocke DM, Hammock BD, Buchholz BA.</span>
            <span>D.N.Stewart, 2008 dissertation UC Davis, Existence of protein turnover in adult human nuclear fiber
                cells.</span>
            <span>J Theor Biol 218(4): 497-505, Oct 2002.&nbsp; Spread of discrete structural changes in synthetic
                polyanionic gel: a model of propagation of a nerve impulse. Tasaki I.&nbsp;</span>
            <span>J Physiol (Paris) 77: 1055-1059, 1981. Rapid mechanical changes in crab nerve and squid axon during
                action potentials. Tasaki I and Iwasa K.</span>
            <span>Ups J Med Sci. 1980;85(3):211-5. Swelling of nerve fibers during action potentials. Tasaki I, Iwasa
                K.&nbsp;</span>
            <span>Science 210: 338-339, 1980. Swelling of nerve fibers associated with action potentials. Iwasa K,
                Tasaki, I, and Gibbons RC.</span>
            <span>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.</span>
            <span>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.</span>
        </p>

        © Ray Peat Ph.D. 2014. All Rights Reserved. www.RayPeat.com
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    <head><title>Coconut Oil</title></head>
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        <h1>
            Coconut Oil
        </h1>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            General aging, and especially aging of the brain, is increasingly seen as being closely associated with
            lipid peroxidation.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p></p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>

        <p>
            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. &amp; Med. 116(11), 1364-67.
            1993.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p></p>

        <p>
            © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
        </p>
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    <head><title>Progesterone, not estrogen, is the coronary protection factor of women.</title></head>
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        <h1>
            Progesterone, not estrogen, is the coronary protection factor of women.
        </h1>

        <article class="posted">
            <p>
                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
                <em>The Natural Superiority of Women.</em> 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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.)
            </p>
            <p>
                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.
            </p>
            <p>
                Somehow, these two fetid streams converged<strong>: Estrogen, like the unsaturated oils, lowered the
                    amount of cholesterol in the blood,</strong> 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.)
            </p>
            <p>
                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”<strong>:</strong> The relaxation of blood
                vessels would prevent high blood pressure and its consequences, in this new upside down paradigm.
                <strong>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.</strong>
            </p>
            <p>
                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.
            </p>
            <p>
                (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.)
            </p>
            <p>
                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.
            </p>
            <p>
                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 <strong><em>nitric oxide (“NO”)</em></strong> 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.)
            </p>
            <p>
                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.
            </p>
            <p>
                From more realistic perspectives, nitric oxide is being considered as a cause of aging, especially brain
                aging. <strong>Nitric oxide interacts with unsaturated fats to reduce oxygen use, damage mitochondria,
                    and cause edema.
                </strong>
            </p>
            <p>&nbsp;</p>
            <p>
                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 <strong>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.</strong>
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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 <strong>lactic acid, adrenalin, and free fatty
                    acids all stimulate hyperventilation.</strong> 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.
            </p>
            <p>
                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.
            </p>
            <p>
                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 <strong>chronic exposure of the blood vessels to higher levels of free fatty acids (with a bias
                    toward unsaturated fatty acids)</strong>, 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<strong>;</strong> both dilution of the plasma and endotoxemia
                impair heart function.
            </p>
            <p>
                Progesterone’s effects are antagonistic to estrogen’s<strong>:</strong>. Progesterone decreases the
                formation of nitric oxide, decreasing edema<strong>;</strong> 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.
            </p>
            <p>
                The effects of progesterone on the heart and blood vessels are paralleled by those of carbon
                dioxide<strong>: Increased carbon dioxide increases perfusion of the heart muscle, increases its stroke
                    volume, and reduces peripheral resistance.
                </strong> 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.<strong></strong>
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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. <strong>Progesterone, by opposing estrogen, is universally protective against vascular
                    and heart disease.</strong>
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>&nbsp;</p>
            <p><h3>REFERENCES</h3></p>
            <p>
                JAMA 1998 Aug 19;280(7):605-13. <strong>
                    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.</strong>
                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. <strong>Mean age was 66.7 years.</strong> INTERVENTION: Either
                0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily
                (<strong><hr /></strong>. Follow-up averaged 4.1 years;<strong>
                    82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end
                    of 3 years.</strong> MAIN OUTCOME MEASURES: The primary outcome was the occurrence of nonfatal
                myocardial infarction (MI) or CHD death.<strong> Secondary cardiovascular outcomes</strong> 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<strong>
                    occurred despite a net 11% lower low-density lipoprotein cholesterol level</strong> and 10% higher
                high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each
                P&lt;.001). Within the overall null effect, there was a statistically significant time trend, with more
                <strong>CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5.
                </strong>More women in the hormone group than in the placebo group experienced venous thromboembolic
                events (34 vs 12; RH, <strong>2.89</strong>; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH,
                1.38; 95% CI, 1.00-1.92). <strong>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;</strong> 95% CI, 0.84-1.38). CONCLUSIONS: <strong>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,</strong> we do
                not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the
                favorable pattern of CHD
            </p>
            <p>
                Am J Med 1982 Dec;73(6):872-81. <strong>Serum estrogen levels in men with acute myocardial
                    infarction.</strong> 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. <strong>Serum estradiol levels were significantly
                    elevated in the groups with myocardial infarction, unstable angina,</strong> 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. <strong>Serum estradiol levels, then, were elevated in men with confirmed or
                    suspected coronary heart disease</strong> but were not elevated in men without coronary heart
                disease even under the stressful conditions found in an intensive care unit. Serum estradiol <strong
                >levels were significantly and positively correlated (p less than 0.03) with serum total creatine
                    phosphokinase</strong> 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.
            </p>
            <p>
                JAMA 1978 Apr 3;239(14):1407-9. <strong>
                    Noncontraceptive estrogens and nonfatal myocardial infarction.</strong> 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, <strong>comparing
                    estrogen users with nonusers, is 7.5,</strong> 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.
            </p>
            <p>
                JAMA 1978 Apr 3;239(14):1403-6. <strong>
                    Oral contraceptives and nonfatal myocardial infarction.</strong> 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 <strong>(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.</strong> The relative risk
                estimate, comparing oral contraceptive users with nonusers, is <strong>14 with</strong> 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.
            </p>
            <p>
                M. Karmazyn, et al., <strong>"Changes in coronary vascular resistance associated with prolonged hypoxia
                    in isolated rat hearts: A possible role of prostaglandins,"</strong>
                <em>Life Sciences 25,</em> 1991-1999, 1979. "if...hypoxic perfusion is prolonged, the initial dilatation
                passes off and an intense vasoconstriction results." <strong>"The constriction could be prevented by
                    progesterone but not by estradiol or testosterone."</strong> "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."
                <strong>"...hypoxia can cause coronary constriction and...the effect does not occur in young or
                    progesterone-treated hearts...."</strong>
            </p>
            <p>
                Am J Epidemiol 1996 May 15;143(10):971-8.<strong>
                    Prior to use of estrogen replacement therapy, are users healthier than nonusers?</strong> 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<strong>
                    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</strong>
                <hr />
                <strong>
                    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</strong> clinical trials to estimate the
                direct benefit of postmenopausal ERT for protecting women from cardiovascular disease.
            </p>
            <p>
                <strong>"Effects of androgens on haemostasis,"</strong> Winkler UH, Maturitas, 1996 Jul, 24:3, 147-55.
                <strong>"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.</strong> Hypogonadism in males is associated with an
                enhancement of fibrinolytic inhibition via increased synthesis of the plasminogen activator inhibitor
                PAI 1.<strong>” </strong>
            </p>
            <p>
                M. Mabry White, et al., <strong>“Estrogen, progesterone, and vascular reactivity: Potential cellular
                    mechanisms,"</strong> 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.
            </p>
            <p>
                J. Boczkowski, et al., <strong>"Induction of diaphragmatic nitric oxide synthase after endotoxin
                    administration in rats; role on diaphragmatic contractile dysfunction,"</strong> J. Clin. Invest.
                98, 1550-1559, 1996. "We conclude that iNOS [inducible nitric oxide synthase] was induced..." by
                endotoxin.
            </p>
            <p>
                Arch Int Pharmacodyn Ther 1986 May;281(1):57-65. <strong>Effects of 17 beta-estradiol on the isolated
                    rabbit heart.</strong> 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 <strong>induced a negative inotropic effect
                    starting from a concentration of 10(-6) M and a vasodilation</strong> 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.
            </p>
            <p>
                Med Hypotheses 1997 Aug;49(2):183-5.<strong>
                    Coronary artery spasm: a hypothesis on prevention by progesterone.</strong> Kanda I, Endo M.
                Department of Surgery, Heart Institute of Japan, Tokyo Women's Medical College, Japan. <strong>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.
                </strong>
            </p>
            <p>
                J. Bolanos, et al., <strong>"Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in
                    cultured astrocytes,"</strong> J. Neurochem. 63, 910-916, 1994.
            </p>
            <p>
                M. Cleeter, et al., <strong>"Reversible inhibition of cytochrome C oxidase, the terminal enzyme of the
                    mitochondrial respiratory chain, by nitric oxide,"</strong> FEBS Lett. 345, 50-54, 1994.
            </p>
            <p>
                Ann Thorac Surg 1999 Sep;68(3):925-30. <strong>Coronary perfusate composition influences diastolic
                    properties, myocardial water content, and histologic characteristics of the rat left
                    ventricle.</strong> 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 <strong>ventricular diastolic
                    compliance</strong> exhibit quantitative relationships in rats. Edema due to low osmolarity coronary
                perfusates increases myocardial water content and histologic edema score and <strong>decreases left
                    ventricular filling.</strong> 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&lt;0.05 versus other groups) and highest in
                dilute Plegisol (p&lt;0.05). Left ventricular filling volumes were smallest in dilute Plegisol and
                Plegisol (p&lt;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.”
            </p>
            <p>
                <strong>Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide
                    production in murine macrophages.</strong> 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.
            </p>
            <p>
                <strong>Testosterone relaxes rabbit coronary arteries and aorta.</strong> 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 “<strong>Testosterone induces endothelium-independent
                    relaxation in isolated rabbit coronary artery and aorta, which is neither mediated by prostaglandin
                    I2 or cyclic GMP.</strong> Potassium conductance and potassium channels but not ATP-sensitive
                potassium channels may be involved partially in the mechanism of testosterone-induced relaxation. The
                <strong>in vitro relaxation is independent of sex and of a classic receptor.</strong> 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.”
            </p>
            <p>
                J. Nakamura, et al., <strong>"Estrogen regulates vascular endothelial growth permeability factor
                    expression in 7,12-dimethyl- benz(a)anthracene-induced rat mammary tumors,"
                </strong>Endocrinology 137(12_, 5589-5596, 1996.<strong></strong> ("...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.")
            </p>
            <p>
                D. A. Barber, et al., <strong>"Endothelin receptors are modulated in association with endogenous
                    fluctuations in estrogen,"</strong> 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 <strong>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."
                </strong>
            </p>
            <p>
                T. M. Chou, et al, <strong>"Testosterone induces dilation of canine coronary conductance and resistance
                    arteries in vivo,"</strong> Circulation 94(10), 2614-2619, 1996.
            </p>
            <p>
                K. Sudhir, et al., <strong>"Estrogen enhances basal nitric oxide release in the forearm vasculature in
                    perimenopausal women,"</strong> Hypertension 28(3), 330-334, 1996.
            </p>
            <p>
                G. Sitzler, et al., <strong>"Investigation of the negative inotropic effects of 17-beta-oestradiol in
                    human isolated myocardial tissues,"</strong> British J. of Pharmacology 119(1), 43-48, 1996.
            </p>
            <p>
                S. M. Hyder, et al., <strong>"Uterine expression of vascular endothelial growth factor is increased by
                    estradiol and tamoxifen,"</strong> 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.")
            </p>
            <p>
                N. Ferrara and T. Davis-Smyth, <strong>"The biology of vascular endothelial growth factor,"</strong>
                Endocrine Reviews 18(1), 4-<strong>19</strong>,? 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 <strong>decrease
                    in venous return, mediated primarily by endothelial cell-derived nitric oxide...."</strong>
                "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 <strong
                >capillary hyperpermeability</strong> that characterizes ovarian hyperstimulation syndrome as well as in
                the dysfunctional endothelium of preeclampsia."
            </p>
            <p>
                B. Jilma, et al, <strong>"Sex differences in concentrtions of exhaled nitric oxide and plasma
                    nitrate,"</strong> 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."
            </p>
            <p>
                <strong>
                    Progesterone inhibits inducible nitric oxide synthase gene expression and nitric oxide production in
                    murine macrophages.</strong> Miller L; et al J Leukoc Biol, 59(3):442-50 1996 Mar. “Treatment with
                P4 alone caused a time- and dose-dependent <strong>inhibition of NO production</strong> 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.”
            </p>
            <p>
                Int J Epidemiol 1990 Jun;19(2):297-302. <strong>Relationship of menopausal status and sex hormones to
                    serum lipids and blood pressure.</strong> Wu ZY, Wu XK, Zhang YW. <strong>“Conditional logistic
                    regression analysis found that progesterone is a protective factor only and testosterone is one of
                    the risk factors for hypertension.”
                </strong>
            </p>
            <p>
                Pharmacol Biochem Behav 1990 Oct;37(2):325-7. <strong>Steroid sex hormones and cardiovascular function
                    in healthy males and females: a correlational study.</strong>
                <hr />
                <strong>Positive correlations were also found between estradiol and SBP and HR in women.”</strong>
            </p>
            <p>
                Scand J Clin Lab Invest 1993 Jul;53(4):353-8. <strong>Effects of ovarian stimulation on blood pressure
                    and plasma catecholamine levels.</strong> Tollan A, Oian P, Kjeldsen SE, Holst N, Eide I. <strong
                ><hr /></strong>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>strong
                    correlation between adrenaline and blood pressure are unclear, but may be induced by the
                    supraphysiological oestradiol levels.”</strong>
            </p>
            <p>
                J Mol Cell Cardiol 1986 Dec;18(12):1207-18. <strong>Post-ischemic cardiac chamber stiffness and coronary
                    vasomotion: the role of edema and effects of dextran.</strong> 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<strong>
                    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.”
                </strong>
            </p>
            <p>
                Experientia 1980 Dec 15;36(12):1402-3.<strong>
                    Bilinear correlation between tissue water content and diastolic stiffness of the ventricular
                    myocardium.</strong> Pogatsa G<strong>. 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.
                </strong>
            </p>
            <p>
                S Afr Med J 1975 Dec 27;49(55):2251-4. <strong>Effect of natural oestrogens on blood pressure and weight
                    in postmenopausal women.</strong> 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<strong>
                    those in the group increased, but only the diastolic was significantly elevated.”
                </strong>“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.”
            </p>
            <p>
                Am J Hypertens 1995 Mar;8(3):249-53. <strong>
                    Ambulatory blood pressure in mild hypertensive women taking oral contraceptives. A case-control
                    study.</strong> Narkiewicz K, Graniero GR, D'Este D, Mattarei M, Zonzin P, Palatini P. “Both daytime
                and nighttime systolic<strong>
                    blood pressure values were significantly higher in oral contraceptive users. There was an average
                    8.3 mm</strong>
                <hr />
            </p>
            <p>
                Am J Surg Pathol 1995 Apr;19(4):454-62.<strong>
                    Reversible ischemic colitis in young women. Association with oral contraceptive use.</strong> 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.<strong>
                    The calculated odds ratio yielded a greater than sixfold relative risk for the occurrence of
                    ischemic colitis among oral contraceptive users.</strong> 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.” <strong></strong>
            </p>
            <p>
                J Clin Endocrinol Metab 1993 Jun;76(6):1542-7.<strong>
                    Differential changes in serum concentrations of androgens and estrogens (in relation with cortisol)
                    in postmenopausal women with acute illness.
                </strong>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. <strong><hr /></strong> “The decreased serum T levels
                suggest inhibition of 17 beta-OH-dehydrogenase <strong>and/or increased aromatization to
                    estradiol.</strong>
                <strong>The marked increase in serum estrogen levels also suggests increased aromatization.</strong> 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.”.<strong></strong>
            </p>
            <p>&nbsp;</p>
        </article>
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    <head><title>Diabetes, scleroderma, oils and hormones</title></head>
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        <h1>
            Diabetes, scleroderma, oils and hormones
        </h1>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.)
        </p>

        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p></p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.)
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.)
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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..
        </p>
        <p>
            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.
        </p>
        <p>
            <strong><h3>
                    REFERENCES WITH EXCERPTS AND COMMENTS
                </h3></strong>
        </p>

        <p>
            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."
        </p>
        <p>
            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.)
        </p>

        <p>
            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."
        </p>
        <p>
            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>
        <p>
            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>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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>
        <p>
            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."
        </p>
        <p>
            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...."
        </p>

        <p>
            A. Ceriello, et al., "The defence against free radicals protects endothelial cells from
            hyperglycaemia-induced plasminogen activator inhibitor 1 over-production," Blood Coagulation &amp;
            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.]
        </p>
        <p>
            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."
        </p>

        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            M. Garnier, et al., "Red blood cell sodium conent in NID diabetic patients with hemorheological
            abnormalities," Clinical Hemorheology 15(3), 325-333, 1995.
        </p>
        <p>
            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.
        </p>

        <p>
            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.]
        </p>
        <p>
            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.]
        </p>
        <p>
            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."
        </p>
        <p>
            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.]
        </p>
        <p>
            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%.]
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            J. S. Jensen, et al., "Microalbuminuria reflects a generalized transvascular albumin leakiness in clinically
            healthy subjects," Clin. Sci. 88(6), 629-633, 1995.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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...."
        </p>
        <p>
            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."
        </p>
        <p>
            A. Lazarow, "Protection against alloxan diabetes," Anat. Rec. 97, 353, 1947.
        </p>
        <p>
            A. Lazarow, "Protective effect of glutathione and cysteine against alloxan diabetes in the rat," Proc. Soc.
            Exp. Biol. &amp; 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.]
        </p>
        <p>
            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."
        </p>
        <p>
            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."
        </p>
        <p>
            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.]
        </p>
        <p>
            Y. Matsumoto, et al., "Creatine kinase kinetics in diabetic cardiomyopathy," Amer. J. Physiol.-Endocrinol.
            Met. 31(5), E1070-E1076, 1995.
        </p>
        <p>
            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...."
        </p>

        <p>
            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.
        </p>
        <p>
            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.]
        </p>
        <p>
            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.
        </p>

        <p>
            S. Phillips, et al., "Neuropathic arthropathy of the spine in diabetes," Diabetes Care 18(6), 876-869, 1995.
        </p>
        <p>
            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."
        </p>
        <p>
            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.]
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>

        <p>
            M. A. Smith, et al., "Radical AGEing in Alzheimer's disease," Trends in Neurosciences 18(4), 172-176, 1995.
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>

        <p>
            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."
        </p>
        <p>
            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>
        <p>
            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."
        </p>

        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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..."
        </p>
        <p>
            T. Yamashita, et al., "Increased transendothelial permeation of albumin by high glucose concentration,"
            Metabolism 44(6), 739-744, 1995.
        </p>
        <p>
            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.
        </p>
        <p>
            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.]
        </p>
        <p>
            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.]
        </p>

        <p>
            © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
        </p>
    </body>
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    <head>
        <title>
            Eclampsia in the Real Organism: A Paradigm of General Distress Applicable in Infants, Adults, Etc.
        </title>
    </head>
    <body>
        <h1>
            Eclampsia in the Real Organism: A Paradigm of General Distress Applicable in Infants, Adults, Etc.
        </h1>
        <article class="posted">
            <p>
                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."
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.)
            </p>
            <p>
                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. <strong>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.</strong> 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<strong>;</strong> low birth weight and complications of pregnancy are
                associated with it<strong>: </strong>J. F. Eastman, "Obstetrical background of 753 cases of cerebral
                palsy," Obstet. Gynecol. Surv. 17, 459-497, 1962.)
            </p>
            <p>
                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 <em>caused</em> maternal sickness and premature labor, <strong>more than 50 years
                    later people were still taking seriously the idea that cerebral palsy might cause maternal
                    complications and prematurity.</strong> (A.M. Lilienfield and E. Parkhurst, "A study of the
                association of factors of pregnancy and parturition with the development of cerebral palsy," <em>Am. J.
                    Hyg. 53,</em> 262-282, 1951.)
            </p>
            <p>
                Medical textbooks and articles still commonly list the conditions that are associated with
                eclampsia<strong>: </strong> 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.)<strong>*</strong> 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.
            </p>
            <p>
                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.
            </p>
            <p>
                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," <em>Guy's Hospital Reports, Volume 1, series 2,</em
                > 495-517, 1843.) S. S. Rosenstein observed that eclampsia was preceded by changes in the serum (<em
                >Traite Pratique des Maladies des Reins,</em> Paris, 1874). L. A. A. Charpentier specifically documented
                low serum albumin as a cause of eclampsia (<em>A Practical Treatise on Obstetrics, Volume 2,</em>
                William Wood &amp; Co., 1887). Robert Ross, M.D., documented the role of malnutrition as the cause of
                proteinuria and eclampsia (<em>Southern Medical Journal 28,</em> 120, 1935).
            </p>

            <p>
                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, <em>Control of
                    Messenger RNA Stability,</em> 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.) <em>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<strong>;</strong> 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.</em>
            </p>
            <p>
                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.
            </p>
            <p>
                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
                <em>Toxemias of Pregnancy,</em> 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.)
            </p>
            <p>
                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."
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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<strong>;</strong> 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<strong
                >:</strong> M. Jeevanandam, et al., <em>Metabolism 40,</em> 1199-1206, 1991.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.)
            </p>
            <p>
                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.)
            </p>
            <p>
                National nutritional data show that in the U.S. <strong>the development of at least a million babies a
                    year is "substantially compromised" by prenatal malnutrition.</strong> Miscarriages, which are also
                causally related to poor nutrition, occur at a rate of a few hundred thousand per year. (Williams.)
            </p>
            <p>
                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<strong>;</strong> 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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.)
            </p>
            <p>
                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<strong>...</strong>until the moment fluids
                were introduced into the body<strong>...</strong>" [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<strong>....</strong>" 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..
            </p>
            <p>
                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.
            </p>

            <p>
                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.
            </p>

            <p>
                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..
            </p>
            <p>
                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.
            </p>
            <p><strong> &nbsp;</strong></p>
            <p>
                <strong>*Note:</strong> 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. <strong></strong>
            </p>
            <p><strong> &nbsp;</strong></p>
            <p><strong><h3>ADDITIONAL REFERENCES</h3></strong></p>

            <p>
                G. Wiener, et al., "Correlates of low birth weight: Psychological status at eight to ten years of age,"
                Pediatr. Res. 2, 110-118, 1968.
            </p>

            <p>A. Chase, "The great pellagra cover-up," Psychol. Today, pp. 83-86, Feb., 1975.</p>

            <p>Prevention Handbook, Natl. Assoc. for Retarded Citizens, 1974.</p>

            <p>US HEW, The Women and Their Pregnancies, W.B. Saunders Co., 1972.</p>

            <p>
                M. Winick and P. Rosso, "The effect of severe early malnutrition on cellular growth of human brain,"
                Pediatr. Res. 3, 181-184, 1969.
            </p>

            <p>Roger Williams, Nutrition Against Disease, Pitman Publ., 1971.</p>

            <p>H.M. Schmeck, Jr., "Brain harm in US laid to food lack," N.Y. times, Nov. 2, 1975.</p>

            <p>R. Hurley, Poverty and Mental Retardation: A Causal Relationship, Random House, 1970.</p>

            <p>D. Shanklin and J. Hodin, Maternal Nutrition and Child Health, C. C. Thomas, 1978.</p>

            <p>
                H.H. Reese, H. A. Paskind, and E. L. Sevringhaus, 1936 Year Book of Neurology, Psychiatry and
                Endocrinology, Year Book Publishers, Chicago, 1937.
            </p>

            <p>
                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.
            </p>

            <p>"Albumin concentration can be used for mild preeclampsia," Obstet. Gynecol. News, October 1, 1974.</p>
            <p>
                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.
            </p>

            <p>
                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.
            </p>

            <p>"Plasma volume 'a clue' to hypertension risks," Obstet. Gynecol. Observer, August/September, 1975.</p>

            <p>C. A. Crenshaw, MD, J. Hansen and J. G. Shaw, JFK: Conspiracy of Silence, Signet, 1992.</p>

            <p>
                T. Backstrom, "Epileptic seizures in women related to plasma estrogen and progesterone during the
                menstrual cycle," Acta Neurol. Scand. 54, 321-347, 1976.
            </p>

            <p>
                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.)
            </p>

            <p>
                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.
            </p>

            <p>
                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.
            </p>

            <p><hr /></p>

            <p>
                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.
            </p>

            <p>
                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.
            </p>
            <p>
                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.
            </p>
        </article>
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    <head><title>Fats and degeneration</title></head>
    <body>
        <h1>
            Fats and degeneration
        </h1>

        <p>
            <hr />
            <hr />
            <hr />
        </p>
        <p>
            <strong>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.</strong>
        </p>
        <p>
            <strong>In the second phase, the other "essential fatty acid," linolenic acid, was said to be even better
                than linoleic acid.</strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>

        <p>
            <strong>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.
            </strong>
        </p>
        <p>
            <strong>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.
            </strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>
        <p>
            <hr />
            <hr />
            <hr />
        </p>
        <p>
            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.
        </p>
        <p>
            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," B<sub>1</sub>, and the "growth factor," B<sub>2</sub>. Burr had no way
            of really understanding what deficiencies or toxicities were present in his experimental diet.
        </p>

        <p>
            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.
        </p>
        <p>
            Several publications between 1936 and 1944 made it very clear that Burr's basic animal diet was deficient in
            various nutrients, especially vitamin B<sub>6</sub>. <strong>
                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.</strong>
            <strong>
                A zinc deficiency produces similar symptoms,
            </strong>

            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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<strong>
                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.</strong> 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."
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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)
        </p>
        <p>
            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<strong>:</strong> 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.
        </p>
        <p>
            In 1967 a major nutrition publication, <em>Present Knowledge in Nutrition,</em>

            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.
        </p>
        <p>
            Around the same time, there were studies that showed that unsaturated fats retarded brain development and
            produced obesity.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>

        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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).
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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<strong>:</strong>
        </p>
        <p>
            <strong>"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)</strong>
        </p>
        <p>
            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.
        </p>

        <p>
            Brown, et al. (1989), discussed this developmental process (leaky capillaries, fibrosis) in relation to
            wound healing, lung disease, and tumor growth.
        </p>
        <p>
            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).
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>REFERENCES</p>
        <p>
            Alcohol Clin Exp Res 1998 Feb;22(1):192-6.<strong>
                Increased circulating products of lipid peroxidation in patients with alcoholic liver disease.</strong>
            Aleynik SI, Leo MA, Aleynik MK, Lieber CS
        </p>
        <p>
            Ann N Y Acad Sci. 1976;275:28-46. <strong>Metabolic influences in experimental thrombosis.</strong>
            Antoniades HN, Westmoreland N.
        </p>

        <p>
            Nutr Cancer. 2001;41(1-2):91-7.<strong>
                Vaccenic acid feeding increases tissue levels of conjugated linoleic acid and suppresses development of
                premalignant lesions in rat mammary gland.</strong> Banni S, Angioni E, Murru E, Carta G, Melis MP,
            Bauman D, Dong Y, Ip C.
        </p>
        <p>
            Obstet Gynecol. 1987 Sep;70(3 Pt 2):502-4. <strong>The treatment of retroperitoneal fibromatosis with
                medroxyprogesterone acetate.</strong> Barnhill D, Hoskins W, Burke T, Weiser E, Heller P, Park R. Wide
            excision is the recommended primary therapy for retroperitoneal fibromatosis. Radiation therapy and a
            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
            for recurrent retroperitoneal fibromatosis that was refractory to multiple operative resections and
            radiation therapy.
        </p>
        <p>
            Medicina (B Aires). 1978 Mar-Apr;38(2):215-6. <strong>[Fibromatosis, relaxin and progesterone]</strong> [in
            Spanish] Barousse AP. [Letter]
        </p>

        <p>
            Medicina (B Aires). 1985;45(2):159-63.<strong>
                Progesterone as therapy for retroperitoneal fibrosis.</strong> Bilder CR, Barousse AP, Mazure PA.
        </p>
        <p>
            Adv Exp Med Biol. 1976;75:497-503. <strong>Effect of ionizing radiation on liver microcirculation and
                oxygenation.</strong> Bicher HI, Dalrymple GV, Ashbrook D, Smith R, Harris D.
        </p>
        <p>
            Lipids. 1981 May;16(5):323-7. <strong>Iodination of docosahexaenoic acid by lactoperoxidase and thyroid
                gland in vitro: formation of an lodolactone.</strong>
            Boeynaems JM, Watson JT, Oates JA, Hubbard WC. "In the presence of iodide, hydrogen peroxide and
            lactoperoxidase, docosahexaenoic acid (22:6 omega 3) was converted into iodinated compounds."
        </p>
        <p>
            Am Rev Respir Dis 1989 Oct;140(4):1104-7.<strong>
                Leaky vessels, fibrin deposition, and fibrosis: a sequence of events common to solid tumors and to many
                other types of disease.</strong> Brown LF, Dvorak AM, Dvorak HF
        </p>
        <p>
            Medicina (B Aires). 1979 Sep-Oct;39(5):652-4.<strong>
                [Effect of progesterone in the treatment of a patient with idiopathic retroperitoneal fibrosis]</strong>
            [in Spanish] Casadei DH, Najun Zarazaga C, Leanza HJ, Schiappapietra JH.
        </p>
        <p>
            Biochem Mol Biol Int 1993 Jan;29(1):175-83.<strong>
                Influence of antioxidant vitamins on fatty acid inhibition of lymphocyte proliferation.</strong> Calder
            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."
        </p>

        <p>
            Clin Sci (Lond). 1992 Jun;82(6):695-700.<strong>
                Polyunsaturated fatty acids suppress human peripheral blood lymphocyte proliferation and interleukin-2
                production.</strong> Calder PC, Newsholme EA.
        </p>
        <p>
            J Neurochem 1980 Oct;35(4):1004-7. <strong>
                Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling.</strong
            > Chan PH, Fishman RA
        </p>
        <p>
            Int J Cancer 2001 Mar 15;91(6):894-9. <strong>Tumor invasiveness and liver metastasis of colon cancer cells
                correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor,
                etodolac.</strong> Chen WS, Wei SJ, Liu JM, Hsiao M, Kou-Lin J, Yang WK.
        </p>

        <p>
            Free Radic Biol Med. 1999 Jul;27(1-2):51-9. <strong>Arachidonic acid interaction with the mitochondrial
                electron transport chain promotes reactive oxygen species generation.</strong> Cocco T, Di Paola M, Papa
            S, Lorusso M.
        </p>
        <p>
            Clin Exp Metastasis 1997 Jul;15(4):410-7. <strong>Influence of lipid diets on the number of metastases and
                ganglioside content of H59 variant tumors.</strong> Coulombe J, Pelletier G, Tremblay P, Mercier G, Oth
            D.
        </p>
        <p>
            BJU Int. 2003 Jun;91(9):830-8. <strong>Fibrin as an inducer of fibrosis in the tunica albuginea of the rat:
                a new animal model of Peyronie's disease.</strong>

            Davila HH, Ferrini MG, Rajfer J, Gonzalez-Cadavid NF.
        </p>
        <p>
            Carcinogenesis 1994 Jul;15(7):1399-404. <strong>Peroxidation of linoleic, arachidonic and oleic acid in
                relation to the induction of oxidative DNA damage and cytogenetic effects.</strong> de Kok TM, ten
            Vaarwerk F, Zwingman I, van Maanen JM, Kleinjans JC.
        </p>
        <p>
            Biochem Biophys Res Commun. 2000 Oct 14;277(1):128-33. <strong>Arachidonic acid causes cytochrome c release
                from heart mitochondria.</strong> Di Paola M, Cocco T, Lorusso M.
        </p>

        <p>
            J Physiol. 1998 Mar 1;507 ( Pt 2):541-7. <strong>Arachidonic acid increases cerebral microvascular
                permeability by free radicals in single pial microvessels of the anaesthetized rat.
            </strong>
            Easton AS, Fraser PA.
        </p>
        <p>
            Am J Physiol. 1992 May;262(5 Pt 1):E637-43. ATP depletion stimulates calcium-dependent protein breakdown in
            chick skeletal Muscle. Fagan JM, Wajnberg EF, Culbert L, Waxman L.
        </p>
        <p></p>
        <p>
            Cancer Res 1998 Aug 1;58(15):3312-9. <strong>Dietary omega-3 polyunsaturated fatty acids promote colon
                carcinoma metastasis in rat liver.</strong> Griffini P, Fehres O, Klieverik L, Vogels IM, Tigchelaar W,
            Smorenburg SM, Van Noorden CJ.
        </p>

        <p>
            J Indian Med Assoc 1997 Mar;95(3):67-9, 83.<strong>
                Association of dietary ghee intake with coronary heart disease and risk factor prevalence in rural
                males.
            </strong>
            Gupta R, Prakash H
        </p>
        <p>
            Transplantation 1995 Sep 27;60(6):570-7. <strong>The effect of dietary polyunsaturated fatty acids (PUFA) on
                acute rejection and cardiac allograft blood flow in rats.</strong> Haw MP, Linnebjerg H, Chavali SR,
            Forse RA. "The immunosuppressive effect of dietary PUFA warrants further investigation, and their use as a
            possible adjunctive treatment in organ transplantation should be considered."
        </p>
        <p>
            Dtsch Med Wochenschr. 2003 Jun 20;128(25-26):1395-8. <strong>[Rare cause of chronic abdominal pain:
                retractile mesenteritis]</strong> [in German] Hermann F, Speich R, Schneemann M. "Retractile
            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."
        </p>

        <p>
            Mech Ageing Dev 2001 Apr 15;122(4):427-43. <strong>Effect of the degree of fatty acid unsaturation of rat
                heart mitochondria on their rates of H2O2 production and lipid and protein oxidative damage.</strong>
            Herrero A, Portero-Otin M, Bellmunt MJ, Pamplona R, Barja G. "Previous comparative studies have shown that
            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."
        </p>
        <p>
            Biochem J. 1994 May 15;300 ( Pt 1):251-5. <strong>Regulation of fibrinolysis by non-esterified fatty
                acids.</strong> Higazi AA, Aziza R, Samara AA, Mayer M. "<strong>Examination of the fatty acid
                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."
            </strong>
        </p>
        <p>
            Science. 1976 Feb 27;191(4229):861-2. <strong>Nicotinic acid reduction of plasma volume loss after thermal
                trauma.</strong> 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.
        </p>

        <p>
            Z Gesamte Inn Med. 1976 Oct 15;31(20):838-43. <strong>[Age-dependence of catecholamine effects in man. IV.
                Effects of specific inhibitors on the lipolytic action of alpha and beta adrenergics]</strong> [in
            German] Hoffmann H.
        </p>
        <p>
            Neurochem Res. 2000 Feb;25(2):269-76. <strong>Cortical impact injury in rats promotes a rapid and sustained
                increase in polyunsaturated free fatty acids and diacylglycerols.</strong> Homayoun P, Parkins NE,
            Soblosky J, Carey ME, Rodriguez de Turco EB, Bazan NG.<strong> </strong>"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<strong>
                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."</strong>
        </p>
        <p>
            Thromb Res. 1989 Jan 1;53(1):45-53. <strong>Normalization by dietary cod-liver oil of reduced thrombogenesis
                in essential fatty acid deficient rats.</strong>
            Hornstra G, Haddeman E, Don JA.
        </p>
        <p>
            Radiographics. 2003 Nov-Dec;23(6):1561-7. <strong>CT Findings in Sclerosing Mesenteritis (Panniculitis):
                Spectrum of Disease.</strong> Horton KM, Lawler LP, Fishman EK.
        </p>
        <p>
            Nutr Cancer. 1985;7(4):199-209. <strong>Isomeric fatty acids and tumorigenesis: a commentary on recent
                work.</strong> 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<strong>
                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.</strong>"
        </p>

        <p>
            Medicina (B Aires). 1978 Mar-Apr;38(2):215. <strong>[Progesterone and retroperitoneal fibrosis]</strong> [in
            Spanish] Introzzi A.[Letter]
        </p>
        <p>
            Cancer Res. 1985 May;45(5):1997-2001. <strong>Requirement of essential fatty acid for mammary tumorigenesis
                in the rat.</strong> Ip C, Carter CA, Ip MM. "<strong>Mammary tumorigenesis was very sensitive to
                linoleate intake and increased proportionately in the range of 0.5 to 4.4% of dietary
                linoleate."</strong>
        </p>
        <p>
            Biochim Biophys Acta. 1984 Nov 6;802(1):17-23.<strong>
                Activation of bovine platelets induced by long-chain unsaturated fatty acids at just below their lytic
                concentrations, and its mechanism.</strong> Kitagawa S, Endo J, Kametani F.
        </p>

        <p>
            Clin Exp Metastasis 2000;18(5):371-7. <strong>Promotion of colon cancer metastases in rat liver by fish oil
                diet is not due to reduced stroma formation.</strong>
            Klieveri L, Fehres O, Griffini P, Van Noorden CJ, Frederiks WM. <strong>
                "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."</strong>
        </p>
        <p>
            Folia Haematol Int Mag Klin Morphol Blutforsch. 1977;104(1):1-10. <strong>[Review: hemorrhagic diathesis
                resulting from acute exposure to ionizing Radiation]</strong>
            [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.
        </p>
        <p>
            Prostaglandins. 1978 Apr;15(4):557-64. <strong>Prostaglandin I2 as a potentiator of acute inflammation in
                rats.</strong> Komoriya K, Ohmori H, Azuma A, Kurozumi S, Hashimoto Y, Nicolaou KC, Barnette WE, Magolda
            RL.
        </p>
        <p>
            Gerontology 1993;39(1):7-18. <strong>Modulation of membrane phospholipid fatty acid composition by age and
                food restriction.</strong> 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." <strong>"The data revealed characteristic patterns of
                age-related changes in ad libitum (AL) fed rats:</strong>
            <strong>
                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.</strong>" "<strong>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.</strong>"
        </p>
        <p>
            Medicina (B Aires). 1978 Mar-Apr;38(2):123-32. <strong>[Effective treatment of several types of fibromatosis
                with progesterone. Fibrous mediastinitis, desmoid tumors, paraneoplastic fibrosis]</strong> [in Spanish]
            Lanari A, Molinas FC, Castro Rios M, Paz RA.
        </p>

        <p>
            Medicina (B Aires). 1979 Nov-Dec;39(6):826-35. <strong>[Progesterone in fibromatosis and
                atherosclerosis]</strong> [in Spanish] Lanari A.
        </p>
        <p>
            Free Radic Biol Med 1999 Feb;26(3-4):260-5. <strong>Modulation of cardiac mitochondrial membrane fluidity by
                age and calorie intake.</strong> Lee J, Yu BP, Herlihy JT. <strong>"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."</strong> "Considered together, these results suggest that DR <strong>maintains the
                integrity of the cardiac mitochondrial membrane fluidity by minimizing membrane damage through
                modulation of membrane fatty acid profile."</strong>
        </p>
        <p>
            Lipids 2001 Jun;36(6):589-93. <strong>
                Effect of dietary restriction on age-related increase of liver susceptibility to peroxidation in
                rats.</strong> Leon TI, Lim BO, Yu BP, Lim Y, Jeon EJ, Park DK.
        </p>
        <p>
            Acta Chir Scand. 1976;142(1):20-5. <strong>Induction of endogenous fibrinolysis inhibition in the dog.
                Effect of intravascular coagulation and release of free fatty acids.</strong> 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 <strong>
                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.</strong> 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."
        </p>

        <p>
            Proc Natl Acad Sci U S A 1990 Nov;87(22):8845-9. <strong>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.</strong>
            Malis CD, Weber PC, Leaf A, Bonventre JV.
        </p>
        <p>
            Prostaglandins Leukot Essent Fatty Acids 1994 Jul;51(1):33-40.<strong>
                Suppression of human T-cell growth in vitro by cis-unsaturated fatty acids: relationship to free
                radicals and lipid peroxidation.</strong> Madhavi N, Das UN, Prabha PS, Kumar GS, Koratkar R, Sagar PS.
        </p>
        <p>
            Clin Exp Metastasis 1998 Jul;16(5):407-14.<strong>
                Diminution of the development of experimental metastases produced by murine metastatic lines in
                essential fatty acid-deficient host mice.</strong> Mannini A, Calorini L, Mugnai G, Ruggieri S.
        </p>
        <p>
            Biochem Pharmacol. 1990 Mar 1;39(5):879-89. <strong>Histamine release from rat mast cells induced by
                metabolic activation of polyunsaturated fatty acids into free radicals.</strong> Masini E, Palmerani B,
            Gambassi F, Pistelli A, Giannella E, Occupati B, Ciuffi M, Sacchi TB, Mannaioni PF.
        </p>
        <p>
            Journal of Lipid Research, Vol. 44, 271-279, February 2003. <strong>Arachidonic acid and prostacyclin
                signaling promote adipose tissue development : a human health concern?</strong>
            F. Massiera, P. Saint-Marc, J. Seydoux , T. Murata , T. Kobayashi , S. Narumiya , P. Guesnet, Ez-Zoubir
            Amri, R. Negrel and G. Ailhaud1.
        </p>
        <p>
            Infection. 1994 Mar-Apr;22(2):106-12. <strong>Influence of dietary (n-3)-polyunsaturated fatty acids on
                leukotriene B4 and prostaglandin E2 synthesis and course of experimental tuberculosis in guinea
                pigs.</strong> Mayatepek E, Paul K, Leichsenring M, Pfisterer M, Wagner D, Domann M, Sonntag HG, Bremer
            HJ.
        </p>

        <p>
            Biochim Biophys Acta 1994 Sep 15;1214(2):209-20. <strong>Reinvestigation of lipid peroxidation of linolenic
                acid.</strong> 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."
        </p>
        <p>
            Prostaglandins Leukot Essent Fatty Acids. 2003 May;68(5):305-10. <strong>Synergistic effect of D-003 and
                aspirin on experimental thrombosis models.</strong> Molina V, Arruzazabala ML, Carbajal D, Mas R.
        </p>
        <p>
            Chem Res Toxicol. 2001 Apr;14(4):431-7. <strong>Defining mechanisms of toxicity for linoleic acid
                monoepoxides and diols in Sf-21 cells.</strong> Moran JH, Mon T, Hendrickson TL, Mitchell LA, Grant DF.
        </p>

        <p>
            J Biochem (Tokyo). 1977 Aug;82(2):529-33. <strong>Effects of free fatty acids on fibrinolytic
                activity.</strong> 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<strong>
                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.</strong>
        </p>
        <p>
            Alcohol Clin Exp Res. 1986 Jun;10(3):271-3. <strong>Dietary factors and alcoholic cirrhosis.</strong> Nanji
            AA, French SW.
        </p>
        <p>
            Gastroenterology. 1995 Aug;109(2):547-54. <strong>Dietary saturated fatty acids: a novel treatment for
                alcoholic liver disease.
            </strong>

            Nanji AA, Sadrzadeh SM, Yang EK, Fogt F, Meydani M, Dannenberg AJ.
        </p>
        <p>
            J Pharmacol Exp Ther. 1996 Jun;277(3):1694-700. <strong>Medium chain triglycerides and vitamin E reduce the
                severity of established experimental alcoholic liver disease.</strong> Nanji AA, Yang EK, Fogt F,
            Sadrzadeh SM, Dannenberg AJ.
        </p>
        <p>
            Hepatology. 1997 Dec;26(6):1538-45.<strong>
                Dietary saturated fatty acids down-regulate cyclooxygenase-2 and tumor necrosis factor alfa and reverse
                fibrosis in alcohol-induced liver disease in the rat.</strong> Nanji AA, Zakim D, Rahemtulla A, Daly T,
            Miao L, Zhao S, Khwaja S, Tahan SR, Dannenberg AJ.
        </p>

        <p>
            J Pharmacol Exp Ther. 2001 Nov;299(2):638-44. <strong>
                Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued
                ethanol administration.</strong> Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ.
        </p>
        <p>
            Gastroenterology 1995 Apr;108(4):1124-35.<strong>
                Accumulation and cellular localization of fibrinogen/fibrin during short-term and long-term rat liver
                injury.</strong>
            Neubauer K, Knittel T, Armbrust T, Ramadori G "<strong>Fibrinogen/fibrin deposition in damaged livers was
                studied by immunohistology."
            </strong>
            "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."
        </p>
        <p>
            Ophthalmic Res. 1999;31(4):273-9. <strong>Age-related accumulation of free polyunsaturated fatty acids in
                human retina.</strong> Nourooz-Zadeh J, Pereira P.
        </p>
        <p>
            Chem Res Toxicol. 2002 Mar;15(3):367-72. <strong>Formation of cyclic deoxyguanosine adducts from omega-3 and
                omega-6 polyunsaturated fatty acids under oxidative conditions.</strong> Pan J, Chung FL.
        </p>
        <p>
            Radiobiologiia. 1985 Nov-Dec;25(6):763-7. <strong>[Mechanism of circulatory disorders in animals irradiated
                at high doses]</strong> [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. <strong>The signs of disseminated intravascular
                blood coagulation have been revealed.</strong>
        </p>
        <p>
            J Biol Chem. 1998 May 29;273(22):13605-12. <strong>Formation of isoprostane-like compounds (neuroprostanes)
                in vivo from docosahexaenoic acid.</strong> Roberts LJ 2nd, Montine TJ, Markesbery WR, Tapper AR, Hardy
            P, Chemtob S, Dettbarn WD, Morrow JD.
        </p>
        <p>
            Nutr Cancer 1995;24(1):33-45.<strong>
                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.</strong> Rose DP, Connolly JM,
            Liu XH
        </p>
        <p>
            Arch Toxicol. 1997;71(9):563-74.<strong>
                Impaired cellular immune response in rats exposed perinatally to Baltic Sea herring oil or
                2,3,7,8-TCDD.</strong>

            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.
        </p>
        <p>
            Nutr Cancer 1998;30(2):137-43. <strong>
                Effects of dietary n-3-to-n-6 polyunsaturated fatty acid ratio on mammary carcinogenesis in rats.
            </strong>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. <strong>
                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.</strong>"
        </p>
        <p>
            J. Biol. Chem. 1940 132: 539-551.<strong> Essential fatty acids, vitamin B</strong>
            <sub><strong>6</strong></sub>
            <strong>, and other factors in the cure of rat acrodynia</strong>. H. Schneider, H. Steenbock, and Blanche
            R. Platz
        </p>

        <p>
            Science. 1988 May 20;240(4855):1032-3. <strong>Essential fatty acid depletion of renal allografts and
                prevention of rejection.</strong> Schreiner GF, Flye W, Brunt E, Korber K, Lefkowith JB.
        </p>
        <p>
            Physiol Bohemoslov. 1990;39(2):125-34.<strong>
                Proportion of individual fatty acids in the non-esterified (free) fatty acid (FFA) fraction in the serum
                of laboratory rats of different ages.</strong> Smidova L, Base J, Mourek J, Cechova I.
        </p>
        <p>
            Placenta. 2003 Nov;24(10):965-73. <strong>Augmented PLA(2)Activity in Pre-eclamptic Decidual Tissue-A Key
                Player in the Pathophysiology of 'Acute Atherosis' in Pre-eclampsia?</strong> Staff AC, Ranheim T,
            Halvorsen B.
        </p>
        <p>
            Acta Neurochir Suppl (Wien) 1994;60:20-3<strong>. Mechanisms of glial swelling by arachidonic acid.</strong>
            Staub F, Winkler A, Peters J, Kempski O, Baethmann A.
        </p>
        <p>
            Arch Biochem Biophys. 1991 Aug 15;289(1):33-8. <strong>A possible mechanism of mitochondrial dysfunction
                during cerebral ischemia: inhibition of mitochondrial respiration activity by arachidonic acid.
            </strong>
            Takeuchi Y, Morii H, Tamura M, Hayaishi O, Watanabe Y.
        </p>
        <p>
            J Drug Target. 2003 Jan;11(1):45-52.<strong>
                Modulation of tumor-selective vascular blood flow and extravasation by the stable prostaglandin 12
                analogue beraprost sodium.</strong> Tanaka S, Akaike T, Wu J, Fang J, Sawa T, Ogawa M, Beppu T, Maeda H.
        </p>
        <p>
            Am J Clin Nutr. 2003 May;77(5):1125-32. <strong>Effect of individual dietary fatty acids on postprandial
                activation of blood coagulation factor VII and fibrinolysis in healthy young men.</strong> Tholstrup T,
            Miller GJ, Bysted A, Sandstrom B.
        </p>
        <p>
            Biochem Soc Trans. 2003 Oct;31(Pt 5):1075-9. <strong>Regression of pre-established atherosclerosis in the
                apoE-/- mouse by conjugated linoleic acid.</strong>

            Toomey S, Roche H, Fitzgerald D, Belton O.
        </p>
        <p>
            Int J Biochem Cell Biol. 2003 May;35(5):749-55. <strong>Increased muscle proteasome activities in rats fed a
                polyunsaturated fatty acid supplemented diet.</strong> 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."
        </p>
        <p>
            J Am Coll Nutr. 2000 Aug;19(4):478S-486S. <strong>Conjugated linoleic acid and bone biology.</strong>
            Watkins BA, Seifert MF. "Recent investigations with<strong> </strong>growing rats given butter fat and
            supplements of CLA demonstrated an increased rate of bone formation and reduced ex vivo bone PGE2
            production, respectively."
        </p>

        <p>
            Ups J Med Sci. 1979;84(3):195-201. <strong>Effect of nicotinic acid on the posttraumatic increase in free
                fatty acids and fibrinolysis inhibition activity in the rat.</strong> 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.
        </p>
        <p>
            Am J Physiol Regul Integr Comp Physiol. 2001 Mar;280(3):R908-12. <strong>CLA reduces antigen-induced
                histamine and PGE(2) release from sensitized guinea pig tracheae.</strong> Whigham LD, Cook EB, Stahl
            JL, Saban R, Bjorling DE, Pariza MW, Cook ME.
        </p>
        <p>
            Toxicol Appl Pharmacol 1993 May;120(1):72-9.<strong>
                Essential fatty acid deficiency in cultured human keratinocytes attenuates toxicity due to lipid
                peroxidation.</strong>

            Wey HE, Pyron L, Woolery M.
        </p>
        <p>
            Nutrition. 2002 Jul-Aug;18(7-8):647-53. <strong>Dietary fat composition alters pulmonary function in
                pigs.</strong> Wolfe RR, Martini WZ, Irtun O, Hawkins HK, Barrow RE. © Ray Peat Ph.D. 2009. All Rights
            Reserved. www.RayPeat.com
        </p>
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    <head><title>The Great Fish Oil Experiment</title></head>
    <body>
        <h1>
            The Great Fish Oil Experiment
        </h1>

        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
        <em>("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)")</em> 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. <hr />
        <hr />
        <hr />

        "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&amp;H Foods. Although the dollar amount of the contract between Omega Protein and H&amp;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

        <hr />
        <hr />
        <hr />

        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.<p></p>

        <p>
            <em>*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"
            </em>
            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."

            <strong><em> </em></strong>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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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).
        </p>
        <p>
            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).
        </p>

        <p>
            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 <strong><em>oxidized</em></strong> 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<strong> </strong>of the
            rabbit experiments now seem very different.
        </p>
        <p>
            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.
        </p>
        <p>
            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).
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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<strong> </strong>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).
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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).
        </p>
        <p>
            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).
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            In Woody Allen's 1973 movie, <strong><em>Sleeper,</em></strong> 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<em>
                Present Knowledge in Nutrition</em>, 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.
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            Sep;16(9):983-9. <strong>Release of arachidonic acid by NMDA-receptor activation in the rat
                hippocampus.</strong> Pellerin L, Wolfe LS. Biochim Biophys Acta. 2001 Feb 14;1535(2):145-52. <strong
            >Acrolein inhibits respiration in isolated brain mitochondria.
            </strong>
            Picklo MJ, Montine TJ. Neurochem Res. 1994 Jan;19(1):57-63. <strong>Inhibition of bioenergetics alters
                intracellular calcium, membrane composition, and fluidity in a neuronal cell line.</strong> Ray P, Ray
            R, Broomfield CA, Berman JD. Neurobiol Aging. 2005 Apr;26(4):465-74. <strong>Immunochemical crossreactivity
                of antibodies specific for "advanced glycation endproducts" with "advanced lipoxidation
                endproducts".</strong> 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. <strong>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.</strong> 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. <strong>Enhanced level of n-3
                fatty acid in membrane phospholipids induces lipid peroxidation in rats fed dietary docosahexaenoic acid
                oil.</strong> Song JH, Miyazawa T. Neurochem Res. 1995 Dec;20(12):1417-27. <strong>Free radical-induced
                endothelial membrane dysfunction at the site of blood-brain barrier: relationship between lipid
                peroxidation, Na,K-ATPase activity, and 51Cr release.</strong>
            Stanimirovic DB, Wong J, Ball R, Durkin JP. Atherosclerosis, November 1997, vol. 135, no. 1, pp.
            1-7(7<strong>) Oxidized Cholesterol in the Diet Accelerates the Development of Atherosclerosis in LDL
                Receptor and Apolipoprotein EDeficient Mice</strong>
            <em>. </em>

            Staprans, I; Pan, X-M; Rapp, JH; Grunfeld, C; Feingold, KR. J Neurosci Res. 2001 Sep 15;65(6):565-72.<strong
            >
                Involvement of the 5-lipoxygenase pathway in the neurotoxicity of the prion peptide PrP106-126.</strong>
            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. <strong>(n-3) Polyunsaturated fatty acids promote activation-induced
                cell death in murine T lymphocytes.</strong> Switzer KC, McMurray DN, Morris JS, Chapkin RS. Arch
            Biochem Biophys. 1995 Oct 20;323(1):97-107. <strong>Effect of linoleic acid hydroperoxide on endothelial
                cell calcium homeostasis and phospholipid hydrolysis.</strong> Sweetman LL, Zhang NY, Peterson H,
            Gopalakrishna R, Sevanian A. Biosci Biotechnol Biochem. 1997 Dec;61(12):2085-8. <strong>Oxidative stability
                of docosahexaenoic acid-containing oils in the form of phospholipids, triacylglycerols, and ethyl
                esters.</strong> Song JH, Inoue Y, Miyazawa T. J Nutr. 2000 Dec;130(12):3028-33. <strong>Polyunsaturated
                (n-3) fatty acids susceptible to peroxidation are increased in plasma and tissue lipids of rats fed
                docosahexaenoic acid-containing oils.</strong> Song JH, Fujimoto K, Miyazawa T. Atherosclerosis. 2001
            Mar;155(1):9-18. <strong>Enhanced level of n-3 fatty acid in membrane phospholipids induces lipid
                peroxidation in rats fed dietary docosahexaenoic acid oil.</strong> Song JH, Miyazawa T. Clin Exp
            Allergy. 2004 Feb;34(2):194-200. <strong>Maternal breast milk long-chain n-3 fatty acids are associated with
                increased risk of atopy in breastfed infants.</strong> Stoney RM, Woods RK, Hosking CS, Hill DJ,
            Abramson MJ, Thien FC. Free Radic Res. 2001 Apr;34(4):427-35. <strong>Docosahexaenoic acid
                supplementation-increased oxidative damage in bone marrow DNA in aged rats and its relation to
                antioxidant vitamins.</strong> Umegaki K, Hashimoto M, Yamasaki H, Fujii Y, Yoshimura M, Sugisawa A,
            Shinozuka K. J Neurochem 1986 Oct;47(4):1181-9. <strong>Effects of arachidonic acid on glutamate and
                gamma-aminobutyric acid uptake in primary cultures of rat cerebral cortical astrocytes and
                neurons.</strong> Yu AC, Chan PH, Fishman RA.
        </p>

        © Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com
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    <head><title>Gelatin, stress, longevity</title></head>
    <body>
        <h1>
            Gelatin, stress, longevity
        </h1>

        <p>
            <hr />
            <hr />
        </p>
        <p>
            <strong>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.</strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>
        <p>
            <strong>Other amino acids act as nerve-modifiers ("transmitters"), causing, for example, excitation or
                inhibition.</strong>
        </p>
        <p>
            <strong>Some of these amino acids, such as glycine, have a very broad range of cell-protective
                actions.</strong>
        </p>

        <p>
            <strong>Their physical properties, rather than their use for production of energy or other metabolic
                function, are responsible for their important cytoprotective actions.</strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>
        <p>
            <strong>The degenerative and inflammatory diseases can often be corrected by the use of gelatin-rich foods.
            </strong>
        </p>
        <p>
            <hr />
            <hr />
        </p>
        <p>
            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.
        </p>
        <p>
            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").
        </p>
        <p>
            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.
        </p>
        <p>
            But still, the emphasis was on the match between a specific chemical and the <strong><em>genetic
                    constitution</em></strong> 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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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. <strong>
                Restricting only tryptophan, or only cysteine, produces a greater extension of the life span than
                achieved in most of the studies of caloric restriction.</strong>
            How great would be the life-span extension if both tryptophan and cysteine were restricted at the same time?
        </p>

        <p>
            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<strong>; </strong>
            would the restriction of histidine in the diet have a longevity promoting effect, too?
        </p>
        <p>
            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.
        </p>
        <p>
            The main amino acids in gelatin are glycine and proline<strong>; </strong>
            alanine is also present in significant quantity. Glycine and proline are responsible for the unusual fibrous
            property of collagen.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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<strong>;</strong>
            unfortunately, results of this sort haven't led researchers to question the idea of "balance" that developed
            within the setting of agricultural research.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            One of estrogen's "excitatory" effects is to cause lipolysis, the release of fatty acids from storage
            fat<strong>; </strong>
            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."
        </p>
        <p>
            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).
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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<strong>;</strong> Soderwall observed that estrogen caused enlargement of the
            adrenals, sometimes with hemorrhage and necrosis<strong>;</strong> 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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p><strong> </strong></p>
        <p>
            <strong><h3>REFERENCES</h3></strong>
        </p>
        <p>
            Am J Physiol. 1990 Jul;259(1 Pt 2):F80-7. <strong>Mechanisms of perfused kidney cytoprotection by alanine
                and glycine.</strong> Baines AD, Shaikh N, Ho P.
        </p>
        <p>
            Neurol. 1974; 24:392. <strong>Preliminary study of glycine administration in patients with
                spasticity.</strong> Barbeau A.
        </p>

        <p>
            Virchows Arch B Cell Pathol Incl Mol Pathol. 1981;36(2-3):195-206. <strong>Peliosis of the female adrenal
                cortex of the aging rat.</strong> 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.
            <strong>This lesion occurs almost exclusively in female animals and was seen in only one of 50 male animals
                older than 600 days examined.</strong> 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 <strong>constant estrus in aging female rats
                will be discussed.</strong>
        </p>
        <p>
            Riv Neurol. 1976 Mar-Jun;46(3):254-61.<strong>
                [Antagonism between focal epilepsy and taurine administered by cortical Perfusion]</strong> 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, <strong>suggests the hypothesis of
                a taurine direct inhibitory action against Premarin focus</strong> and, on the contrary, a mediated
            action towards the cobalt's. The latter might be related to the metabolic production of some taurine
            derivative.
        </p>

        <p>
            Ann Neurol. 1998; 44:261-265. <strong>Beneficial effects of L-serine and glycine in the management of
                seizures in 3-phosphoglycerate dehydrogenase deficiency.</strong> de Kooning JT, Duran M, Dorling L, et
            al.
        </p>
        <p>
            Arch Gen Psychiatry. 1999; 56:29-36.<strong>
                Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia.</strong>
            Heresco-Levy U, Javitt DC, Ermilov M, et al.
        </p>
        <p>
            Free Radic Biol Med. 2001 Nov 15;31(10):1236-44. <strong>Dietary glycine inhibits activation of nuclear
                factor kappa B and prevents liver injury in hemorrhagic shock in the rat.</strong> Mauriz JL, Matilla B,
            Culebras JM, Gonzalez P, Gonzalez-Gallego J. "Feeding the rats glycine significantly reduced mortality, the
            elevation of plasma<strong> </strong>

            transaminase levels and hepatic necrosis. <strong>The increase in plasma TNFalpha and nitric oxide (NO) was
                also blunted by glycine feeding."</strong>
        </p>
        <p>
            Am Fam Phys 1979 May;19(5):77-86. <strong>
                'Not Cushing's syndrome'.</strong> 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 <strong>capillary fragility.</strong> 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.
        </p>

        <p>
            Carcinogenesis. 1999; 20:2075-2081. <strong>Dietary glycine prevents the development of liver tumors caused
                by the peroxisome proliferator WY-14, 643</strong>. Rose ML, Cattley RC, Dunn C, et al.
        </p>
        <p>
            Carcinogenesis, Vol. 20, No. 5, 793-798, May 1999.<strong>
                Dietary glycine inhibits the growth of B16 melanoma tumors in mice.</strong>
            <hr />
        </p>
        <p>
            Carcinogenesis, Vol. 20, No. 11, 2075-2081, November 1999. <strong>Dietary glycine prevents the development
                of liver tumors caused by the peroxisome proliferator WY-14,643.</strong> 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. <strong>The
                influence of glycine and related compounds on spinal cord injury-related spasticity.</strong>

            Neurochem Res. 1995; 20:1203-1210.
        </p>
        <p>
            Neurochem Res. 1995 Oct;20(10):1203-10. <strong>
                The influence of glycine and related compounds on spinal cord injury-induced spasticity.</strong>
            Simpson RK Jr, Gondo M, Robertson CS, Goodman JC.
        </p>
        <p>
            Neurochem Res. 1996 Oct;21(10):1221-6. <strong>Reduction in the mechanonociceptive response by intrathecal
                administration of glycine and related compounds.</strong>
            Simpson RK Jr, Gondo M, Robertson CS, Goodman JC.
        </p>
        <p>
            Neurol Res. 1998 Mar;20(2):161-8. <strong>Glycine receptor reduction within segmental gray matter in a rat
                model in neuropathic pain.</strong> Simpson RK Jr, Huang W.
        </p>

        <p>
            Neurol Res. 2000 Mar;22(2):160-4. <strong>Long-term intrathecal administration of glycine prevents
                mechanical hyperalgesia in a rat model of neuropathic pain.
            </strong>Huang W, Simpson RK.
        </p>
        <p>
            Pharmacol Biochem Behav. 1992 Nov;43(3):669-71. <strong>Branched-chain amino acids increase the seizure
                threshold to picrotoxin in rats.</strong> Skeie B, Petersen AJ, Manner T, Askanazi J, Jellum E, Steen
            PA.
        </p>
        <p>
            Thromb Diath Haemorrh Suppl 1968;30:165-9<strong> [Purpura of the premenstrum and climacteric]. </strong>
            [Article in German]<strong> </strong>Stamm H.
        </p>

        <p>
            Toth E, Lajtha A. <strong>Glycine potentiates the action of some anticonvulsant drugs in some seizure
                models.</strong> Neurochem Res. 1984; 9:1711-1718.
        </p>
        <p>
            Sheng Li Ke Xue Jin Zhan. 2000 Jul;31(3):231-3. <strong>
                [The roles of estrogen and progestin in epileptogenesis and their mechanisms of action]</strong>
            [Article in Chinese] Wang Q.
        </p>
        <p>
            FASEB J. 2000; 14:476-484.<strong>
                Glycine-gated channels in neutrophils attenuate calcium influx and superoxide production.</strong>
            Wheeler M, Stachlewitz RT, Yamashina S, et al.
        </p>

        <p>
            Cell Mol Life Sci.1999; 56:843-856. <strong>Glycine: a new anti-inflammatory immunonutrient.</strong>
            Wheeler MD, Ikejema K, Mol Life Sci. Enomoto N, et al.
        </p>
        <p>
            Nutr Cancer. 2001;40(2):197-204. <strong>Endothelial cells contain a glycine-gated chloride channel.</strong
            > Yamashina S, Konno A, Wheeler MD, Rusyn I, Rusyn EV, Cox AD, Thurman RG. "<strong>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.</strong>
        </p>
        <p>
            Biull Eksp Biol Med. 1981 Nov;92(11):599-601. <strong>[Repair processes in wound tissues of experimental
                animals following administration of glycine]
            </strong>
            [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.
        </p>

        <p>
            <strong>"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."
            </strong>
        </p>
        <p>
            <strong> </strong>
            Zhong Z, Wheeler MD, Li X, Froh M, Schemmer P, Yin M, Bunzendaul H, Bradford B, Lemasters JJ.<strong>,
            </strong>"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
        </p>
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        <h1></h1>

        <p>
            <strong>
                Genes, Carbon Dioxide and Adaptation</strong>
        </p>
        <p>
            <em>"Over the oxygen supply of the body carbon dioxide spreads its protecting wings." - Friedrich Miescher,
                Swiss physiologist, 1885</em>
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p><h3>REFERENCES</h3></p>
        <strong>O. Rahn, "Protozoa need carbon dioxide for growth," Growth 5, 197-199, 1941. "</strong>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."<strong>Y. Henderson, "Carbon Dioxide," Cyclopedia of
            Medicine, 1940. "</strong>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."<span style="font-size: 14px"><strong>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 IG</strong
            ></span>Carbon 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.<strong>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 MV</strong>Functional 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.<strong>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 S</strong>Studies 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.<strong>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 MA</strong>Cooling 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.<strong>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 EN</strong>In 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.<strong>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 MA</strong>In 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.<p>
            <a href="http://www.members.westnet.com.au/pkolb/buteyko.htm" target="_blank"><span
                    style="text-decoration: underline; color: #033aee"
                >ASTHMA: Buteyko's Cure.</span></a>
        </p>
        <p>
            © Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com
        </p>
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        <p>
            <strong>
                Glucose and sucrose for diabetes</strong>
        </p>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<strong>: </strong>"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.<u> </u>(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. <span style="white-space: pre-wrap"> </span>
        <h3>REFERENCES</h3>Ann Nutr Aliment. 1975;29(4):305-12. <strong>[Effects of administering diets with starch or
            sucrose basis on certain parameters of calcium metabolism in the young, growing rat]</strong> Artus
        M.Diabetes Metab. 2008 Oct 24. <strong>The growing incidence of type 1 diabetes in children: The 17-year French
            experience in Aquitaine.</strong> Barat P, Valade A, Brosselin P, Alberti C, Maurice-Tison S, L"vy-Marchal
        C.Pancreas. 1995 Jul;11(1):26-37. <strong>Essential fatty acid deficiency prevents autoimmune diabetes in
            nonobese diabetic mice through a positive impact on antigen-presenting cells and Th2 lymphocytes.</strong>
        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. <strong>Effects of
            sucrose, caffeine, and cola beverages on obesity, cold resistance, and adipose tissue cellularity.</strong>
        Bukowiecki LJ, Lupien J, Foll"a N, Jahjah L.Cardiovasc Res. 2003 Jul 1;59(1):143-51. <strong>Partial inhibition
            of fatty acid oxidation increases regional contractile power and efficiency during demand-induced ischemia.
        </strong>Chandler MP, Chavez PN, McElfresh TA, Huang H, Harmon CS, Stanley WC.Med Sci (Paris). 2003
        Aug-Sep;19(8-9):827-33.<strong>
            [Contribution of free fatty acids to impairment of insulin secretion and action: mechanism of beta-cell
            lipotoxicity]</strong> [Article in French] Girard J.Diabetes Metab. 21(2), 79-88, 1995. <strong>Role of free
            fatty acids in insulin resistance of subjects with non-insulin-dependent diabetes,</strong> Girard J.
        "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.]Med Sci (Paris). 2005 Dec;21 Spec No:19-25.
        <strong>[Contribution of free fatty acids to impairment of insulin secretion and action. mechanism of beta-cell
            lipotoxicity]</strong> Girard J.Acta Diabetologica 32(1), 44-48, 1995.<strong>Effect of lipid oxidation on
            the regulation of glucose utilization in obese patients</strong>, 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. <strong
        >Suppressive effect of GABA on insulin secretion from the pancreatic beta-cells in the rat.</strong> Gu XH,
        Kurose T, Kato S, Masuda K, Tsuda K, Ishida H, Seino Y.Exp Clin Endocrinol 1989 May;93(2-3):225-30. <strong
        >Spontaneous recovery of streptozotocin diabetes in mice.</strong> Hartmann K, Besch W, Zuhlke H.Proc. Nat.
        Acad. Sci. USA 92(8), 3096-3099, 1995. <strong>High fat diet-induced hyperglycemia: Prevention by low level
            expression of a glucose transporter (GLUT4) minigene in transgenic mice</strong>. Ikemoto S, et al. "...mice
        fed a high-fat (safflower oil) diet develop defective glycemic control, hyperglycemia, and obesity."
        Biochemistry (Mosc). 2008 Feb;73(2):149-55.<strong>
            Mitochondrial free radical production induced by glucose deprivation in cerebellar granule neurons.</strong>
        Isaev NK, Stelmashook EV, Dirnagl U, Plotnikov EY, Kuvshinova EA, Zorov DB.J Pharmacol Exp Ther. 2008
        Feb;324(2):850-7. <strong>Investigation of the mechanisms involved in the high-dose and long-term acetyl
            salicylic acid therapy of type I diabetic rats.</strong> Jafarnejad A, Bathaie SZ, Nakhjavani M, Hassan
        MZ.Am J Physiol Endocrinol Metab. 2008 Apr;294(4):E679-87. <strong>Enhanced beta-cell mass without increased
            proliferation following chronic mild glucose infusion.</strong> Jetton TL, Everill B, Lausier J, Roskens V,
        Habibovic A, LaRock K, Gokin A, Peshavaria M, Leahy JL.World J Surg. 2001 Feb;25(2):142-6. <strong>Effect of
            sucrose on collagen metabolism in keloid, hypertrophic scar, and granulation tissue fibroblast
            cultures.</strong> K"ssi J, V"h"-Kreula M, Peltonen J, Risteli J, Laato M.Clin Endocrinol (Oxf). 1994
        Jan;40(1):47-53. <strong>Impaired glucose tolerance and insulin insensitivity in primary
            hyperparathyroidism.</strong> Kumar S, Olukoga AO, Gordon C, Mawer EB, France M, Hosker JP, Davies M,
        Boulton AJ.Diabetes 44(6), 718-720, 1995. <strong>Amelioration of high fat feeding-induced insulin resistance in
            skeletal muscle with the antiglucocorticoid RU486.</strong> Kusunoki M, et al. "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."Osteoporos Int. 2008 Sep 30. <strong>High prevalence of vitamin K and D
            deficiency and decreased BMD in inflammatory bowel disease.</strong> Kuwabara A, Tanaka K, Tsugawa N, Nakase
        H, Tsuji H, Shide K, Kamao M, Chiba T, Inagaki N, Okano T, Kido S.Am J Physiol Cell Physiol. 2008
        Jun;294(6):C1542-51. <strong>Octylphenol stimulates resistin gene expression in 3T3-L1 adipocytes via the
            estrogen receptor and extracellular signal-regulated kinase pathways.
        </strong>Lee MJ, Lin H, Liu CW, Wu MH, Liao WJ, Chang HH, Ku HC, Chien YS, Ding WH, Kao YH.J Immunol 1990 Sep
        1;145(5):1523-9, <strong>Manipulation of the acute inflammatory response by dietary polyunsaturated fatty acid
            modulation,</strong>Lefkowith JB, Morrison A, Lee V, Rogers M.Rev Alerg Mex. 2006 Nov-Dec;53(6):212-6.
        <strong>Effect of glycine on the immune response of the experimentally diabetic rats.</strong> Lezcano Meza D,
        Ter"n Ortiz L, Carvajal Sandoval G, Guti"rrez de la Cadena M, Ter"n Escand"n D, Estrada Parra S.Circ Shock 1990
        Jun;31(2):159-170, <strong>Resistance of essential fatty acid-deficient rats to endotoxin-induced increases in
            vascular permeability,</strong> Li EJ, Cook JA, Spicer KM, Wise WC, Rokach J, Halushka PV.Diabetologia. 2007
        Apr;50(4):764-73.<strong>
            Regulation of pancreatic islet cell survival and replication by gamma-aminobutyric acid.
        </strong>Ligon B, Yang J, Morin SB, Ruberti MF, Steer ML.Horm Res. 2001;55(2):81-7. <strong>Decreased levels of
            ionized calcium one year after hemithyroidectomy: importance of reduced thyroid hormones.</strong> Lindblom
        P, Valdemarsson S, Linderg"rd B, Westerdahl J, Bergenfelz A.Am J Physiol. 1998 Sep;275(3 Pt 1):E392-9. <strong
        >Acute effects of triiodothyronine on glucose and fatty acid metabolism during reperfusion of ischemic rat
            hearts.</strong> Liu Q, Clanachan AS, Lopaschuk GD.J Biol Chem. 2005 May 27;280(21):20389-96. <strong
        >Glucose suppresses superoxide generation in metabolically responsive pancreatic beta cells.</strong>Martens GA,
        Cai Y, Hinke S, Stang" G, Van de Casteele M, Pipeleers D.Diabet Med. 1998;15 Suppl 4:S60-2. <strong>Accelerated
            complications in Type 2 diabetes mellitus: the need for greater awareness and earlier detection.</strong>
        Muggeo M. "Persistent hyperglycaemia is the underlying pathogenic factor responsible for chronic diabetic
        complications in Type 1 and Type 2 diabetes mellitus."Eur J Pediatr. 2006 Aug;165(8):540-5. <strong>The effect
            of vitamin K supplementation on biochemical markers of bone formation in children and adolescents with
            cystic fibrosis.</strong> Nicolaidou P, Stavrinadis I, Loukou I, Papadopoulou A, Georgouli H, Douros K,
        Priftis KN, Gourgiotis D, Matsinos YG, Doudounakis S.Metabolism. 2007 May;56(5):599-607. <strong>Long-term
            consumption of caffeine improves glucose homeostasis by enhancing insulinotropic action through islet
            insulin/insulin-like growth factor 1 signaling in diabetic rats.</strong> Park S, Jang JS, Hong
        SM.Cardiovasc Res. 2003 Oct 1;59(4):963-70.<strong>
            Reduction of endothelial NOS and bradykinin-induced extravasation of macromolecules in skeletal muscle of
            the fructose-fed rat model.</strong> Plante GE, Perreault M, Lanthier A, Marette A, Maheux P.Cell Physiol
        Biochem. 2007;20(1-4):213-26.<strong>
            Effect of lipid infusion on metabolism and force of rat skeletal muscles during intense
            contractions.</strong> Silveira L, Hirabara SM, Alberici LC, Lambertucci RH, Peres CM, Takahashi HK, Pettri
        A, Alba-Loureiro T, Luchessi AD, Cury-Boaventura MF, Vercesi AE, Curi R.Can J Physiol Pharmacol. 2002
        Dec;80(12):1203-7. <strong>Inhibitory effect of a novel bradykinin B1 receptor antagonist, R-954, on enhanced
            vascular permeability in type 1 diabetic mice.</strong> Simard B, Gabra BH, Sirois P.Obesity (Silver
        Spring). 2008 Oct 23. <strong>Changes in the Serum Composition of Free-fatty Acids During an Intravenous Glucose
            Tolerance Test.
        </strong>Soriguer F, Garc"a-Serrano S, Garc"a-Almeida JM, Garrido-S"nchez L, Garc"a-Arn"s J, Tinahones FJ,
        Cardona I, Rivas-Mar"n J, Gallego-Perales JL, Garc"a-Fuentes E.Biochim Biophys Acta. 2000 Sep
        27;1487(2-3):190-200. <strong>Augmented resistance to oxidative stress in fatty rat livers induced by a
            short-term sucrose-rich diet.</strong>Spolarics Z, Meyenhofer M.Gen Pharmacol. 1993 Jan;24(1):95-100.<strong
        >
            A possible mechanism for increased cerebrovascular permeability in diabetic rats: effects of insulin and
            2-deoxy-glucose.</strong> Uezu Y, Murakami K.Wound Repair Regen. 2008 Mar-Apr;16(2):288-93.<strong>
            Impaired wound healing in an acute diabetic pig model and the effects of local hyperglycemia.</strong>
        Velander P, Theopold C, Hirsch T, Bleiziffer O, Zuhaili B, Fossum M, Hoeller D, Gheerardyn R, Chen M, Visovatti
        S, Svensson H, Yao F, Eriksson E.Proc Natl Acad Sci U S A. 1988 Aug;85(16):6137-41. <strong>Essential fatty acid
            deficiency prevents multiple low-dose streptozotocin-induced diabetes in CD-1 mice.</strong>Wright JR Jr,
        Lefkowith JB, Schreiner G, Lacy PE.Endocrinology. 2008 Oct;149(10):5136-45. <strong>Inhibition of cholesterol
            biosynthesis impairs insulin secretion and voltage-gated calcium channel function in pancreatic beta-cells.
        </strong>Xia F, Xie L, Mihic A, Gao X, Chen Y, Gaisano HY, Tsushima RG.Science. 2001 Aug
        31;293(5535):1673-7.<strong>
            Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta.
        </strong>Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE.
        <p>
            © Ray Peat Ph.D. 2012. All Rights Reserved. www.RayPeat.com
        </p>
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        <h1></h1>
        <p></p>
        <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                    style="font-size: xx-large"
                ><span style="font-size: large"><blockquote>
                            <strong>Growth hormone: Hormone of Stress, Aging, &amp; Death?</strong>
                        </blockquote></span><span style="font-size: medium">
                        <blockquote>
                            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.
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: xx-medium"
                                    ><span style="font-size: medium"
                                        >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.</span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: xx-medium"
                                    ><span style="font-size: medium"
                                        >The osmoregulatory problem--keeping water under control--is centrally involved
                                            in stress.</span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: xx-medium"
                                    ><span style="font-size: medium"
                                        >In mammals, the kidneys and bowel are the main regulators of water
                                            balance.</span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: xx-medium"
                                    ><span style="font-size: medium"
                                        >GH is a stress hormone. Its effects can be produced osmotically, for example
                                            inducing milk production and cartilage growth, by osmotic (dilution)
                                            shock.</span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: xx-medium"
                                    ><span style="font-size: medium"
                                        >Estrogen produces increased GH, and increases its production in stress.</span
                                        ></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: xx-medium"
                                    ><span style="font-size: medium"
                                        >Nitric oxide is a pro-aging free radical induced by estrogen, releasing GH; all
                                            three produce edema.</span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: xx-medium"
                                    ><span style="font-size: medium"
                                        >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.</span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: xx-medium"
                                    ><span style="font-size: medium"
                                        >The absence of GH protects kidneys against degeneration. Osteoarthritis, a
                                            characteristic aging condition, is caused by estrogen and GH.</span></span
                                    ></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: xx-medium"
                                    ><span style="font-size: medium"
                                        >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.</span><span
                                            style="font-family: Lucida Grande"
                                        ><span style="font-size: medium"></span></span><span
                                            style="font-size: medium"
                                        ><hr /></span><span style="font-family: Lucida Grande"><span
                                                style="font-size: medium"
                                            ></span></span><span style="font-size: medium"
                                        >Bovine Growth Hormone is used to make cows give more milk.</span><span
                                            style="font-family: Lucida Grande"
                                        ><span style="font-size: medium"></span></span><span style="font-size: medium"
                                        >Human Growth Hormone is supposed to make men lean and muscular, not to increase
                                            their milk production.</span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    ><hr /><span style="font-family: Lucida Grande"></span>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.</span></span
                                ></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.</span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.*</span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >________________________________________________________________________________<span
                                            style="font-family: Lucida Grande"
                                        ></span>*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.</span></span
                                ></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span style="font-family: Lucida Grande"></span>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.</span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.</span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span
                                            style="font-family: Lucida Grande"
                                        ></span>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.</span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span style="font-family: Lucida Grande"></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >And the normally functioning pituitary appears to be unnecessary to grow to normal
                                        height. (Kageyama, et al., 1998.)<span style="font-family: Lucida Grande"></span
                                        ></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.)<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span
                                            style="font-family: Lucida Grande"
                                        ></span>Growth hormone plays an important role in puberty, influencing ovarian
                                        function, for example.&nbsp;<span style="font-family: Lucida Grande"></span
                                        ></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >Denckla's experiments are reminiscent of many others that have identified changes
                                        in pituitary function as driving forces in aging and degenerative diseases.<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >Menopause, for example, is the result of overactivity of the pituitary gonatropins,
                                        resulting from the cumulatively toxic effects of estrogen in the
                                        hypothalamus.<span style="font-family: Lucida Grande"></span></span></span
                                ></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.&nbsp;<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span style="font-family: Lucida Grande"></span>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.<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span style="font-family: Lucida Grande"></span></span
                                    ></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >Besides being involved in kidney degeneration, vascular leakiness contributes to
                                        brain edema, and probably contributes to the "autoimmune" diseases.<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span style="font-family: Lucida Grande"></span></span
                                    ></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >Growth hormone blocks gonadotropin-stimulated progesterone production, and this
                                        could also affect thyroid and respiratory metabolism.<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span
                                            style="font-family: Lucida Grande"
                                        ></span></span></span></span>
                        </blockquote>
                        <blockquote>
                            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                                        style="font-size: medium"
                                    >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.<span
                                            style="font-family: Lucida Grande"
                                        ></span><h3>REFERENCES</h3><span style="font-family: Lucida Grande"></span
                                        >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)."&nbsp;<span
                                            style="font-family: Lucida Grande"
                                        ></span>Pediatr. Pulmonol. 1998 26(4):241-9. Sleep, respiratory rate, and growth
                                        hormone in chronic neonatal lung disease, D. Fitzgerald, et al.<span
                                            style="font-family: Lucida Grande"
                                        ></span>"Insulin resistance in puberty [editorial]," Anonymousm Lancet, 1991 May
                                        25, 337:8752, 1259-60.&nbsp;<span style="font-family: Lucida Grande"></span>"The
                                        gonadotropic function of insulin," Poretsky L; Kalin MF, Endocr Rev, 1987 May,
                                        8:2, 132-4.1.<span style="font-family: Lucida Grande"></span><hr /><span
                                            style="font-family: Lucida Grande"
                                        ></span>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."&nbsp;<span style="font-family: Lucida Grande"></span>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)."<span style="font-family: Lucida Grande"></span>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."&nbsp;<span
                                            style="font-family: Lucida Grande"
                                        ></span>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."<span
                                            style="font-family: Lucida Grande"
                                        ></span>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.&nbsp;<span style="font-family: Lucida Grande"></span>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.<span style="font-family: Lucida Grande"></span>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."<span style="font-family: Lucida Grande"></span>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."&nbsp;<span
                                            style="font-family: Lucida Grande"
                                        ></span>N Engl J Med 1999 Sep 9;341(11):785-92. Increased mortality associated
                                        with growth hormone treatment in critically ill adults.</span></span></span>
                        </blockquote>
                        <p>&nbsp;</p>
                    </span></span></span></span>

        © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com
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        <p></p>
        <p>
            <strong>Heart and hormones &nbsp;</strong>&nbsp; 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.
        </p>
        <p>
            <span>&nbsp;&nbsp; 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.&nbsp; &nbsp;</span>
            <span>&nbsp;&nbsp; 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.</span>
            <span>&nbsp;&nbsp;&nbsp; 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.</span>
            <span>&nbsp;&nbsp; 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.</span>
            <span>(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.)</span>
            <span>&nbsp;&nbsp; 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.&nbsp;</span>
            <span>&nbsp;&nbsp; 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.</span>
            <span>&nbsp;&nbsp; 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.</span>
            <span>&nbsp;&nbsp; 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).&nbsp;</span>
            <span>&nbsp;&nbsp; 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).</span>
            <span>&nbsp;&nbsp;&nbsp; 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.</span>
            <span>&nbsp;&nbsp; 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.</span>
            <span>&nbsp;&nbsp; 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.&nbsp;</span>
            <span>&nbsp;&nbsp; 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).</span>
            <span>&nbsp;&nbsp; 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).</span>
            <span>&nbsp;&nbsp; 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).&nbsp;</span>
            <span>&nbsp;&nbsp; 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.&nbsp;</span>
            <span>&nbsp;&nbsp; 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.&nbsp;</span>
            <span>&nbsp;&nbsp; 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).&nbsp;</span>
            <span>&nbsp;&nbsp; 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).&nbsp;</span>
            <span>&nbsp;&nbsp; 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.&nbsp;</span>
            <span>&nbsp;&nbsp; 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.</span>
            <span>&nbsp;&nbsp; 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.</span>
            <span>&nbsp;&nbsp; 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.&nbsp;</span>
            <span>&nbsp;&nbsp; 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."&nbsp; 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.</span>
            <span>&nbsp;&nbsp; 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.</span>
            <span>&nbsp;&nbsp; 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).</span>
            <span>&nbsp;&nbsp; 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.</span>
            <span>&nbsp;&nbsp; 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).</span>
            <span>&nbsp;&nbsp;&nbsp; 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.</span>
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        </p>

        © Ray Peat Ph.D. 2015. All Rights Reserved. www.RayPeat.com
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        <p></p>
        <blockquote>
            <strong><span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                            style="font-size: large"
                        >Hot flashes, energy, and aging</span></span></span></strong>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span
                    ></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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."</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span
            >
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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).</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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).</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span
                ></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span
                    ></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.&nbsp;</span
                    ></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span
                ></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.&nbsp;</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >One of the animal "models" used to study hot flashes is morphine withdrawal.&nbsp; 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).</span></span
                ></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span
                ></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span
                    ></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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).</span></span
                ></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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).</span></span></span
            >
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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).</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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).</span
                    ></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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).</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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).</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222">&nbsp;<span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    ><span style="font-style: normal"><span style="font-weight: normal"
                            >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.</span
                            ></span></span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222">&nbsp; <span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    ><span style="font-style: normal"><span style="font-weight: normal"><hr /></span></span></span
                    ></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >*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.</span></span></span>
        </blockquote>
        <blockquote></blockquote>
        <blockquote>
            <span style="color: #222222">&nbsp;&nbsp;&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; <span
                    style="font-family: georgia, times, serif"
                ><span style="font-size: medium"><span style="font-style: normal"><span style="font-weight: normal"><h3>
                                    REFERENCES
                                </h3></span></span></span></span></span>
        </blockquote>
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            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >J Biol Chem. 2007 Aug 31;282(35):25501-8. A novel ligand-independent function of the estrogen
                        receptor is essential for osteocyte and osteoblast mechanotransduction. Aguirre JI, Plotkin LI,
                        Gortazar AR, Millan MM, O'Brien CA, Manolagas SC, Bellido T.</span></span></span>
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            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
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                    >Prog Clin Biol Res. 1981;67:161-77. Metabolic adaptations to starvation, semistarvation, and
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            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
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                    >Ascheim, P. (1983). Relation of neuroendocrine system to reproductive decline in female rats. In
                        "Neuroendocrinology of Aging" (J. Meittes, ed.), 73-101, Plenum, NY.</span></span></span>
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            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
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                    >J Neuroendocrinol. 2010 Jun;22(6):599-607. Effects of hypoglycaemia on neurotransmitter and hormone
                        receptor gene expression in laser-dissected arcuate neuropeptide Y/agouti-related peptide
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            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
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                    >J Appl Physiol. 1997 Aug;83(2):477-84. Chronic hormone replacement therapy alters thermoregulatory
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                        O'Gorman JT, Derr JA, Kenney WL.</span></span></span>
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            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
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                    >Thorax. 2002 Apr;57(4):361-3. Caffeine decreases exhaled nitric oxide. Bruce C, Yates DH, Thomas
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        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >J Endocrinol. 1982 Apr;93(1):123-32. Effects of adrenocortical and gonadal steroids on the
                        secretion in vitro of corticotrophin and its hypothalamic releasing factor. Buckingham JC.</span
                    ></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >L. B. Butareva, et al., "Pathogenetic mechanisms of the development of 'hot flushes' in patients
                        with climacteric disorders of the sympathetic-adrenal type," Akush. Ginekol. (Mosk.) 10, 30-33,
                        1989.&nbsp; (Besides activation of the sympathoadrenal system associated with hot flushes,
                        thyrotrophic hormone also increased.)</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >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.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >R. F. Casper, et al., "Objective measurement of hot flushes associated with the premenstrual
                        syndrome," Fertil. Steril. 47(2), 341-344, 1987.&nbsp; ("These physiologic changes are identical
                        to those seen during menopausal flushes and suggest that PMS may be associated with
                        neuroendocrine events typical of estrogen withdrawal.")</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >Zhonghua Fu Chan Ke Za Zhi. 2002 Dec;37(12):726-8. Changes of plasma serotonin precursor metabolite
                        concentrations in postmenopausal women with hot flushes. Chen Y, Lu X, Huang Y, Xin X, Ye
                        X.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >Brain Res. 2009 Jul 14;1280:77-83. Epub 2009 May 13. Estradiol impairs hypothalamic molecular
                        responses to hypoglycemia. Cheng H, Isoda F, Mobbs CV.</span></span></span>
        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
                    >Angiogenesis. 2012 Jul 25. Estrogen receptor alpha as a key target of organochlorines to promote
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        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
                        style="font-size: medium"
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        </blockquote>
        <blockquote>
            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
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        </blockquote>
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            <span style="color: #222222"><span style="font-family: georgia, times, serif"><span
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                        CL.</span></span></span>
        </blockquote>
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                    >J Bone Miner Res. 2006 Aug;21(8):1297-306. Osteocytes use estrogen receptor alpha to respond to
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        </blockquote>
        <p>&nbsp;</p>

        © Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com
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    <head><title>How do you know? Students, patients, and discovery</title></head>
    <body>
        <h1>
            How do you know? Students, patients, and discovery
        </h1>

        <p></p>
        <p>
            "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." <em>
                N. Hartmann</em>
        </p>
        <p>
            "I am myself plus my circumstances" <em>
                Jose Ortega y Gasset</em>
        </p>
        <p>
            Knowledge should be useful and provisional.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Our nervous systems are made up of physiology and culture.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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 <em>is</em> 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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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).
        </p>
        <p>
            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).
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Every meaningful interaction involves formative systems.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            While self-regulation and the generation of knowledge are pleasurable, having knowledge imposed isn't.
        </p>
        <p>
            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. <strong>Once named, the world in its turn reappears to the namers as a problem and requires of
                them a new naming.</strong> 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).
        </p>
        <p>
            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.
        </p>

        <p>
            The person who is learning is critically interacting with both nature and culture, with practical issues and
            theories.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            "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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            "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.
        </p>
        <p>
            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.
        </p>
        <p>
            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<strong>: </strong>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            Every communicative interaction is an opportunity for the discovery of new meanings and potentials.
        </p>
        <p><hr /></p>
        <p>
            <strong><em>Aristotelian motto: If the knower and the known form a functional system they are substantially
                    the same.</em></strong>
        </p>
        <p><hr /></p>
        <p><strong><h3>REFERENCES</h3></strong></p>

        <p>
            P.K. Anokhin: 1975, <strong>The essays on physiology of functional systems.</strong>
        </p>
        <p>
            1978, <strong>Philosophical aspects of the theory of functional systems.</strong>
        </p>
        <p>
            1998, <strong>Cybernetics of functional systems: Selected works,</strong> Moscow, Medicine, 400 p., (in
            Russian).
        </p>
        <p>
            <strong>Pedagogy of the Oppressed,
            </strong>by Paulo Freire. New York: Continuum Books, 1993.
        </p>
        <p>
            <strong>Synectics,</strong>
            W.J.J. Gordon, Harper &amp; Row, 1961.
        </p>
        <p>
            <strong>Crystals, Fabrics, and Fields : Metaphors of Organicism in Twentieth-Century Developmental
                Biology,</strong> Donna Jeanne Haraway, 1976.
        </p>
        <p>
            <strong>We Make the Road by Walking</strong>: <strong>Conversations on Education and Social Change,</strong>
            Myles Horton, Paolo Freire, 1990.
        </p>
        <p><strong>Science and Sanity,</strong> Alfred Korzybski, 1933.</p>
        <p>
            Alfred Korzybski, "The Role of Language in the Perceptual Processes," in <strong>Perception: An Approach to
                Personality,</strong> edited by Robert R. Blake and Glenn V. Ramsey. 1951, The Ronald Press Company, New
            York.
        </p>

        <p>
            Marshall McLuhan: <em>"...the devil is in the media,"</em> quoted by Derrick DeKerkhove, Director of the
            McLuhan Program in Culture and Technology at the University of Toronto.
        </p>
        <p>
            <strong>Biochemistry and Morphogenesis</strong>, by Joseph Needham. Cambridge University Press, 1942.
        </p>
        <p>
            <strong>Cybernetics--or Control and Communication in the Animal and the Machine,
            </strong>
            Norbert Wiener 1948
        </p>

        <p>
            <strong>The Human Use of Human Beings,</strong> The Riverside Press (Houghton Mifflin Co.), 1950.
        </p>
        <p>
            <em>
                "...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.</em>
            <strong><em>"</em> </strong>
            Norbert Weiner,<strong> God and Golem, Inc.,</strong> 1964<strong>.</strong>
        </p>
        <p>
            <em>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.</em>
        </p>
        <p>
            <em>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?</em>
        </p>
        <p>
            J Intern Med. 1999 Jan;245(1):57-61. <strong>Decreased heart rate variability in patients with type 1
                diabetes mellitus is related to arterial wall stiffness.</strong> Jensen-Urstad K, Reichard P,
            Jensen-Urstad M.
        </p>

        <p>
            Eur J Appl Physiol. 2010 Apr 23. <strong>Heart period sensitivity to forced oscillations in ventilatory
                pressure.</strong> Quint SR, Vaughn BV.
        </p>

        Copyright 2007. Raymond Peat, P.O. Box 5764, Eugene OR 97405. All Rights Reserved. www.RayPeat.comNot for
        republication without written permission.
    </body>
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    <head>
        <title>
            TSH, temperature, pulse rate, and other indicators in hypothyroidism
        </title>
    </head>
    <body>
        <h1>
            TSH, temperature, pulse rate, and other indicators in hypothyroidism
        </h1>

        <p>
            <strong>Each of the indicators of thyroid function can be useful, but has to be interpreted in relation to
                the physiological state.</strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>
        <p>
            <strong>"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.</strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>

        <p>
            <strong>The T wave on the electrocardiogram, and the relaxation rate on the Achilles reflex test are
                useful.</strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>
        <p>
            <strong>Less common blood or urine tests (adrenaline, cortisol, ammonium, free fatty acids), if they are
                available, can help to understand compensatory reactions to hypothyroidism.</strong>
        </p>
        <p>
            <strong>A book such as McGavack's <em>The Thyroid,</em> that provides traditional medical knowledge about
                thyroid physiology, can help to dispel some of the current dogmas about the thyroid.</strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>

        <p>
            <hr />
            <hr />
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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).
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Occasionally, a small supplement of thyroid in addition to a good diet is needed to quickly escape from the
            stress-induced "hypophysectomized" condition.
        </p>

        <p>
            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.
        </p>
        <p>
            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.")
        </p>
        <p>
            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.
        </p>
        <p>
            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).
        </p>
        <p>
            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).
        </p>

        <p>
            During the night, at the time adrenaline and free fatty acids are at their highest, TSH usually reaches its
            peak<strong>.</strong> 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.
        </p>
        <p>
            These are the basic reasons for thinking that the TSH tests should be given only moderate weight in
            interpreting thyroid function.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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).
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p><strong><h3>REFERENCES</h3></strong></p>
        <p>
            Clin Chem Lab Med. 2002 Dec;40(12):1344-8. <strong>Transthyretin: its response to malnutrition and stress
                injury. Clinical usefulness and economic implications.</strong> Bernstein LH, Ingenbleek Y.
        </p>

        <p>
            Endokrinologie. 1968;53(3):217-21.<strong>[Influence of hypophysectomy and pituitary hormones on dextran
                edema in rats]</strong> German. Boeskor A, Gabbiani G.
        </p>
        <p>
            J Clin Endocrinol Metab. 2001 Nov;86(11):5148-51. <strong>Sudden enlargement of local recurrent thyroid
                tumor after recombinant human TSH administration.</strong>
            Braga M, Ringel MD, Cooper DS.
        </p>
        <p>
            J Investig Med. 2002 Sep;50(5):350-4; discussion 354-5. <strong>The nocturnal serum thyrotropin surge is
                inhibited in patients with adrenal Incidentaloma.</strong>
            Coiro V, Volpi R, Capretti L, Manfredi G, Magotti MG, Bianconcini M, Cataldo S, Chiodera P.
        </p>

        <p>
            Rev Neurol (Paris). 1992;148(5):371-3.<strong>
                [Hashimoto's encephalopathy: toxic or autoimmune mechanism?]</strong> [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).
        </p>
        <p>
            Am J Clin Nutr. 1986 Mar;43(3):406-13. <strong>Thyroid hormone and carrier protein interrelationships in
                children recovering rom kwashiorkor.
            </strong>
            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) <strong>increased TSH secretion appears to be an integral part of the recovery from PEM.</strong>
        </p>
        <p>
            Neuroendocrinology. 1982;35(2):139-47. <strong>
                Neurotransmitter control of thyrotropin secretion.
            </strong>
            Krulich L. "The central dopaminergic system seems to have an inhibitory influence on the secretion of
            thyrotropin (TSH) both in humans and rats."
        </p>
        <p>
            Endocrinology 1972 Mar;90(3):795-801. <strong>TSH-induced release of 5-hydroxytryptamine and histamine rat
                thyroid mast cells.</strong> Ericson LE, Hakanson R, Melander A, Owman C, Sundler F.
        </p>
        <p>
            Rev Neurol. 2002 Oct 16-31;35(8):741-2. <strong>[Hypothyroidism concealed by Parkinson's disease][</strong
            >in Spanish] Garcia-Moreno JM, Chacon J. Servicio de Neurologia, Hospital Universitario Virgen Macarena,
            Sevilla, Espana.

            <a href="mailto:Sinue@arrakis.es" target="_blank">Sinue@arrakis.es</a> 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.
        </p>
        <p>
            Endocrine. 2003 Feb-Mar;20(1-2):149-54.<strong>
                Body composition of prolactin-, growth hormone, and thyrotropin-deficient Ames dwarf mice.</strong>
            Heiman ML, Tinsley FC, Mattison JA, Hauck S, Bartke A. Lilly Research Labs, Corporate Center, Indianapolis,
            IN, USA.<strong>
                Ames dwarf mice have primary deficiency of prolactin (PRL), growth hormone (GH), and thyroid-stimulating
                hormone (TSH), and live considerably longer than normal</strong>
            <strong>
                animals from the same line.</strong>
        </p>
        <p>
            (Lancet. 1975 Nov 1;2(7940):845-8<strong>.. Triiodothyronine and thyroid-stimulating hormone in
                protein-calorie malnutrition in infants.</strong> Ingenbleek Y, Beckers C.)
        </p>

        <p>
            Am J Med Sci. 1995 Nov;310(5):202-5. <strong>Case report: thyrotropin-releasing hormone-induced myoclonus
                and tremor in a patient with Hashimoto's encephalopathy.</strong>
            Ishii K, Hayashi A, Tamaoka A, Usuki S, Mizusawa H, Shoji S.
        </p>
        <p>
            Rev Neurol (Paris). 1985;141(1):55-8. [<strong>Hashimoto's thyroiditis and myoclonic encephalopathy.
                Pathogenic hypothesis]</strong> [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.<strong>
                Some parallelism was noted between the clinical state and TSH levels.</strong> 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.
        </p>

        <p>
            J Clin Endocrinol Metab. 1992 Jun;74(6):1361-5. <strong>Fatty acid-induced increase in serum dialyzable free
                thyroxine after physical exercise: implication for nonthyroidal illness.</strong> Liewendahl K, Helenius
            T, Naveri H, Tikkanen H.
        </p>
        <p>
            Adv Exp Med Biol. 1990;274:315-29. <strong>Role of monokines in control of anterior pituitary hormone
                release.</strong> McCann SM, Rettori V, Milenkovic L, Jurcovicova J, Gonzalez MC.
        </p>
        <p>
            Acta Endocrinol (Copenh). 1979 Feb;90(2):249-58. <strong>Dual action of adrenergic system on the regulation
                of thyrotrophin secretion in the male rat.</strong>
            Mannisto, Ranta T, Tuomisto J. <strong><em>"</em></strong>
            <em>....noradrenaline (NA) (1 h), and L-Dopa (1 h) were also effective in decreasing serum TSH
                levels...."</em>
        </p>

        <p>
            Endocrinology 1971 Aug;89(2):528-33. <strong>TSH-induced appearance and stimulation of amine-containing mast
                cells in the mouse thyroid.
            </strong>
            Melander A, Owman C, Sundler F.
        </p>
        <p>
            Epilepsy Res. 1988 Mar-Apr;2(2):102-10. <strong>Evidence of hypothyroidism in the genetically epilepsy-prone
                rat.</strong> 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.<strong>
                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</strong> critical impact of neonatal hypothyroidism on brain function coupled with the development
            of the audiogenic seizure susceptible trait by the GEPR-9 rat during<strong>
                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.</strong>
        </p>

        <p>
            Przegl Lek. 1998;55(5):250-8. <strong>[Mastopathy and simple goiter--mutual relationships]</strong> [Article
            in Polish] Mizia-Stec K, Zych F, Widala E. <strong>"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,</strong>
            and there was found significantly higher thyroid volume in these patients." Endocrinology. 1997
            Apr;138(4):1434-9. <strong>Thyroxine administration prevents streptococcal cell wall-induced inflammatory
                responses.</strong> Rittenhouse PA, Redei E.
        </p>
        <p>
            Eur J Appl Physiol Occup Physiol. 1998;77(1-2):37-43. <strong>Pre-adaptation, adaptation and de-adaptation
                to high altitude in humans: hormonal and biochemical changes at sea level.
            </strong>
            Savourey G, Garcia N, Caravel JP, Gharib C, Pouzeratte N, Martin S, Bittel J.
        </p>

        <p>
            Endocrinol Jpn. 1992 Oct;39(5):445-53. <strong>Plasma free fatty acids, inhibitor of extrathyroidal
                conversion of T4 to T3 and thyroid hormone binding inhibitor in patients with various nonthyroidal
                illnesses.</strong> Suzuki Y, Nanno M, Gemma R, Yoshimi T.
        </p>
        <p>
            Natl Med J India. 1998 Mar-Apr;11(2):62-5. <strong>Neuropsychological impairment and altered thyroid hormone
                levels in epilepsy.</strong> 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 &lt; 0.001) lower scores on attention, memory, constructional praxis, finger tapping time,
            and verbal intelligence quotient (i.q.) when compared with controls. <strong>Their T3, T4 and Free T3 levels
                were significantly lower;
            </strong>
            and <strong>TSH and Free T4 levels were significantly higher than that of controls.
            </strong>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.
        </p>

        <p>
            Crit Care Med. 1994 Nov;22(11):1747-53. <strong>Dopamine suppresses pituitary function in infants and
                children.</strong> Van den Berghe G, de Zegher F, Lauwers P.
        </p>
        <p>
            Ned Tijdschr Geneeskd. 2000 Jan 1;144(1):5-8.<strong>
                [Epilepsy, disturbances of behavior and consciousness in presence of normal thyroxine levels: still,
                consider the thyroid gland]
            </strong>
            [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 <strong>Hashimoto's encephalopathy, associated with
                Hashimoto thyroiditis.</strong> Treatment with prednisone in addition to thyroxine suppletion resulted
            in a remarkable remission of their neuropsychiatric symptoms. The disease is probably under-recognized.
        </p>

        <p>
            Cell Immunol. 1999 Mar 15;192(2):159-66. <strong>Neuroendocrine-induced synthesis of bone marrow-derived
                cytokines with inflammatory immunomodulating properties.
            </strong>Whetsell M, Bagriacik EU, Seetharamaiah GS, Prabhakar BS, Klein JR.
        </p>

        © Ray Peat Ph.D. 2007. All Rights Reserved. www.RayPeat.com
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    <head><title>Immunodeficiency, dioxins, stress, and the hormones</title></head>
    <body>
        <h1>
            Immunodeficiency, dioxins, stress, and the hormones
        </h1>

        <strong>
            CRITICAL POINTS</strong>: <p>
            <em>
                *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.
            </em>
        </p>
        <p>
            <em>
                *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.)
            </em>
        </p>
        <p>
            <em>
                *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."
            </em>
        </p>
        <p>
            <em>
                *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.
            </em>
        </p>
        <p>
            <em>
                *Estrogen activates the production of cortisol, and damages the normal feedback control, causing both
                cortisol and ACTH to be elevated.
            </em>
        </p>
        <p>
            <em>
                *Estrogen causes chronically elevated free fatty acids, and synergizes with unsaturated fats.
            </em>
        </p>
        <p>
            <em>
                *Estrogen inhibits thyroid function.
            </em>
        </p>
        <p>
            <em>
                Hypercortisolism is typically associated with hypothyroidism, and both tend to cause the loss of lean
                body mass.
            </em>
        </p>
        <p>
            <em>
                *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.
            </em>
        </p>
        <p>
            <em>
                *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.
            </em>
        </p>
        <p>
            <em>
                *Progesterone can contribute to the inhibition of HIV replication and transmission.
            </em>
        </p>
        <p>
            <em>
                *Common environmental factors can produce hormonal changes leading to immunodeficiency.
            </em>
        </p>
        <p></p>
        <hr />
        &nbsp; &nbsp; 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. &nbsp; &nbsp; 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.
        <hr />

        It has been over ten years since I wrote about "AIDS" (e.g., "Repairing the Immune System," in <em>Cofactors in
            AIDS and HIV infection,</em> 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<strong> </strong>

        have become increasingly prevalent in our<strong> </strong>
        environment<strong>--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.</strong> 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.

        <strong>
            Environmental stress
        </strong>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<strong>: </strong>

        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<strong>:</strong> 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<strong
        >;</strong> Deas, et al., 1998.) Treatments for roundworms and other parasites cause antibodies to retroviruses
        to appear in animals that previously tested negative<strong>;</strong> 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.
        <strong><em>
                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.</em></strong>
        <em>
            Some of these conditions are strongly associated with each other, for example, primary biliary cirrhosis,
            breast cancer, and osteoporosis.
        </em>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 <em>Medical Nemesis,</em>
        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. <strong>The incidence of low birth-weight babies in the U.S. peaked around 1965, and 28
            years later AIDS mortality in the US peaked.
        </strong>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.

        <strong>
            A Synthesis
        </strong>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<strong>; </strong>
        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 <strong>increases progesterone synthesis, but decreases estrogen.
        </strong>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.

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        <strong>and there is no obvious explanation for this phenomenon</strong>. Unfallchirurg 1993 Apr;96(4):181-91
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        [Article in German] Kach K, Kossmann T, Trentz O. Necrotizing soft tissue infections are a group of life- and
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        </strong>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. <strong>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.</strong>
        <strong>The sensitivity of the host is linked to the genetic expression of the V. beta. elements on the surface
            of lymphocytes.
        </strong>J Infect 1989 May;18(3):231-48 <strong>Invasive streptococcal infections in the era before the acquired
            immune deficiency syndrome: a 10 years' compilation of patients with streptococcal bacteraemia in North
            Yorkshire.
        </strong>
        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
        <strong>Stress protein-induced immunosuppression: inhibition of cellular immune effector functions following
            overexpression of haem oxygenase (HSP 32).</strong> Woo J, Iyer S, Cornejo MC, Mori N, Gao L, Sipos I,
        Maines M, Buelow R. <strong>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.
        </strong>Genome 1998 Oct;41(5):662-8. <strong>A single-primer PCR-based retroviral-related DNA polymorphism
            shared by two distinct human populations.</strong> Deb P, Klempan TA, O'Reilly RL, Singh SM Department of
        Zoology, University of Western Ontario, London, Canada. <strong>"Almost 10% of the human genome consists of DNA
            sequences that share homology with retroviruses.</strong>
        These sequences, which represent a stable component of the human genome <strong>
            (although some may retain the ability to transpose),</strong> 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, <strong>Imprinting of thymic
            glucocorticoid receptor and uterine estrogen receptor by a synthetic steroid hormone at different times
            after birth.</strong> Csaba G, Inczefi-Gonda A. J Clin Endocrinol Metab 1998 Dec;83(12):4373-81.<strong>
            Human immunodeficiency virus induction of corticotropin in lymphoid cells.</strong> Hashemi FB, Hughes TK,
        Smith EM. Eur J Cancer Clin Oncol 1988 Jul;24(7):1179-83. <strong>Abnormal free fatty acids and cortisol
            concentrations in the serum of AIDS patients.</strong>
        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, <strong>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.
        </strong>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. <strong>Serum cortisol concentrations were significantly higher, 50% (P less than 0.001), but the
            urinary 17-hydroxycorticosteroids and 17-oxosteroids were 2-fold lower
        </strong>
        (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. <strong>Lipids, lipoproteins, triglyceride clearance, and cytokines in human
            immunodeficiency virus infection and the acquired immunodeficiency syndrome.</strong> 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 <strong>(AIDS) without active
            secondary infection,</strong>
        patients with evidence of human immunodeficiency virus infection but without clinical AIDS (HIV+), and controls.
        <strong>Plasma TGs and FFA were increased in AIDS,</strong> 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.<strong>
            Human immunodeficiency virus type 1 infection of human placenta: potential route for fetal
            infection.</strong>
        Amirhessami-Aghili N, Spector SA. AIDS Res Hum Retroviruses 1997 Sep 20;13(14):1235-42. <strong>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.</strong>
        Lee AW, Mitra D, Laurence J. Folia Biol (Krakow) 1996;44(3-4):111-6. <strong>Preovulatory dynamics of ovarian
            steroid hormones in two mouse strains differing in the rate of meiotic maturation.</strong> Krzanowska H,
        Szoltys M. J Clin Invest 1997 Apr 1;99(7):1484-91.<strong>
            Human chorionic gonadotropin hormone prevents wasting syndrome and death in HIV-1 transgenic mice.</strong>

        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 <strong>Nuclear fallout, low birthweight, and immune deficiency. Gould JM, Sternglass
            EJ</strong> 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 <strong>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.
        </strong>
        The 1945-1965 rise<strong>
            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.</strong> In the 1980s, for the baby boom generation (those
        born<strong>
            between 1945 and 1965), cancer incidence and mortality due to infectious diseases associated with a</strong>
        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 <strong>[Activation of lipolysis and ketogenesis in
            tumor-bearing animals as a reflection of chronic stress states].</strong>
        Chekulaev VA, Shelepov VP, Pasha-zade GR, Shapot VS. Arkh Patol 1987;49(6):10-8 <strong>[Combination of
            immunodepression and disorders in nucleic acid metabolism of lymphoid tissue as a manifestation of a
            paraneoplastic syndrome].</strong> [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<strong>
            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.
        </strong>
        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 <strong>[Relation between disorders of glucose
            metabolism, secretion of somatotropic hormone, thyroxine, thyrotropin and hematocrit indices in rats with
            transplanted hepatomas].</strong> Shelepov VP, Pasha-zade GR, Chekulaev VA, Shapot VS. Am J Pathol 1987
        Jan;126(1):103-13 <strong>Dietary fatty acid effects on T-cell-mediated immunity in mice</strong>
        <strong>infected with mycoplasma pulmonis or given carcinogens by injection.</strong> 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<strong>
            POLY diet were significantly immunosuppressed, and only T-cell-mediated cutaneous sensitivity reactions were
            affected.</strong>
        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<strong>
            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.
        </strong>Tumour Biol 1988;9(5):225-32 <strong>Modulation of cell-mediated immune response by steroids and free
            fatty acids in AIDS patients: a critical survey.</strong> 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<strong>
            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.
        </strong>Basic Life Sci 1988;49:615-20 <strong>Vitamin E and immune functions</strong>. Bendich A.
        Supplementation of these diets with higher than nutritionally adequate<strong>
            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</strong>
        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
        <strong>Enhancement of immunosuppression by substitution of fish oil for olive oil as a vehicle for
            cyclosporine.</strong>
        Kelley VE, Kirkman RL, Bastos M, Barrett LV, Strom TB. J Am Coll Nutr 1992 Oct;11(5):512-8 <strong>Role of
            nutrition in the management of malnutrition and immune dysfunction of trauma.
        </strong>
        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
        <strong>immunosuppression appears to be part of the inflammatory response that accompanies trauma, and in part,
            to represent the need for conditional</strong> 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 <strong>Dietary butter protects against ultraviolet radiation-induced
            suppression of contact hypersensitivity in Skh:HR-1 hairless mice.</strong> 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 &gt; 0.9) between protection
        against<strong>
            photoimmunosuppression and the proportion of clarified butter in mice fed a series of 200 g/kg mixed
            fat</strong> 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 <strong>Dependence of photocarcinogenesis and photoimmunosuppression
            in the hairless mouse on dietary polyunsaturated fat.</strong> 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 <strong
        >diet of 20% saturated fat provided almost complete protection from the suppression of CHS, whereas feeding 20%
            polyunsaturated fat resulted in 57% suppression</strong>; 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 <strong>predisposition to persistent immunosuppression
        </strong>

        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.<strong>
            Clinical implications of food contaminated by aflatoxins.</strong> Hendrickse RG. Arch Toxicol
        1996;70(10):661-71. <strong>Host resistance to rat cytomegalovirus (RCMV) and immune function in adult PVG rats
            fed herring from the contaminated Baltic Sea.</strong> 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) <strong>fed herring from the contaminated Baltic Sea had
            lower natural killer cell activity, T-lymphocyte functionality and delayed-type hypersensitivity
            responses</strong> 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 <strong>titres and changes in thymus cellularity</strong> 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<strong>
            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.
        </strong>Environ Health Perspect 1995 Apr;103(4):366-71 <strong>Dioxin activates HIV-1 gene expression by an
            oxidative stress pathway requiring a functional cytochrome P450 CYP1A1 enzyme.</strong> Yao Y, Hoffer A,
        Chang CY, Puga A. <strong>
            Aflatoxin B1, 2,3,7,8-tetrachlorodibenzo-p-dioxin
        </strong>
        (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<strong>
            epidemiologic reports suggesting that exposure to aromatic hydrocarbons, such as found in cigarette smoke,
            is associated with an acceleration in AIDS progression.
        </strong>Ann Trop Med Parasitol 1997 Oct;91(7):787-93 <strong>Of sick turkeys, kwashiorkor, malaria, perinatal
            mortality, heroin addicts and food poisoning: research on the influence of aflatoxins on child health in the
            tropics.
        </strong>
        <hr />

        Ann N Y Acad Sci 1986;475:320-8. <strong>Hormonal approaches to immunotherapy of autoimmune disease.</strong>
        Talal N, Ahmed SA, Dauphinee M. Cell Immunol 1998 Nov 1;189(2):125-34.<strong>
            Estrogen increases the number of plasma cells and enhances their autoantibody production in nonautoimmune
            C57BL/6 mice.</strong> Verthelyi DI, Ahmed SA. J Rheumatol 1987 Jun;14 Suppl 13:21-5. <strong>Interleukin 2,
            T cell receptor and sex hormone studies in autoimmune mice.</strong> Talal N, Dang H, Ahmed SA, Kraig E,
        Fischbach M. The <strong>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. T</strong>his phenomenon may have etiopathological
        significance for familial SLE. Endocrinology 1994 Dec;135(6):2615-22. <strong>17 beta-estradiol, but not 5
            alpha-dihydrotestosterone, augments antibodies to double-stranded deoxyribonucleic acid in nonautoimmune
            C57BL/6J mice.</strong> Verthelyi D, Ahmed SA. J Autoimmun 1993 Jun;6(3):265-79 <strong>Antibodies to
            cardiolipin in normal C57BL/6J mice: induction by estrogen but not dihydrotestosterone.</strong>
        Ahmed SA, Verthelyi D. J Autoimmun 1989 Aug;2(4):543-52.<strong>
            Estrogen induces the development of autoantibodies and promotes salivary gland lymphoid infiltrates in
            normal mice.</strong> Ahmed SA, Aufdemorte TB, Chen JR, Montoya AI, Olive D, Talal N. . . . normal mice were
        <strong>prenatally exposed to estrogens.</strong>
        . . . 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.<strong>
            Sex hormones, CD5+ (Lyl+) B-cells, and autoimmune diseases.</strong> Talal N, Ahmed SA. Ann N Y Acad Sci
        1986;475:320-8 <strong>Hormonal approaches to immunotherapy of autoimmune disease.</strong> Talal N, Ahmed SA,
        Dauphinee M. Life Sci 1998;63(20):1815-22. <strong>Exacerbated immune stress response during experimental
            magnesium deficiency results from abnormal cell calcium homeostasis.</strong> Malpuech-Brugere C, Rock E,
        Astier C, Nowacki W, Mazur A, Rayssiguier Y. These studies first showed that an <strong>abnormal calcium
            handling induced by extracellular magnesium depression in vivo may be at the origin of exacerbated
            inflammatory response.
        </strong>Magnes Res 1998 Sep;11(3):161-9. <strong>Early morphological and immunological alterations in the
            spleen during magnesium deficiency in the rat.</strong>

        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 <strong>
            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.</strong> Nelson PN, Lever AM,
        Bruckner FE, Isenberg DA, Kessaris N, Hay FC. Clin Diagn Lab Immunol 1998, Mar;5(2):181-5. <strong>Reactivity of
            sera from systemic lupus erythematosus and Sjogren's syndrome patients with peptides derived from human
            immunodeficiency virus p24 capsid antigen.</strong> Deas, JE, et al.<strong> </strong>We have previously
        demonstrated that <strong>about one-third of patients with either Sjogren's syndrome (SS) or systemic lupus
            erythematosus (SLE) react to human immunodeficiency virus (HIV)</strong> 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. <strong
        >Effect of diethylcarbamazine on serum antibody to feline oncornavirus-associated cell membrane antigen in
            feline leukemia virus cats.</strong> 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, <strong>
            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).
        </strong>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 <strong><hr
            /></strong>
        <hr />
        <p>
            © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
        </p>
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    <head><title>Estrogen, memory and heredity: Imprinting and the stress response</title></head>
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        <h1>
            Estrogen, memory and heredity: Imprinting and the stress response
        </h1>

        <p>
            <hr />
            <hr />
            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.

            <em>Genomic imprinting</em> makes maternal genes behave differently from paternal genes.
            <em>Hormonal imprinting</em> 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.
            <hr />
            <hr />

            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, <em>in natural and holistic ways that don't involve the mechanistic
                interventions of "gene therapy" or "genetic engineering."
            </em> 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.
        </p>
        <p>
            There are still great authoritarian forces opposed to recognizing, and supporting, the organism's full
            potential. <strong>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.
            </strong>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.
        </p>
        <p>
            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 <em>his ideas were already being misrepresented, and that
                he did not hold "natural selection" to be the only mechanism of evolution,</em>

            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 <em>any theory of evolution </em>
            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."
        </p>

        <p>
            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, <em>by selecting the best individuals grown under the best conditions.
            </em> It was known that the miniature ponies, <strong>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.
            </strong> It apparently never occurred to most plant and animal breeders that they might be able to <em
            >improve</em> 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 <em>deletion</em> 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 <em>appearance</em>

            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.
        </p>
        <p>
            The changes produced by <em>subtraction</em> were compatible with the notion of fallen man in a corrupt
            world, while the <em>addition</em> 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.
        </p>

        <p>
            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 <em>
                improvement</em> could be inherited. Although many experiments showed what seemed to be meaningfully <em
            >directed</em> 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 <em>only
                because an old trait was being revealed by the induced loss</em> of another trait.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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. <strong><em>The center of gravity in the study of the nucleic acids has now shifted from
                    heredity to development.
                </em>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.</strong>
        </p>

        <p>
            <strong>
                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.</strong> 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.)
        </p>
        <p>
            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.
        </p>
        <p>
            The issues of cancer, aging, and "hormone receptors," are also illuminated by seeing the organism as capable
            of adaptive modification of its genes.
        </p>

        <p>
            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 <em>telegony, heterosis,</em> and <em>xenia</em> might come
            into common use again, along with <em>genomic imprinting.
            </em>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<strong>;</strong> Salyers &amp; 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. <strong>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.
            </strong>
        </p>

        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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 <em>stress,</em> the <em>endonucleases,</em> and the <em>mobile packets of
                genes,</em> 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."
        </p>

        <p>
            "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.
        </p>
        <p>
            "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>
                Strong</strong>
            <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.</strong>
        </p>

        <p>
            <strong> </strong>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.)
        </p>
        <p>
            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.
        </p>
        <p>
            The importance of the retroviruses in the human genome hasn't been widely appreciated. ("almost 10%<strong>
                . . .</strong> homology with the retroviruses," Deb, et al, 1998.)
        </p>
        <p>
            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<strong
            >;</strong>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            On the level of an individual, the movement away from fitness and sensitivity would resemble the development
            of aging and degenerative disease<strong>; </strong>
            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.
        </p>
        <p>
            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.

            <h3>REFERENCES</h3>

            Taruscio D, et al., <strong>
                Human endogenous retroviruses and environmental endocrine disrupters: a connection worth exploring?
            </strong> Teratology. 1998 Aug;58(2):27-8.
        </p>
        <p>
            Taruscio D, et al., <strong>Human endogenous retroviral sequences: possible roles in reproductive
                physiopathology.
            </strong> Biol Reprod. 1998 Oct;59(4):713-24
        </p>

        <p>
            Genome 1998 Oct;41(5):662-8. <strong>A single-primer PCR-based retroviral-related DNA polymorphism shared by
                two distinct human populations.</strong> Deb P, Klempan TA, O'Reilly RL, Singh SM Department of Zoology,
            University of Western Ontario, London, Canada. <strong>"Almost 10% of the human genome consists of DNA
                sequences that share homology with retroviruses.</strong>
            These sequences, which represent a stable component of the human genome <strong>
                (although some may retain the ability to transpose),</strong> remain poorly understood." "Such novel
            polymorphisms should provide useful markers and permit assessment of evolutionary mechanisms associated with
            retroviral-related genomic evolution. "
        </p>

        <p>
            Chromosoma 1991 Dec;101(3):141-56 <strong>Integration site preferences of endogenous retroviruses.</strong>
            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.".
            <strong>"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."
            </strong>
        </p>
        <p>
            <strong> </strong>APMIS Suppl 1998;84:37-42 <strong>The potential of integrons and connected programmed
                rearrangements for mediating horizontal gene transfer</strong>.. 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<strong>
                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."
            </strong>"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 <strong>in a wider range of host
                systems."</strong>
        </p>

        <p>
            Clin Infect Dis 1996 Dec;23 Suppl 1:S36-43. <strong>Resistance gene transfer in anaerobes: new insights, new
                problems.</strong> Salyers AA, Shoemaker NB. <strong>"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</strong> transfer themselves but also mobilize
            coresident plasmids and excise and mobilize unlinked integrated elements." "An unusual feature of the
            Bacteroides conjugative transposons is that <strong>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</strong> in the first place."
        </p>
        <p>
            Genetics 1991 Aug;128(4):695-701 <strong>Adaptive reversion of a frameshift mutation in Escherichia
                coli.</strong> 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.
            <strong>This doctrine rests on the results of certain classical studies of the mutations that make bacteria
                resistant to phages and antibiotics.</strong> 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 <strong>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.</strong> 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.
        </p>
        <p>
            Science 1993 Oct 15;262(5132):317-319. <strong>Whither directed mutation? </strong>
            Foster, P.L.
        </p>

        <p>
            Science 1995, 268(5209):418-420. <strong>Adaptive mutation in Escherichia coli: a role for
                conjugation.</strong> Radicella JP, Park PU, Fox, M.S. Nature 1998 Mar 12;392(6672):141-2<strong>
                Are retrotransposons long-term hitchhikers?</strong> Burke WD, Malik HS, Lathe WC 3rd, Eickbush TH.
        </p>
        <p>
            J Biomol Struct Dyn 1998 Feb;15(4):717-21 <strong>Mammalian retroposons integrate at kinkable DNA
                sites.</strong> 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."
        </p>

        <p>
            J. Mol Evol 1997 Dec;45(6):599-609 <strong>The evolution of MHC diversity by segmental duplication and
                transposition of retroelements.</strong> Kulski JK, Gaudieri S, Bellgard M, Balmer L, Giles K, Inoko H,
            Dawkins RL.
        </p>
        <p>
            Biochemistry (Mosc) 1997 Nov;62(11):1202-5. <strong>Telomerase is a true reverse transcriptase. A
                review.</strong> Cech TR, Nakamura TM, Lingner J Department of Chemistry and Biochemistry, Howard Hughes
            Medical Institute, University of Colorado,Boulder. <strong>"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</strong>."
        </p>

        <p>
            Gene 1997 Dec 31;205(1-2):177-82 <strong>Mobile elements inserted in the distant past have taken on
                important functions.</strong> Britten RJ.
        </p>
        <p>
            Genetika 1994 Jun;30(6):725-30 <strong>["Adaptive transposition" of retrotransposons in the Drosophila
                melanogaster genome accompanying the increase in features of adaptability].
            </strong> Beliaeva ES, Pasiukova EG, Gvozdev V.A. . "<strong>The transpositions were accompanied by a
                dramatic increase in individual fitness (competitive success)."</strong>
        </p>

        <p>
            Genetika 1997 Aug;33(8):1083-93 <strong>[Stress induction of retrotransposon transposition in Drosophila:
                reality of the phenomenon, characteristic features, possible role in rapid evolution].</strong>
            Vasil'eva LA, Ratner VA, Bubenshchikova EV "This stress response involved mobilization of retrotransposons."
            <strong>"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.</strong>
            Passing through a "bottleneck," a population can rapidly and significantly alter its population norm and
            become the founder of new, normal forms."
        </p>

        <p>
            Mol Biol (Mosk) 1995 May-Jun;29(3):522-8 <strong>[Conserved regions of potential ORF1 protein products of
                mobile elements and retroviral proteins, encoded by the gag gene].
            </strong> Kanapin AA, Ivanov VA, Il'in IuV.
        </p>
        <p>
            Radiats Biol Radioecol 1995 May-Jun;35(3):356-63 <strong>[DNA analysis of retroposon-like genetic LINE
                elements in blood plasma of rats exposed to radio-diapason electromagnetic waves].</strong> [Article in
            Russian] Belokhvostov AS, Osipovich VK, Veselova OM, Kolodiazhnaia VA<strong>
                The elevation of LINE-elements' DNA level was revealed in blood plasma of rats exposed to
                electromagnetic waves.</strong> The amount of full-size 5'-containing LINE-elements copies was
            increased<strong>
                especially. Connection of this effect with retrotransposon activation and genetic instability condition
                of organism development is supposed.
            </strong>
        </p>

        <p>
            <strong> </strong>Dokl Akad Nauk 1995 Jan;340(1):138-40 <strong>[Induction of virus-like particles Tu1 by
                the mini-Tu1 element in the SPT3 mutant strain of Saccharomyces cerevisiae].
            </strong> Reznik NL, Zolotova LI, Shuppe NG.
        </p>
        <p>
            Dokl Akad Nauk 1994 Dec;339(6):838-41 <strong>[Extracellular virus-like particles retrotransposon Gypsy (MDG
                4) as an infectivity factor].</strong> Semin BV, Il'in IuV.
        </p>
        <p>
            Mol Biol (Mosk) 1994 Jul-Aug;28(4):813-21.<strong>
                [Expression of the third open reading frame of the drosophila MDG4 retrotransposon similar to the
                retroviral env-genes, occurring through splicing].
            </strong> 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). <strong>Thus, these elements
                have a strong structural resemblance to the integrated forms of vertebrate retroviruses."</strong>
            "The regulation at the level of splicing is supposed to be one of the most important factors controlling the
            transposition frequency of MDG4."
        </p>
        <p>
            Genetika 1994 Jun;30(6):743-8 <strong>[Introduction of a single transpositionally-active copy of MDG4 into
                the genome of a stable line of Drosophila melanogaster causes genetic instability].</strong>
            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."
        </p>

        <p>
            Genetika 1991 Mar;27(3):404-10 <strong>[Maintenance of the copy number of retrotransposon MDG3 in the
                Drosophila melanogaster genome].</strong> 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 <strong>results in appearance of hybrid genomes carrying
                up to 7-10 copies, instead of 2-4 copies expected.</strong> 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. <strong>
                The data obtained suggest the existence of genomic mechanism for maintenance of retrotransposon copy
                number on a definite level.</strong>
        </p>
        <p>
            <strong> </strong>Biull Eksp Biol Med 1998 Jul;126(7):4-14 <strong>[The role of retroposition in the
                self-regulation of genome processes (do genes program the body and retroposons program genome]?</strong>
            Bebikhov DV, Postnov AIu, Nikonenko TA.
        </p>
        <p>
            Genetika 1996 Jul;32(7):902-13 <strong>[Analysis of motifs of functional MDG2 sites in assuring its possible
                molecular functions].</strong> Ratner VA, Amikishiev VG "Enhancers of mobile genetic elements are
            assumed to determine modification of adjacent genes and polygenes. <strong>Excisions and transpositions of
                mobile elements seem to be induced by external stress factors or physiological factors through a
                heat-shock system."
            </strong>
        </p>
        <p>
            <strong> </strong>Genomics 1998 Dec 15;54(3):542-55 <strong>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.</strong> Long Q, Bengra C, Li C, Kutlar F, Tuan D. "Transcription of the human beta-like <strong
            >
                globin genes in erythroid cells</strong> 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 <strong>retrotransposon belonging to the ERV-9 family of human endogenous retroviruses</strong>
            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. <strong>Our findings suggest the possibility that this LTR
                retrotransposon may serve a relevant host function in regulating the transcription of the
                beta-globin</strong> LCR." Copyright 1998 Academic Press.
        </p>
        <p>
            Genetika 1995 Dec;31(12):1605-13 <strong>[Heterologous induction of the retrotransposon Ty1: reverse
                transcriptase plays a key role in initiating the retrotransposition cycle].
            </strong> 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. <strong>
                Expression of retrotransposons induced formation of viruslike particles (VLPs) associated with
                full-length Ty1 RNA and DNA sequences.</strong> This phenomenon was termed heterologous induction.
            <strong>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.</strong> Possible mechanisms of
            induction of Ty1 transposition by homologous and heterologous elements are discussed. Hum Exp Toxicol 1998
            Oct;17(10):560-3 <strong>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.</strong> 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<strong>
                to a member of the steroid-thyroid receptor superfamily can disturb the normal maturation of other
                members of the family,</strong> 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." <strong>
                "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."
            </strong>
        </p>
        <p>
            <strong> </strong>Life Sci 1998;63(6):PL 101-5 <strong>Neonatal vitamin E treatment induces long term
                glucocorticoid receptor changes: an unusual hormonal imprinting effect.</strong> Csaba G, Inczefi-Gonda
            A. "Thousandfold tocopherol did not compete with labeled dexamethasone for their receptors,
            suggesting<strong>
                that neonatal vitamin E imprinting effect was not done at direct receptorial level."</strong>
        </p>
        <p>
            <strong> </strong>J Hypertens 1998 Jun;16(6):823-8 <strong>Female Wistar-Kyoto and SHR/y rats have the same
                genotype but different patterns of expression of renin and angiotensinogen genes.</strong> 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 <strong>genome imprinting</strong> of these genes or of another gene that
            functions as a common regulator of renin and angiotensinogen."
        </p>

        <p>
            Gen Pharmacol 1998 May;30(5):685-7 <strong>Imprinting of thymic glucocorticoid receptor and uterine estrogen
                receptor by a synthetic steroid hormone at different times after birth.</strong> 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."
        </p>
        <p>
            Gen Pharmacol 1998 May;30(5):647-9 <strong>Fetal digoxin treatment enhances the binding capacity of thymic
                glucocorticoid receptors in adult female rats.</strong> 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.
        </p>

        <p>
            Hum Exp Toxicol 1998 Feb;17(2):88-92 <strong>Transgenerational effect of a single neonatal benzpyrene
                treatment on the glucocorticoid receptor of the rat thymus.</strong> Csaba G, Inczefi-Gonda A. Hormonal
            imprinting is provoked perinatally by the appropriate <strong>hormone on its receptor,</strong>
            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 <strong>up to the third (F2) generation.
            </strong>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 <strong>
                transgenerational transmission</strong> 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.
        </p>

        <p>
            Genetika 1994 Apr;30(4):437-44 [Tv1--a new family of Drosophila virilis retrotransposons]. Andrianov BV,
            Shuppe NG.<strong>"The method is based on the hypothesis about the universal character of retrotransposition
                through reverse transcription."</strong>
        </p>
        <p>
            <strong> </strong>Genetika 1990 Mar;26(3):399-411 <strong>[Transpositional bursts and chromosome
                rearrangements in unstable lines of Drosophila].
            </strong> 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<strong>
                it embraces total genome and includes not only transpositions of different mobile elements but also
                recombination processes--homologous recombination</strong>
            for LTR's and gene conversion."
        </p>

        <p>
            Eksp Onkol 1986;8(2):29-32 <strong>
                [Nature of the endogenous retrovirus-like particles of the rat liver].
            </strong>
            Korokhov NP, Pyrinova GB, Kurtsman MIa, Tomsons VP, Salganik RI.
        </p>

        © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
    </body>
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    <head><title>Intelligence and metabolism</title></head>
    <body>
        <h1>
            Intelligence and metabolism
        </h1>

        <p>
            <hr />
            <hr />
        </p>

        <p>
            <strong>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.</strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>
        <p>
            <strong>Stress early in life can impair learning, cause aggressive or compulsive behavior, learned
                helplessness, shyness, alcoholism, and other problems.</strong>
        </p>
        <p>
            <strong>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.
            </strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>

        <p>
            <hr />
            <hr />
        </p>
        <p>
            <strong>Baroness Blatch: "My Lords, the levels of achievement are well above the national average of our own
                state schools."
            </strong>
        </p>
        <p>
            <strong>"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?"</strong>
        </p>
        <p>
            <strong>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.
            </strong>
        </p>
        <p>
            <strong>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.</strong>
        </p>

        <p>
            <hr />
            <hr />
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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 <strong><em>preferences</em></strong>

            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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"
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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 <strong><em>The Kallikak Family: A Study in the
                    Heredity of Feeble- Mindedness</em>)</strong>, 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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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 <strong><em>feel.</em></strong> He
            had developed only part of his personality.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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 <strong><em
                >Genetic Studies of Genius</em></strong>). 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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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., <em>
                Client-Centered Therapy.</em>
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            "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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p><h3>REFERENCES</h3></p>
        <p>
            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."
        </p>
        <p>
            John Holt, from an interview in <em>Mother Earth News,</em> July/August, 1980<strong>:</strong>
            "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."
        </p>
        <p>
            John Holt, from the introduction to his book, <em>Teach Your Own,</em> (New York: Dell, 1981)<strong
            >:</strong> "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."
        </p>

        <p>
            "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?"
        </p>
        <p>
            Psychosom Med 1984 Nov-Dec;46(6):546-8. <strong>Rapid communication: whole blood serotonin and the type A
                behavior pattern.</strong> Madsen D, McGuire MT.<strong>
                In 72 young males, whole blood serotonin is shown to have a pronounced relationship with the Type A
                behavior pattern.</strong> The relationship is explored with multivariate statistical techniques.
        </p>
        <p>
            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.<strong>
                Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor
                function in rat brain.</strong>
        </p>

        <p>
            Ann Med 2000 Apr;32(3):210-21. <strong>Role of serotonin in memory impairment.</strong> Buhot MC, Martin S,
            Segu L.
        </p>
        <p>
            Ivan Illich and Etienne Verne, <strong><em>Imprisoned in the global classroom.</em></strong>
            London, Writers and Readers Publishing Cooperative, 1976.
        </p>
        <p>
            Ivan Illich, <strong><em>Deschooling society.</em></strong> Harmondsworth: Penguin, 1976 (1971).
        </p>

        <p>
            ----Tools for Conviviality<em> </em>(1973).
        </p>
        <p><strong><em>----Toward a history of needs.</em></strong> New York, Pantheon Books, c1978.</p>
        <p>
            ----Limits to medicine. medical nemesis : the expropriation of health. Harmondsworth New York, Penguin,
            1977.
        </p>
        <p>
            <strong><em>----Celebration of awareness: a call for institutional revolution.</em></strong> Harmondsworth,
            Penguin Education, 1976. Pelican books Originally published: Garden City [N.Y.]: Doubleday, 1970; London:
            Calder and Boyars, 1971.
        </p>

        <p><strong><em>----Disabling professions.</em></strong> London, Boyars, 1977, Ideas in progress series.</p>
        <p>
            Eur J Pharmacol 1992 Feb 25;212(1):73-8. <strong>5-HT3 receptor antagonists reverse helpless behaviour in
                rats.</strong> 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.
        </p>
        <p>
            Neuropharmacology 1992 Apr;31(4):323-30. <strong>Presynaptic serotonin mechanisms in rats subjected to
                inescapable shock.</strong> 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."
        </p>
        <p>
            Neurochem Int 1992 Jul;21(1):29-35.<strong>
                In vitro neurotransmitter release in an animal model of depression</strong>. 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."
        </p>
        <p>
            Psychiatry Res 1994 Jun;52(3):285-93. <strong>In vivo serotonin release and learned helplessness.</strong>
            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. <strong>These data support the hypothesis that a cortical serotonergic excess is causally related
                to the development of learned helplessness.</strong>
        </p>
        <p>
            Pharmacol Biochem Behav 1994 Jul;48(3):671-6. <strong>Does learned helplessness induction by haloperidol
                involve serotonin mediation?</strong> 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.
        </p>
        <p>
            Arzneimittelforschung 1975 Nov; 25(11):1737-44<strong>. [Central action of WA-335-BS, a substance with
                peripheral antiserotonin and antihistaminic activity].</strong> Kahling J, Ziegler H, Ballhause H. "In
            rats and mice the serotonin and histamine antagonistic drug <strong>. . .</strong> (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<strong> </strong>

            effects:<strong>
                therefore it may have antidepressant properties. WA 335-BS proved to be</strong>
            <strong>very effective against isolation-induced aggression in male mice.</strong> 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."
        </p>
        <p>
            Neuroscience 2000;100(4):749-68<strong>. Behavioral, neurochemical and endocrinological characterization of
                the early social isolation syndrome.</strong> 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<strong>
                understanding the genesis of depression and related affective disorders.</strong> Recent studies from
            our laboratory point to the relevance of studying the social isolation syndrome as a function of home caging
            conditions."
        </p>

        <p>
            Stroke 1991 Nov;22(11):1448-51. <strong>Platelet secretory products may contribute to neuronal
                injury.</strong> 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.<strong>
                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.</strong>
        </p>
        <p>
            Am J Psychiatry 1981 Aug;138(8):1082-5.<strong>
                Tryptophan metabolism in children with attentional deficit disorder.</strong> 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.
        </p>
        <p>
            J Neuropsychiatry Clin Neurosci 1990 Summer;2(3):268-74.<strong>
                Autistic children and their first-degree relatives: relationships between serotonin and norepinephrine
                levels and intelligence.</strong> 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. <strong>Both plasma NE and whole-blood
                5-HT were negatively correlated with vocabulary performance."
            </strong>

            "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."
        </p>
        <p>
            Biol Psychiatry 1998 Dec 15;44(12):1321-8. <strong>Cerebrospinal fluid monoamines in Prader-Willi
                syndrome.</strong> 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<strong>
                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
            </strong>
            in PWS individuals . . . ."
        </p>
        <p>
            Pharmacol Biochem Behav 1976 Jul;5(1):55-61. <strong>The role of serotonergic pathways in isolation-induced
                aggression in mice.</strong> 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<strong>
                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</strong>

            or impaired inclined-screen performance. <strong>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.</strong> PCPA, a serotonin depletor,
            also significantly <strong>antagonized isolation-induced aggression</strong> 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.
        </p>
        <p>
            Probl Endokrinol (Mosk) 1979 May-Jun;25(3):49-52<strong>
                [Role of serotonin receptors of the medial-basal hypothalamus in the mechanisms of negative feedback of
                the hypophyseal-testicular complex].</strong> 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."
        </p>
        <p>
            Encephale 1994 Sep-Oct;20(5):521-5. <strong>[Can a serotonin uptake agonist be an authentic antidepressant?
                Results of a multicenter, multinational therapeutic trial].</strong> 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. <strong>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.</strong> Biochemical studies have
            revealed that in contrast to classical tricyclic antidepressant,<strong>
                tianeptine stimulates 5-HT uptake
            </strong>
            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<strong>
                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</strong> 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%).
        </p>
        <p>
            Psychopharmacology (Berl) 1998 Oct;139(3):255-60.<strong>
                Ca2+ dependency of serotonin and dopamine release from CNS slices of chronically isolated rats.</strong>
            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. <strong>A
                significant increase in KCl stimulated release of 5-HT was observed in chronically isolated animals when
                compared to controls.
            </strong>
            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." <strong>"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</strong> several CNS structures."
        </p>

        <p>
            Gen Pharmacol 1994 Oct;25(6):1257-1262.<strong>
                Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of
                plasma hemoglobin; the protective action of calmodulin antagonists.</strong> Koren-Schwartzer N,
            Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
            <strong>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</strong> 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<strong>.. Injection of serotonin also induced a marked elevation of plasma hemoglobin,
                reflecting lysed erythrocytes,</strong> which was also prevented by treatment with the CaM antagonists.
            5.<strong>
                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.</strong>
        </p>
        <p>
            Gen Pharmacol 1994 Oct;25(6):1257-1262.<strong>
                Serotonin-induced decrease in brain ATP, stimulation of brain anaerobic glycolysis and elevation of
                plasma hemoglobin; the protective action of calmodulin antagonists.</strong> Koren-Schwartzer N,
            Chen-Zion M, Ben-Porat H, Beitner R Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
            <strong>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</strong> 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.
        </p>

        <p>
            J Neural Transm 1998;105(8-9):975-86. <strong>Role of tryptophan in the elevated serotonin-turnover in
                hepatic encephalopathy.</strong> 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."
        </p>
        <p>
            Tugai VA; Kurs'kii MD; Fedoriv OM. <strong>[Effect of serotonin on Ca2+ transport in mitochondria conjugated
                with the respiratory chain].</strong> Ukrainskii Biokhimicheskii Zhurnal, 1973 Jul-Aug, 45(4):408-12.
        </p>
        <p>
            Kurskii MD; Tugai VA; Fedoriv AN.<strong>
                [Effect of serotonin and calcium on separate components of respiratory chain of mitochondria in some
                rabbit tissues].</strong>
            Ukrainskii Biokhimicheskii Zhurnal, 1970, 42(5):584-8.
        </p>

        <p>
            Watanabe Y; Shibata S; Kobayashi B. <strong>Serotonin-induced swelling of rat liver mitochondria.</strong>
            Endocrinologia Japonica, 1969 Feb, 16(1):133-47.
        </p>
        <p>
            Mahler DJ; Humoller FL. <strong>The influence of serotonin on oxidative metabolism of brain
                mitochondria.</strong> Proceedings of the Society for Experimental Biology and Medicine, 1968 Apr,
            127(4):1074-9.
        </p>
        <p>
            Eur J Pharmacol 1994 Aug 11;261(1-2):25-32. <strong>The effect of alpha 2-adrenoceptor antagonists in
                isolated globally ischemic rat hearts.</strong> 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<strong>
                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."
            </strong>
        </p>

        <p>
            Zubovskaia AM. <strong>[Effect of serotonin on some pathways of oxidative metabolism in the mitochondria of
                rabbit heart muscle].</strong> Voprosy Meditsinskoi Khimii, 1968 Mar-Apr, 14(2):152-7.
        </p>
        <p>
            Warashina Y. <strong>
                [On the effect of serotonin on phosphorylation of rat liver mitochondria</strong>]. Hoppe-Seylers
            Zeitschrift fur Physiologische Chemie, 1967 Feb, 348(2):139-48.
        </p>
        <p>
            Eur Neuropsychopharmacol 1997 Oct;7 Suppl 3:S323-S328. <strong>Prevention of stress-induced morphological
                and cognitive consequences</strong>.. 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. <strong>
                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.</strong> Tianeptine
            is known to enhance serotonin uptake, and we compared it with fluoxetine, an inhibitor of 5-HT reuptake, as
            well as with desipramine. <strong>Tianeptine treatment (10 mg/kg/day) prevented the stress-induced atrophy
                of dendrites of CA3 pycamidal neurons,</strong> whereas neither fluoxetine (10 mg/kg/day) nor
            desipramine (10 mg/kg/day) had any effect. <strong>Tianeptine treatment also prevented the stress-induced
                impairment of radial maze learning.</strong>

            Because <strong>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.</strong>
        </p>

        © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
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        <title>
            Intuitive knowledge and its development
        </title>
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    <body>
        <h1>
            Intuitive knowledge and its development
        </h1>

        <p></p>
        <p>
            <strong>Understanding consciousness is necessary for understanding life. Variations of consciousness, such
                as dementia, depression, delusion, or insight, originality, curiosity have to be understood
                biologically.
            </strong>
            <strong> </strong>
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>

        <p>
            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":
        </p>
        <p>
            "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."
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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, <strong><em>intelligo</em></strong>
            meant "I perceive." I suspect that a Roman might have perceived the word <strong><em>intelligens</em
                ></strong> as being derived from roots such as <strong><em>tele</em></strong>--from Greek, or <strong
            >tela,</strong> web, warp thread--and <strong><em>
                    ligo or lego</em></strong>, connoting the binding in or gathering of what is distant or extended.)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p><h3>NOTES AND REFERENCES</h3></p>

        <p>
            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.
        </p>
        <p>
            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).
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            Neurosci Behav Physiol 1985 Jan-Feb;15(1):27-32 Bioelectrical correlates of protective mechanisms of the
            brain. Bekhtereva NP.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            Fiziol Zh SSSR Im I M Sechenova 1984 Jul;70(7):1071-5 [Natal'ia Petrovna Bekhtereva]. Iliukhina VA Biography
        </p>
        <p>
            Hum Physiol 1982 Sep-Oct;8(5):303-16 Cerebral organization of emotional reactions and states. Bekhtereva NP,
            Kambarova DK, Ivanov GG
        </p>
        <p>
            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.
        </p>

        <p>
            Vestn Akad Med Nauk SSSR 1979;(7):30-7 [Potentials of neurophysiology in the study of a resistant
            pathological state]. Bekhtereva NP
        </p>
        <p>
            Act Nerv Super (Praha) 1976;18(3):157-67 The neurophysiological code of simplest mental processes in man.
            Bekhtereva NP
        </p>
        <p>
            Vestn Akad Med Nauk SSSR 1975;(8):8-19 [Cerebral organization of human emotions]. Bekhtereva NP, Smirnov VM
        </p>
        <p>
            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.
        </p>
        <p>
            Vopr Neirokhir 1972 Jan-Feb;36(1):7-12 [Therapeutic electric stimulation of deep brain structures].
            Bekhtereva NP, Bondarchuk AN, Smirnov VM, Meliucheva LA
        </p>

        <p>
            Vestn Akad Med Nauk SSSR 1972;27(9):43-9 [Principles of functional organization of the human brain].
            [Article in Russian] Bekhtereva NP.
        </p>
        <p>
            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
        </p>
        <p>
            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."
        </p>

        © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
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    <head><title>Iron's Dangers</title></head>
    <body>
        <h1>
            Iron's Dangers
        </h1>
        <p>
            Q: You believe iron is a deadly substance. Why?
        </p>
        <p>
            Iron is a potentially toxic heavy metal. In excess, it can cause cancer, heart disease, and other illnesses.
        </p>
        <p>
            Q: Could you tell us about some of these studies?
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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."
        </p>
        <p>
            Q: How does excess iron accelerate our aging process?
        </p>
        <p>
            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.
        </p>
        <p>
            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.]
        </p>
        <p>
            Q: Exactly how much iron do we need to eat?
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Q. Don't women need extra iron?
        </p>

        <p>
            That's a misunderstanding.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Q: Don't you need iron supplements if you are anemic?
        </p>
        <p>
            In general, no.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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?
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            Q. What foods contain iron?
        </p>
        <p>
            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.
        </p>

        <p>
            Q.: Why does federal law require the addition of iron to those foods?
        </p>
        <p>
            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.
        </p>
        <p>
            Q: Can cooking in an iron frying pan put iron into food?
        </p>
        <p>
            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.
        </p>
        <p>
            Q: What about aluminum?
        </p>
        <p>
            Aluminum and iron react similarly in cells and are suspected causes of Alzheimer's disease.
        </p>
        <p>
            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.
        </p>
        <p>
            Q: What kind of cooking pots or utensils are safe?
        </p>
        <p>
            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.
        </p>

        <p>
            Q: How do I know which stainless steels are safe?
        </p>
        <p>
            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.
        </p>
        <p>
            Q: Why is there iron in most multi-vitamin and mineral products?
        </p>
        <p>
            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.
        </p>
        <p>
            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?
        </p>
        <p>
            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.
        </p>
        <p>
            Q: How does copper help us?
        </p>
        <p>
            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.
        </p>

        <p>SUMMARY:</p>
        <p>
            Iron is a potentially toxic heavy metal; an excess can cause cancer, heart disease, and other illnesses.
        </p>
        <p>
            Other heavy metals, including lead and aluminum, are toxic; pans and dishes should be chosen carefully.
        </p>
        <p>
            Iron causes cell aging.
        </p>
        <p>
            Drinking coffee with iron rich foods can reduce iron's toxic effects.
        </p>
        <p>
            Use shrimp and oysters, etc., to prevent the copper deficiency which leads to excess storage of iron.
        </p>
        <p>
            Avoid food supplements which contain iron.
        </p>
        <p>
            Take about 100 units of vitamin E daily; your vitamin E requirement increases with your iron consumption.
        </p>
        <p>GLOSSARY:</p>
        <p>
            Free radicals are fragments of molecules that are very destructive to all cells and system of the body.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p><h3>REFERENCES</h3></p>

        <p>
            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.
        </p>
        <p>
            M. Bartal, et al., "Lipid peroxidation in iron deficiency anemia--Reply," Acta Haematol. 91(3), 170, 1994.
        </p>
        <p>
            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>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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>
        <p>
            P. C. Elwood, "Iron, magnesium, and ischemic heart disease," Proc. of Nutrition Society 53(3), 599-603,
            1994.
        </p>
        <p>
            J. Goodfield, An Imagined World, Penguin Books, N.Y., 1984.
        </p>
        <p>
            M. Galleano and S. Puntarulo, "Mild iron overload effect on rat liver nuclei," Toxicol. 93(2-3), 125-34,
            1994.
        </p>
        <p>
            E. C. Hirsch, "Biochemistry of Parkinson's disease with special reference to the dopaminergic systems," Mol.
            Neurobiol. 9(1-3), 135-142, 1994.
        </p>
        <p>
            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. &amp; Med. 109(1), 43-45, 1989.
        </p>

        <p>
            S. Kiechl, et al., "Body iron stores and presence of carotid atherosclerosis--results from the Bruneck
            study," Arterioscler. Thromb. 14(10), 1625-1630, 1994.
        </p>
        <p>
            A. V. Kozlov, et al., "Role of endogenous free iron in activation of lipid peroxidation during ischemia,"
            Bull. Exp. Biol. Med. 99(1), 1984.
        </p>
        <p>
            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.
        </p>
        <p>
            E. E. Letendre, "Importance of iron in the pathogenesis of infection and neoplasm," Trends in Biochemical
            Sci., April, 1985, 166-168.
        </p>
        <p>
            V. M. Mann, et al., "Complex 1, iron and ferritin in Parkinson's disease substantia nigra," Ann. of
            Neurology 36(6), 876-81, 1994.
        </p>
        <p>
            Z. Maskos and W. H. Koppenol, "Oxyradicals and multivitamin tablets," Free Radical Biol. &amp; Med. 11,
            669-670, 1991.
        </p>
        <p>
            S. Ozsoylu, "Lipid peroxidation in iron deficiency anemia," Acta Haematol. 91(3), 170, 1994.
        </p>
        <p>
            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.
        </p>
        <p>
            M. Savoiardo, et al., "Magnetic resonance imaging in progressive supranuclear palsy and other parkinsonian
            disorders," J. Neural Trans. (suppl. 42), 93-110, 1994.
        </p>
        <p>
            J. J. Strain, "Putative role of dietary trace elements in coronary heart disease and cancer," Brit. J.
            Biomed. Sci. 51(3), 241-251, 1994.
        </p>
        <p>
            Vanrensburg, S. J., et al., "Lipid peroxidation and platelet membrane fluidity--implications for Alzheimer's
            disease?", Neuroreport 5(17), 2221-2224, 1994.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            *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.
        </p>

        <p>
            © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
        </p>
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    <head><title>BSE - mad cow - scrapie, etc.: Stimulated amyloid degeneration and the toxic fats</title></head>
    <body>
        <h1>
            BSE - mad cow - scrapie, etc.: Stimulated amyloid degeneration and the toxic fats
        </h1>

        <article class="posted">
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.)
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.)
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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<strong>,</strong> 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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                Beginning in 1946, Bikini Island was used to test atomic bombs. In 1954, they began to test hydrogen
                bombs in the Pacific<strong>;</strong> 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.
            </p>
            <p>
                Within two years, hundreds of people in that area (of the Fore tribe) were dying from kuru, with the
                mortality highest among the women<strong>;</strong> 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.
            </p>
            <p>
                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.)
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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<strong>;
                </strong>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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                Serum amyloid P is called “the female protein” in hamsters, because of its association with
                estrogen<strong>;</strong> 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.
            </p>
            <p>
                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.
            </p>
            <p>
                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).
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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<strong>: </strong>Campbell, et
                al., 2004<strong>; </strong>Dave, et al., 1994<strong>; </strong>Ronnback and Hansson, 1992<strong
                >)</strong>.
            </p>
            <p>
                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.
            </p>
            <p>
                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<strong>:</strong> In the aging or injured brain, the glial cells (mainly
                astrocytes) proliferate, in reparative processes that sometimes become exaggerated and harmful.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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, <strong
                ><em>Atlas of the cellular structure of the human nervous system,</em></strong> 1991), so the
                objectivity of pathological studies shouldn’t be over-estimated.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>
                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.
            </p>
            <p>&nbsp;</p>
            <p><h3>REFERENCES</h3></p>
            <p>
                J Autoimmun. 1989 Aug;2(4):543-52. <strong>Estrogen induces the development of autoantibodies and
                    promotes salivary gland lymphoid infiltrates in normal mice.</strong> Ahmed SA, Aufdemorte TB, Chen
                JR, Montoya AI, Olive D, Talal N. “We hypothesize that an imbalance of the in utero sex hormone
                microenvironment critically influences the<strong>
                    fetal immune system. We have termed this influence immunological imprinting. After birth this
                    imprinting could contribute to immune-mediated disorders. To test this hypothesis, we developed a
                    mouse model in which normal mice were</strong> prenatally exposed to estrogens. In preliminary
                experiments, these mice produced higher numbers of APFC to Br-ME, particularly in the peritoneal cavity
                cell exudates. Furthermore, mice prenatally exposed to <strong>estrogens had accelerated development of
                    autoimmune salivary gland lesions indistinguishable from Sjogren's syndrome
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            </p>
            <p>
                J Gen Virol. 1978 Dec;41(3):503-16. <strong>The scrapie agent: evidence against its dependence for
                    replication on intrinsic nucleic acid.</strong> Alper T, Haig DA, Clarke MC. Exposure of the scrapie
                agent to u.v. light at various wavelengths has shown<strong>
                    that light of 237 nm is 4 to 5 times as effective in inactivating it as 'germicidal' wavelengths
                    (250 to 270 nm); whereas with systems that depend on</strong> RNA or DNA for function, inactivation
                is most effective by wavelengths in the germicidal range and there is a minimum of response in the
                wavelength region round 240 nm. The action spectrum for the scrapie agent is reminiscent of the
                absorption spectrum for purified bacterial endotoxin, identified as a lipopolysaccharide complex.
            </p>
            <p>
                Am J Pathol. 1971 Oct; 65(1): 43-50. <strong>Disseminated amyloidosis in germfree mice. Spontaneous
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                Neurobiol Dis. 2002 Dec; 11(3): 386-93. <strong>Astrocytes accumulate 4-hydroxynonenal adducts in murine
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                Biol Chem. 1999 Nov;380(11):1295-306. <strong>Prion rods contain an inert polysaccharide
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                    by acid hydrolysis of the remnant and methylation analysis showed 80% 1,4-, 15% 1,6- and 5%
                    1,4,6-linked glucose units. The physical and chemical properties as well as the absence of terminal
                    glucose units indicate a very high molecular mass of the polysaccharide. No evidence was found for
                    covalent bonds between PrP and the polysaccharide. The polysaccharide certainly contributes to the
                    unusual chemical and physical stability of prion rods, acting like a scaffold.</strong>”
            </p>
            <p>
                Arch Neurol. 1974 Sep; 31(3): 174-82. <strong>Altered cell membranes in Creutzfeldt-Jakob
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            <p>
                Neuropathol Appl Neurobiol. <strong> 1999</strong> Feb;25(1):20-8. <strong>The acute inflammatory
                    response in CNS following injection of prion brain homogenate or normal brain homogenate.</strong>
                Betmouni S, Perry VH. “The neuropathological hallmarks of end-stage prion disease are vacuolation,
                neuronal loss, astrocytosis and deposition of PrPSc amyloid. We have also shown that there is an
                inflammatory response in the brains of scrapie-affected mice from 8 weeks post-injection.” <strong>“The
                    well circumscribed inflammatory response seen previously at 8 weeks is therefore a consequence of a
                    disease process rather than a surgical artefact. This disease process may be related to a localized
                    accumulation of PrPSc sufficient to stimulate an inflammatory response which in turn may contribute
                    to neuronal loss.”</strong>
            </p>
            <p>
                Neuropathol Appl Neurobiol. 1999 Feb; 25(1): 20-8. <strong>The acute inflammatory response in CNS
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            </p>
            <p>
                Curr Biol. 1999 Sep 23;9(18):R677-9. <strong>Vacuolation in murine prion disease: an informative
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            </p>
            <p>
                Neuroscience. 1996 Sep; 74(1): 1-5. <strong>Evidence for an early inflammatory response in the central
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                Ann N Y Acad Sci 1982;396:131-43. <strong>Alzheimer's disease and transmissible virus dementia
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                Neuroscience. 1996 Sep;74(1):1-5. <strong>Evidence for an early inflammatory response in the central
                    nervous system of mice with scrapie.</strong> Betmouni S, Perry VH, Gordon JL. “In Alzheimer's
                disease, the most prevalent of the neurodegenerative diseases, inflammation of the CNS contributes to
                the pathology and is a target for therapy. In contrast, the group of neurodegenerative conditions known
                as the Prion Diseases have been widely reported as lacking any inflammatory elements despite the many
                similarities between the pathologies of Alzheimer's Disease and Prion Diseases We have found evidence
                for an inflammatory component in mouse scrapie, characterized by microglial activation and T-lymphocyte
                recruitment, which appears long before any clinical signs of the disease and spreads along well-defined
                anatomical pathways.”
            </p>
            <p>
                Nat Med. 1999 Jun;5(6):694-7. <strong>Serum amyloid P component controls chromatin degradation and
                    prevents antinuclear autoimmunity.</strong> Bickerstaff MC, Botto M, Hutchinson WL, Herbert J,
                Tennent GA, Bybee A, Mitchell DA, Cook HT, Butler PJ, Walport MJ, Pepys MB. “Serum amyloid P component
                (SAP)<strong> . . .</strong> is the single normal circulating protein that shows specific
                calcium-dependent binding to DNA and chromatin in physiological conditions. The avid binding of SAP
                displaces H1-type histones and thereby solubilizes native long chromatin, which is otherwise profoundly
                insoluble at the physiological ionic strength of extracellular fluids.” “Here we show that mice with
                targeted deletion of the SAP gene spontaneously develop antinuclear autoimmunity and severe
                glomerulonephritis, a phenotype resembling human systemic lupus erythematosus, a serious autoimmune
                disease.” “These findings indicate that SAP has an important physiological role, inhibiting the
                formation of pathogenic autoantibodies against chromatin and DNA, probably by binding to chromatin and
                regulating its degradation.”
            </p>
            <p>
                J Neurosci Res. 2004 Feb 15;75(4):565-72. <strong>Chronic exposure to aluminum in drinking water
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            </p>
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                    century clearly suggests that inherited variation is not restricted to the changes in genomic
                    sequences.</strong> The prion model, originally based on unusual transmission of certain
                neurodegenerative diseases in mammals, provides a molecular mechanism for the template-like reproduction
                of alternative protein conformations. <strong>Recent data extend this model to protein-based genetic
                    elements in yeast and other fungi</strong>.” “Prion-forming abilities appear to be conserved in
                evolution, despite the divergence of the corresponding amino acid sequences. Moreover, a wide variety of
                proteins of different origins appear to possess the ability to form amyloid-like aggregates, that in
                certain conditions might potentially result in prion-like switches. <strong>This suggests a possible
                    mechanism for the inheritance of acquired traits,</strong> postulated in the Lamarckian theory of
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                    Hamster female protein, a sex-limited pentraxin, is a constituent of Syrian hamster amyloid.</strong
                > Coe JE, Ross MJ.
            </p>
            <p>
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                Y, Setoguchi M, Gondo T, Ishihara T. “We herein report that experimental murine amyloid A (AA)
                deposition is accelerated by oral administration of semipurified amyloid fibrils extracted from
                different species. Three groups of mice were treated with semipurified murine AA amyloid fibrils,
                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.”
                “Amyloid deposits were detected in 14 out of 15 mice treated with murine AA amyloid fibrils, 12 out of
                15 mice treated with bovine AA amyloid fibrils and 11 out of 15 mice treated with human A(lambda)
                amyloid fibrils. No amyloid deposits were detected in control mice receiving the inflammatory stimulant
                alone or in amyloid fibril-treated mice without inflammatory stimulation. Our results suggest that AA
                amyloid deposition<strong>
                    is accelerated by oral administration of semipurified amyloid fibrils when there is a concurrent
                    inflammatory stimulation.”
                </strong>
            </p>
            <p>
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                Lara DR. “This constitutes the first in vitro evidence to suggest that adenosine A(2A) receptors may be
                the molecular target responsible for the <strong>observed beneficial effects of caffeine consumption in
                    the development of Alzheimer's disease.</strong>”<strong></strong>
            </p>
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                long time, the aggregated form of the Abeta was supposed to be responsible for the neurodegeneration
                that occurs in AD. Recently, the attention has been diverted to the monomeric or oligomeric forms of
                Abeta and their interaction with cellular targets.”
            </p>
            <p>
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            </p>
            <p>
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                    the formation of ceroid in Batten Disease.</strong> Dawson G, Dawson SA, Siakotos AN. “Lysosomal
                ceroid/lipofuscinosis storage in human, canine, and ovine forms of neuronal ceroidlipofuscinosis is
                predominantly in neurons and retinal pigment epithelial cells. Despite problems in identifying
                individual storage materials, it is believed that non-enzymic oxidation of unsaturated fatty acids in
                phospholipids and inhibition of lysosomal proteolysis, leading to massive deposition of autofluorescent
                pigment, is the cause of the disease.” <strong>“We believe that the PLA1 deficiency leads to transient
                    lysosomal storage of phospholipids containing peroxy fatty acids which are then chemically converted
                    to hydroxynonenal, a potent inhibitor of a thiol-dependent enzymes.</strong> Inhibition of proteases
                is believed to be intrinsic to the formation of lipofuscin.”
            </p>
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                </strong>Du Clos TW. “The pentraxins are a family of proteins characterized by cyclic pentameric
                structure, calcium-dependent ligand binding and sequence homology. The two main representatives of this
                family are the serum proteins, C-reactive protein (CRP) and serum amyloid P component (SAP). In man CRP
                is an acute phase reactant which increases up to 1,000 fold during the acute phase<strong></strong
                >response whereas SAP is a constitutive protein expressed at about 30 micrograms/ml. These proteins
                activate complement through the classical pathway and participate in opsonization of particulate
                antigens<strong></strong>and bacteria. In the past several years it has been determined that both of
                these pentraxins interact with nuclear antigens including chromatin and small nuclear ribonucleoproteins
                (snRNPs). Both CRP and SAP have nuclear transport signals which facilitate their entry into the nuclei
                of intact cells. Furthermore, these pentraxins have been shown to affect the clearance of nuclear
                antigens in vivo.”
            </p>
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            </p>
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            <p>
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            </p>
            <p>
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                EJ, Shenton BK.
            </p>
            <p>
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            </p>
            <p>
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                EJ, Shenton BK.
            </p>
            <p>
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                    in sheep.</strong> Field EJ, Shenton BK.
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            <p>
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                Field EJ, Shenton BK.
            </p>
            <p>
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                Shenton BK.
            </p>
            <p>
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            </p>
            <p>
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            </p>
            <p>
                Arch Gesamte Virusforsch. 1970;30(2):224-37. <strong>The incorporation of (3H) thymidine and (14C)
                    glucosamine into a DNA-polysaccharide complex in normal and scrapie-affected mouse brain.</strong>
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            </p>
            <p>
                Biochem J. 1969 Sep;114(2):19P-20P. <strong> Structural changes in scrapie affected brain.</strong>
                Field EJ, Peat A.
            </p>
            <p>
                J Gen Virol. 1969 Jul;5(1):149-50. <strong>Failure of interferon to modify scrapie in the mouse.</strong
                > Field EJ, Joyce G, Keith A.
            </p>
            <p>
                Nature. 1969 Apr 5;221(188):90-1. <strong>Susceptibility of scrapie agent to ionizing radiation.</strong
                > Field EJ, Farmer F, Caspary EA, Joyce G.
            </p>
            <p>
                Nature. 1969 Mar 29;221(187):1265-6.<strong>
                    Neurological illness after inoculation of tissue from tumour bearing animals.</strong> Field EJ,
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            </p>
            <p>Lancet. 1968 May 4;1(7549):981-2. <strong>Transmission of kuru to mice.</strong> Field EJ.</p>
            <p>
                Br J Exp Pathol. 1967 Dec;48(6):662-4. <strong>Invasion of the mouse nervous system by scrapie
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            </p>
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                Ben-Nun A, Schwartz M. “<strong>T-cell autoimmunity to myelin basic protein was recently shown to be
                    neuroprotective in injured rat optic nerves.</strong>” “The results of this study show that survival
                of RGCs after axonal injury can be<strong>
                    enhanced by vaccination with an appropriate self-antigen.</strong> Furthermore, the use of
                nonencephalitogenic myelin peptides for immunization apparently allows neuroprotection without incurring
                the risk of an autoimmune disease.”
            </p>
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                Furukawa S, Nabeshima T. “NGF levels in the hippocampus were<strong>
                    increased only in adult rats. These results suggest that Abeta is toxic only in the matured adult
                    brain, and that the mechanism of toxicity is related to NGF synthesis.”</strong>
            </p>
            <p>
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            </p>
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            </p>
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            <p>
                Arch Pathol. 1966 Oct; 82(4): 353-5.<strong>
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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 <strong>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
                </strong>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.”
                <strong><hr /></strong>Higher CRP levels also correlated with age, male gender, body mass index and a
                history of myocardial infarction. After adjustments for these factors, <strong>CRP levels still appeared
                    to have increased significantly with increasing radiation dose (about 28% increase at 1Gy,
                </strong>
                <hr />
                <strong><hr /></strong>
                <hr />
                <strong>“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.</strong>”
            </p>
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            </p>
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                    geographical Variations.</strong> Imaizumi Y. “The death rate in Japan from amyloidosis was analyzed
                using Japanese Vital Statistics for 1969-1985. <strong>The amyloidosis death rate has increased
                    gradually year by year for both sexes.</strong>” “The mean age at death from amyloidosis gradually
                increased year by year for both sexes, although the age was <strong>11-23 years shorter for males and
                    20-25 years shorter for females</strong> than that of the general population.”
            </p>
            <p>
                Stroke. 1991 Nov;22(11):1448-51. <strong>Platelet secretory products may contribute to neuronal
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            </p>
            <p>
                J Neurochem. 1997 Jul; 69(1): 266-72.<strong>
                    Aggregation of beta-amyloid peptide is promoted by membrane phospholipid metabolites elevated in
                    Alzheimer's disease brain.</strong> 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.<strong></strong>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.”<strong></strong>
            </p>
            <p>
                J Pharm Sci. 1971 Feb; 60(2): 167-80. <strong>Experimental modification of the chemistry and biology of
                    the aging process.</strong> Kormendy CG, Bender AD.
            </p>
            <p>
                Radiobiologiia. 1990 May-Jun;30(3):317-20. <strong>[Cholesterol and fatty acids of the nuclei and
                    chromatin of the rat thymus at long intervals following gamma irradiation]</strong> 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.”
            </p>
            <p>
                J Neuropathol Exp Neurol. 1968 Jan; 27(1): 157-8.<strong>
                    Amyloid in late postradiation necrosis of brain.</strong> Mandybur TJ, Gore y.
            </p>
            <p>
                Hepatology. 1995 Dec;22(6):1754-62. <strong>Effect of donor age and sex on the outcome of liver
                    transplantation.</strong> Marino IR, Doyle HR, Aldrighetti L, Doria C, McMichael J, Gayowski T, Fung
                JJ, Tzakis AG, Starzl TE.
            </p>
            <p>
                Brain Res. 673(1), 149-152, 1995. <strong>"Glucose deprivation increases aspartic acid release from
                    synaptosomes of aged mice,"</strong>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." "...<strong
                >there is an age-dependent dysfunction in this process linked to energy metabolism disturbance</strong
                >."
            </p>
            <p>
                Neurobiol Aging. 1995 Nov-Dec; 16(6): 977-81. <strong>Estrogen induction of glial heat shock proteins:
                    implications for hypothalamic Aging.</strong> 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.” “<strong>Our findings indicate that
                    estrogen elicits a heat shock response and subsequent granulation in astrocytes</strong> 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.”
            </p>
            <p>
                Proc. Natl. Acad. Sci. USA, vol. 44, pp. 712-717 (1958): <strong>"Epigenetic Control Systems".</strong>
                D. L. Nanney.
            </p>
            <p>
                Journal of the Neurological Sciences 1995;134:61-6.<strong>
                    Mortality from motor neuron disease in Japan, 1950-1990: association with radioactive fallout from
                    atmospheric weapons testing.
                </strong>Neilson S, Robinson I, Rose FC.
            </p>
            <p>
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                nicotine may be exerted not only by the inhibition of fAbeta formation but also by the disruption of
                preformed fAbeta.”
            </p>
            <p>
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            </p>
            <p>
                <strong>
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                </strong> Price TR, Netsky MG.
            </p>
            <p>
                Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1580-5. Epub 2003 Feb 03. <strong>
                    Short-term administration of omega 3 fatty acids from fish oil results in increased transthyretin
                    transcription in old rat hippocampus.</strong> Puskas LG, Kitajka K, Nyakas C, Barcelo-Coblijn G,
                Farkas T.
            </p>
            <p>
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                    formation by 2,4-dinitrophenol through tetramer stabilization.
                </strong>Raghu P, Reddy GB, Sivakumar B.
            </p>
            <p>
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            </p>
            <p>
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            </p>
            <p>
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                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."
            </p>
            <p>
                Int J Radiat Oncol Biol Phys. 1995 Jan 1;31(1):57-64. <strong>Radiation-induced changes in the profile
                    of spinal cord serotonin, prostaglandin synthesis, and vascular permeability.</strong> Siegal T,
                Pfeffer MR. “Serotonin levels were unchanged at 2, 14,<strong></strong>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 &lt; 0.01) and age-matched controls (p &lt; 0.03).<strong>”
                </strong>“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.”
            </p>
            <p>
                Annual Meeting of the American Psychological Association, New York, New York, September 3, 1979, <strong
                >"Fallout and the Decline of Scholastic Aptitude Scores,"</strong> Ernest Sternglass and Stephen Bell.
            </p>
            <p>
                Acta Neuropathol (Berl). 1995; 90(2): 135-41. <strong>Cerebral beta amyloid deposition in patients with
                    malignant neoplasms: its prevalence with aging and effects of radiation therapy on vascular
                    amyloid.</strong> 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 &lt; 0.05) with
                radiation therapy (22.2%) than without (8.0%).”
            </p>
            <p>
                Diabetes. 2003 Dec;52(12):2882-7. <strong>Elevation of free fatty acids induces inflammation and impairs
                    vascular reactivity in healthy subjects.</strong> Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim
                H, Aljada A, Dandona P.
            </p>
            <p>
                Arterioscler Thromb Vasc Biol. 2003 Dec 29. <strong>Effect of Lower Dosage of Oral Conjugated Equine
                    Estrogen on Inflammatory Markers and Endothelial Function in Healthy Postmenopausal Women.</strong>
                Wakatsuki A, Ikenoue N, Shinohara K, Watanabe K, Fukaya T. {Oral estrogen) “... <strong>increases plasma
                    C-reactive protein (CRP) and interleukin-6 (IL-6) concentration.</strong> The proinflammatory effect
                of oral ERT may explain the increased risk of coronary heart disease (CHD) associated with this
                treatment.”
            </p>
            <p>
                Am J Pathol. 1997 Jun; 150(6): 2181-95. <strong>Free fatty acids stimulate the polymerization of tau and
                    amyloid beta peptides.</strong>
                <strong>In vitro evidence for a common effector of pathogenesis in Alzheimer's disease.</strong> Wilson
                DM, Binder LI. “We have discovered that free fatty acids (FFAs) stimulate the assembly of both amyloid
                and tau filaments in vitro.” <strong>“Utilizing fluorescence spectroscopy, unsaturated FFAs were also
                    demonstrated to induce beta-amyloid assembly.</strong>” [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.”
            </p>
            <p>
                Lab Invest. 2001 Apr; 81(4): 493-9. <strong>Transmission of mouse senile amyloidosis.</strong> 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.”
            </p>
        </article>
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        <strong>Meat physiology, stress, and degenerative physiology&nbsp;&nbsp;</strong>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.&nbsp;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.)&nbsp; 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.&nbsp;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.&nbsp;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.&nbsp;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.&nbsp;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.&nbsp;"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.&nbsp;"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.&nbsp;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
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        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.&nbsp;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.&nbsp;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
    </body>
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    <head><title>Membranes, plasma membranes, and surfaces</title></head>
    <body>
        <h1>
            Membranes, plasma membranes, and surfaces
        </h1>

        <p>
            <hr />
            <hr />
        </p>
        <p>
            The "essential fatty acids":
        </p>
        <p>
            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....
        </p>
        <p>
            <hr />
            <hr />
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            As I understand it, the doctrine of the "essential fatty acids" goes this way:
        </p>
        <p>
            1. They are essential because they are required for making cell membranes and prostaglandins.
        </p>
        <p>
            2. Rats deprived of the unsaturated fatty acids develop a skin disease, and "lose water" through the skin.
        </p>
        <p>
            3. Human skin diseases (etc.) can be cured with polyunsaturated fats.
        </p>
        <p>
            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.
        </p>
        <p>
            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.)
        </p>

        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>
        <p>
            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:
        </p>
        <p>
            "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.)
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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, <strong>"Increase in osmiophilia of axonal membranes of crayfish as a result of electrical
                stimulation, asphyxia, or treatment with reducing agents,"</strong> 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.
        </p>
        <p>
            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 <strong>osmium compound that "reveals" the
                lipid bilayer for the electron microscope destroys the apparent membrane in the freezing
                technique.</strong> (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, <strong>"Effect of fixatives on fracture plane in red blood
                cells," J. Microsc. 102, 29-39, 1974.)</strong>
        </p>
        <p>
            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."
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            <h3>
                ADDITIONAL REFERENCES
            </h3>
        </p>
        <p>
            Gilbert N. Ling, A Revolution in the Physiology of the Living Cell, Krieger Publ., Melbourne, Florida, 1993.
        </p>

        <p>
            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.
        </p>
        <p>
            G. N. Ling, A Physical Theory of the Living State, Blaisdell, New York, 1960.
        </p>
        <p>
            S. W. Fox, Nature 205, 328, 1965; Naturwissenschaften 60, 359, 1973.
        </p>
        <p>
            S. W. Fox and K. Dose, Molecular Evolution and the Origin of Life, Marcel Dekker, New York, 1977.
        </p>
        <p>
            S. Fleischer, B. Fleischer, and W. Stoeckenius, J. Cell Ciol. 32, 193, 1967.
        </p>

        <p>
            H. J. Morowitz and T. M. Terry, Biochem. Biophys. Acta 183, 276, 1969.
        </p>
        <p>
            L. Napolitano, F. Le Baron, and J. Scaletti, J. Cell Biol. 34, 817, 1967.
        </p>
        <p>
            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.
        </p>
        <p>
            R. Damadian, "Biological ion exchanger resins. III. Molecular interpretations of cellular ion exchange,"
            Biophys. J. 11, 773, 1971.
        </p>

        <p>
            R. Damadian, "Biological ion exchanger resins," Ann. NY Acad. Sci. 204, 211, 1973.
        </p>
        <p>
            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.
        </p>
        <p>
            J. S. Clegg and W. Drost-Hansen, "On the density of intracellular water," J. Biol. Phys. 10, 75-84, 1982.
        </p>

        <p>
            J. S. Clegg, "Properties and metabolism of the aqueous cytoplasm and its boundaries," Am. J. Physiol. 26,
            R133-R151, 1984.
        </p>
        <p>
            J. S. Clegg, "Intracellular water and the cytomatrix: some methods of study and current views," J. Cell
            Biol. 99, 167S-171S, 1984.
        </p>
        <p>
            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.
        </p>

        <p>
            W. Drost-Hansen and J. Clegg, editors, Cell-Associated Water, Academic Press, 1979.
        </p>
        <p>
            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>
        <p>
            P. M. Wiggins, "Water structure as a determinant of ion distribution in living tissue," J. Theor. Biol. 32,
            131-144, 1971.
        </p>
        <p>
            R. Damadian and F. W. Cope, Physiol. Chem. Phys. 5, 511, 1973.
        </p>

        <p>
            F. W. Cope, "A review of the applications of solid state physics concepts to biological systems," J. Biol.
            Phys. 3, 1 1975.
        </p>
        <p>
            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.
        </p>
        <p>
            A. Nathansohn, Jahrb. Wiss. Bot. 39, 607, 1904.
        </p>
        <p>
            A. S. Troshin, Problems of Cell Permeability, Pergamon Press, London, 1966.
        </p>
        <p>
            A. S. Troshin, Byull. Eksp. Biol. Med. 34, 59, 1952.
        </p>

        <p>
            I. Tasaki, Nerve Excitation: A Macromolecular Approach, Thomas, Springfield, 1968.
        </p>
        <p>
            Albert Szent-Gyorgyi, Bioenergetics, Academic Pressn New York, 1957.
        </p>
        <p>
            Albert Szent-Gyorgyi, The Living State and Cancer, Marcel Deker, New York, 1978.
        </p>
        <p>
            T. L. Davis, et al., "Potentials in frog cornea and microelectrode artifact," Amer. J. Physiol. 219(1),
            178-183, 1970.
        </p>

        <p>
            NOTES:
        </p>
        <p>
            # 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.
        </p>
        <p>
            * 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.
        </p>

        <p><hr /></p>

        © Ray Peat Ph.D. 2009. All Rights Reserved. www.RayPeat.com
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    <head><title>Menopause and its causes</title></head>
    <body>
        <h1>
            Menopause and its causes
        </h1>
        <p>
            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<strong>. </strong>

            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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<strong>:</strong> at any stage of pregnancy, a sufficient dose of
            estrogen kills the embryo.
        </p>
        <p>
            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>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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
        </p>
        <p>
            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<strong>;</strong> 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<strong>;</strong> lately there has been talk of
            promoting estrogen to improve memory<strong>.</strong>)
        </p>

        <p>
            Estrogen's nerve-exciting action is known to lower seizure thresholds<strong>;</strong> premenstrual
            epilepsy is probably another acute sign of the neurotoxicity of estrogen.
        </p>
        <p>
            When fatigue and lethargy are associated with aging, the brain stimulating action of estrogen can make a
            woman feel that she has more energy<strong>.</strong>
            (Large doses given to rats will make them run compulsively<strong>;</strong> 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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p><strong>Copyright: Raymond Peat, PhD 1997</strong></p>
        <p>
            <strong><h3>REFERENCES</h3></strong>
        </p>
        <p>
            1. L. C. Strong, Biological Aspects of Cancer and Aging, Pergamon Press, 1968.
        </p>
        <p></p>
        <p>
            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.
        </p>
        <p>
            3. P. W. F. Wilson, et al. [The Framingham Study], N. E. J. M. 313(17), 1038-1043, 1985
        </p>
        <p>
            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.
        </p>
        <p>
            5. Nencioni, T., and F. Polvani, Calcitonin, p. 297-305, A. Pecile, editor, Elsevier, N.Y., 1985.
        </p>
        <p></p>
        <p>
            6. T. I. Belova, "Structural damage to the mesencephalic reticular formation induced by immobilization
            stress," Bull. Exp. Biol. &amp; Med. 108(7), 126030, 1989.
        </p>
        <p>
            7. F. Fourrier, et al., "Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock,"
            Circ. Shock 43(4), 171-178, 1994.
        </p>
        <p>
            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.
        </p>
        <p>
            9. C. Bain, et al., "Use of postmenopausal hormones and risk of myocardial infarction," Circulation 64,
            42-46, 1981.
        </p>
        <p>
            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.
        </p>

        <p>
            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.)
        </p>
        <p>
            12. L. Dennerstein, et al., "Psychological well-being, mid-life and the menopause," Maturitas 20(1), 1-11,
            1994.
        </p>

        <p>
            © Ray Peat 2006. All Rights Reserved. www.RayPeat.com
        </p>
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    <head>
        <title>
            Milk in context: allergies, ecology, and some myths
        </title>
    </head>
    <body>
        <h1>
            Milk in context: allergies, ecology, and some myths
        </h1>

        <p></p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            "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.
        </p>

        <p>
            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)
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.)
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            Several surveys have found that of children who have a diagnosed milk allergy, about 2/3 of them grow out of
            the allergy.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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).
        </p>

        <p>
            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.
        </p>
        <p>
            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).
        </p>
        <p>
            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).
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            These changes are clearly related to the anti-obesity effect of calcium, but those enzymes are important for
            many other problems.
        </p>
        <p>
            The "metabolic syndrome," that involves diabetes, hypertension, and obesity, is associated with high PTH
            (Ahlstr"m, et al., 2009; Hjelmesaeth, et al., 2009).
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            There are components of milk that might protect against tooth decay by inhibiting the binding of bacteria to
            teeth (Danielsson, et al., 2009).
        </p>
        <p>
            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.
        </p>
        <p>
            Intravenous infusion of calcium can relax blood vessels and improve heart function. The suppression of PTH
            is probably the main mechanism.
        </p>
        <p>
            PTH (like estrogen) causes mast cells to release promoters of inflammation, including histamine and
            serotonin. Serotonin and nitric oxide contribute to increasing PTH secretion.
        </p>

        <p>
            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.
        </p>
        <p>
            Increased carbon dioxide, for example when adapted to high altitude, can greatly decrease PTH. Frequent, but
            smaller, meals can reduce PTH.
        </p>
        <p>
            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).
        </p>
        <p>
            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.
        </p>
        <p>
            Dividing any food into smaller meals can lower the PTH, and milk is a convenient food to use in small
            amounts and frequently.
        </p>
        <p>
            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).
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p><h3>REFERENCES</h3></p>
        <p>
            Agents Actions. 1975 Oct;5(4):371-3. <strong>Effect of calcitonin on carrageenan foot oedema.</strong>
            Abdullahi SE, De Bastiani G, Nogarin L, Velo GP.
        </p>

        <p>
            Am Nat. 2001 May;157(5):555-69. <strong>Transgenerational consequences of plant responses to herbivory: an
                adaptive maternal effect?</strong> Agrawal AA.
        </p>
        <p>
            Clin Endocrinol (Oxf). 2009 Nov;71(5):673-8. <strong>Correlation between plasma calcium, parathyroid hormone
                (PTH) and the metabolic syndrome (MetS) in a community-based cohort of men and women.
            </strong>
            Ahlstr"m T, Hagstr"m E, Larsson A, Rudberg C, Lind L, Hellman P.
        </p>
        <p>
            Indian J Exp Biol. 2003 Apr;41(4):367-9. <strong>Protection of adrenocortical activity by dietary casein in
                ether anaesthetized rats.</strong> Biswas NM, Chattopadhyay A, Sarkar M. "Ether anaesthesia to 20%
            casein fed rats caused no change in adrenal delta5-3beta-HSD activity and serum corticosterone level when
            compared with controls fed 20% casein diet. <strong>The results suggest that high milk protein diet may
                prevent acute stress effects by protecting adrenocortical activity.</strong> The present investigation
            opens up a new area of management of stress."
        </p>

        <p>
            Am J Clin Nutr. 2008 Oct;88(4):877-85. <strong>Dairy calcium supplementation in overweight or obese persons:
                its effect on markers of fat metabolism.</strong>
            Bortolotti M, Rudelle S, Schneiter P, Vidal H, Loizon E, Tappy L, Acheson KJ.
        </p>
        <p>
            J Am Coll Nutr. 2005 Dec;24(6 Suppl):569S-73S. <strong>The myth of increased lactose intolerance in
                African-Americans.
            </strong>
            Byers KG, Savaiano DA.
        </p>
        <p>
            Exp Eye Res. 2004 Aug;79(2):239-47. <strong>Light damage induced changes in mouse retinal gene
                expression.</strong> Chen L, Wu W, Dentchev T, Zeng Y, Wang J, Tsui I, Tobias JW, Bennett J, Baldwin D,
            Dunaief JL.
        </p>

        <p>
            J Urol. 2008 Sep;180(3):974-9. Epub 2008 Jul 17.<strong>Urinary stone disease in adults with celiac disease:
                prevalence, incidence and urinary determinants.</strong>
            Ciacci C, Spagnuolo G, Tortora R, Bucci C, Franzese D, Zingone F, Cirillo M.
        </p>
        <p>
            Surgery. 2007 Nov;142(5):699-703. <strong>Parathyroidectomy reduces cardiovascular events and mortality in
                renal Hyperparathyroidism.</strong> Costa-Hong V, Jorgetti V, Gowdak LH, Moyses RM, Krieger EM, De Lima
            JJ.
        </p>
        <p>
            Caries Res. 2009;43(3):171-8. <strong>Human milk compounds inhibiting adhesion of mutans streptococci to
                host ligand-coated hydroxyapatite in vitro.</strong>
            Danielsson Niemi L, Hernell O, Johansson I.
        </p>

        <p>
            Cancer Res. 2009 Sep 15;69(18):7402-11. <strong>The neuroendocrine-derived peptide parathyroid
                hormone-related protein promotes prostate cancer cell growth by stabilizing the androgen
                receptor.</strong> DaSilva J, Gioeli D, Weber MJ, Parsons SJ.
        </p>
        <p>
            J Rheumatol. 1976 Mar;3(1):54-62. <strong>Experimental inflammation induced by naturally occurring
                microcrystalline calcium salts.</strong> Denko CW, Whitehouse MW.
        </p>
        <p>
            Dig Liver Dis. 2009 Aug;41(8):541-50. <strong>Transglutaminases in inflammation and fibrosis of the
                gastrointestinal tract and the liver.</strong>
            Elli L, Bergamini CM, Bardella MT, Schuppan D.
        </p>

        <p>
            J Nephrol. 2008 Mar-Apr;21 Suppl 13:S92-6. <strong>Parathyroidectomy improves the quality of sleep in
                maintenance hemodialysis patients with severe hyperparathyroidism.</strong> 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.
        </p>
        <p>
            Endocrinology. 1997 Jul;138(7):2665-73. <strong>Parathyroid hormone-related protein is induced in the adult
                liver during endotoxemia and stimulates the hepatic acute phase response.
            </strong>Funk JL, Moser AH, Grunfeld C, Feingold KR.
        </p>
        <p>
            Arch Pharm Res. 2008 Jul;31(7):891-9. <strong>Effects of calcium channel blockers on hyaluronidase-induced
                capillary vascular permeability.</strong> Halici Z, Suleyman H, Cadirci E.
        </p>

        <p>
            J Am Diet Assoc. 2000 May;100(5):524-8. <strong>Improved lactose digestion and intolerance among
                African-American adolescent girls fed a dairy-rich diet.</strong> Pribila BA, Hertzler SR, Martin BR,
            Weaver CM, Savaiano DA.
        </p>
        <p>
            Dig Dis Sci. 1998 Jan;43(1):39-40. <strong>
                Fecal hydrogen production and consumption measurements. Response to daily lactose ingestion by lactose
                maldigesters.</strong> Hertzler SR, Savaiano DA, Levitt MD.
        </p>
        <p>
            J Am Coll Nutr. 2009 Apr;28(2):142-9. <strong>Effects of dairy products on intracellular calcium and blood
                pressure in adults with essential hypertension.</strong>

            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."
        </p>
        <p>
            Cardiovasc Diabetol. 2009 Feb 3;8:7. <strong>Parathyroid hormone, but not vitamin D, is associated with the
                metabolic syndrome in morbidly obese women and men: a cross-sectional study.
            </strong>Hjelmesaeth J, Hofs" D, Aasheim ET, Jenssen T, Moan J, Hager H, R"islien J, Bollerslev J.
        </p>
        <p>
            Eur J Epidemiol. 2003;18(7):677-84. <strong>The Swedish coeliac disease epidemic with a prevailing twofold
                higher risk in girls compared to boys may reflect gender specific risk factors.</strong> Ivarsson A,
            Persson LA, Nystr"m L, Hernell O.
        </p>
        <p>
            Carbohydr Res. 2008 Feb 4;343(2):364-73. Epub 2007 Oct 30. <strong>Heterogeneity in iota-carrageenan
                molecular structure: insights for polymorph II--&gt;III transition in the presence of calcium
                ions.</strong> Janaswamy S, Chandrasekaran R.
        </p>

        <p>
            Metabolism. 2002 Oct;51(10):1230-4.<strong>
                A calcium-deficient diet caused decreased bone mineral density and secondary elevation of estrogen in
                aged male rats-effect of menatetrenone and elcatonin.
            </strong>
            Kato S, Mano T, Kobayashi T, Yamazaki N, Himeno Y, Yamamoto K, Itoh M, Harada N, Nagasaka A.
        </p>
        <p>
            Nippon Geka Gakkai Zasshi. 1993 Apr;94(4):394-9.<strong>
                [Immunohistological evaluation of parathyroid hormone-related protein in breast cancer with and without
                calcification on mammography]</strong> Kanbara Y, Kono N, Nakaya M, Ishikawa Y, Fujiwara O, Kitazawa R,
            Kitazawa S.
        </p>
        <p>
            J Pak Med Assoc. 1996 Jun;46(6):128-31.<strong>
                Changes in plasma electrolytes during acclimatization at high altitude.</strong> Khan DA, Aslam M, Khan
            ZU.
        </p>

        <p>
            J Am Coll Nutr. 2009 Feb;28 Suppl 1:103S-19S.<strong>
                Milk products, dietary patterns and blood pressure management.
            </strong>
            Kris-Etherton PM, Grieger JA, Hilpert KF, West SG.
        </p>
        <p>
            Br J Cancer. 1996 Jul;74(2):200-7. <strong>A new human breast cancer cell line, KPL-3C, secretes parathyroid
                hormone-related protein and produces tumours associated with microcalcifications in nude mice.</strong>
            Kurebayashi J, Kurosumi M, Sonoo H.
        </p>
        <p>
            J Clin Endocrinol Metab. 2007 Nov;92(11):4180-4. <strong>Association between hypothyroidism and small
                intestinal bacterial overgrowth.
            </strong>

            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.
        </p>
        <p>
            Bone. 2009 Oct 6. <strong>Bone involvement in clusters of autoimmune diseases: Just a complication?
            </strong>Lombardi F, Franzese A, Iafusco D, Del Puente A, Esposito A, Prisco F, Troncone R, Valerio G.
        </p>
        <p>
            Hypertension 1980 Mar-Apr;2(2):162-8.<strong>
                Enhanced parathyroid function in essential hypertension: a homeostatic response to a urinary calcium
                leak.</strong> McCarron DA, Pingree PA, Rubin RJ, Gaucher SM, Molitch M, Krutzik S. <strong>"Recent
                reports . . . suggest that increased parathyroid gland function may be one of the more common endocrine
                disturbances associated with hypertension."
            </strong>
            "Compared to a second age- and sex-matched normotensive population<strong>, the hypertensives demonstrated a
                significant (p less than 0.005) relative hypercalciuria. For any level of urinary sodium, hypertensives
                excreted more calcium.</strong> These preliminary data suggest that parathyroid gland function may be
            enhanced in essential hypertension."
        </p>

        <p>
            Am J Med 1987 Jan 26;82(1B):27-33.<strong>
                The calcium paradox of essential hypertension.</strong> 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."
        </p>
        <p>
            Nephrol Dial Transplant. 2002 Oct;17(10):1854. <strong>Insomnia in maintenance haemodialysis
                patients.</strong> Sabbatini M, Minale B, Crispo A, Pisani A, Ragosta A, Esposito R, Cesaro A,
            Cianciaruso B, Andreucci VE.
        </p>
        <p>
            J Neurol Neurosurg Psychiatry. 2008 Feb;79(2):152-7. <strong>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.</strong> Soilu-H"nninen M, Laaksonen M, Laitinen I, Er"linna JP,
            Lilius EM, Mononen I.
        </p>

        <p>
            J Nutr. 2006 Apr;136(4):1107-13. <strong>Lactose intolerance symptoms assessed by meta-analysis: a grain of
                truth that leads to exaggeration.</strong> Savaiano DA, Boushey CJ, McCabe GP.
        </p>
        <p>
            J Allergy Clin Immunol. 1995 May; 95(5 Pt 1): 933-6.<strong>
                Anaphylaxis to carrageenan: a pseudo-latex allergy.</strong> Tarlo, S M Dolovich, J Listgarten, C
        </p>
        <p>
            Gut. 1990 Jul;31(7):770-6. <strong>Effects of an enteric anaerobic bacterial culture supernatant and
                deoxycholate on intestinal calcium absorption and disaccharidase activity.</strong> Walshe K, Healy MJ,
            Speekenbrink AB, Keane CT, Weir DG, O'Moore RR.
        </p>

        <p>
            Metabolism. 2003 Aug;52(8):1072-7. <strong>Dietary sodium restriction exacerbates age-related changes in rat
                adipose tissue and liver lipogenesis</strong>. Xavier AR, Garofalo MA, Migliorini RH, Kettelhut IC.
        </p>
        <p>
            Hypertension 1994 Apr;23(4):513-30. <strong>Dietary calcium and blood pressure in experimental models of
                hypertension. A review.</strong> Hatton DC, McCarron DA.
        </p>
        <p>
            Nippon Geka Gakkai Zasshi. 1993 Apr;94(4):394-9. <strong>[Immunohistological evaluation of parathyroid
                hormone-related protein in breast cancer with and without calcification on mammography]</strong>
            [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."
        </p>

        <p>
            Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku. 1998;(116):46-62. <strong>[Plant defense-related
                proteins as latex allergens]</strong> [Article in Japanese] Yagami T.
        </p>
        <p>
            J Am Geriatr Soc 2003 Mar;51(3):410-4. <strong>Association between dementia and midlife risk factors: the
                Radiation Effects Research Foundation Adult Health Study.
            </strong>Yamada M, Kasagi F, Sasaki H, Masunari N, Mimori Y, Suzuki G.
        </p>
        <p>
            Am J Hypertens 1995 Oct;8(10 Pt 1):957-64. <strong>Regulation of parathyroid hormone and vitamin D in
                essential hypertension.</strong> 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."
        </p>

        <p>
            Mol Immunol. 2007 Mar;44(8):1977-85. <strong>Estradiol activates mast cells via a non-genomic estrogen
                receptor-alpha and calcium influx.
            </strong>
            Zaitsu M, Narita S, Lambert KC, Grady JJ, Estes DM, Curran EM, Brooks EG, Watson CS, Goldblum RM,
            Midoro-Horiuti T.
        </p>

        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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        <h1></h1>

        <p></p>
        <p><strong>Mitonchondria and mortality:</strong></p>
        <p>Diet, exercise, and medicine, damaging or repairing respiratory metabolism</p>
        <p><strong><em>MAIN IDEAS AND CONTEXTS</em></strong></p>
        <strong><em>Lactic acid and carbon dioxide</em></strong>
        <em> have opposing effects.</em>
        <p>
            <strong><em>Intense exercise damages cells</em></strong>
            <em>
                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. &nbsp; Within five
                minutes, exercise lowers the activity of enzymes that oxidize glucose. Diabetes, Alzheimer's disease,
                and general aging involve increased lactic acid production&nbsp; &nbsp; and&nbsp; &nbsp;
                accumulated&nbsp; &nbsp; metabolic (mitochondrial) damage.</em>
        </p>
        <p>
            <strong><em>The products of glycolysis,</em></strong>
            <em> lactic acid and pyruvic acid, suppress oxidation of glucose.</em>
        </p>
        <p>
            <em>&nbsp;</em>
            <strong><em>Adaptation</em></strong>
            <em>
                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.</em>
        </p>
        <p>
            <strong><em>Lactic acidosis,</em></strong>
            <em>
                by suppressing oxidation of glucose, increases oxidation of fats, further suppressing glucose
                oxidation.&nbsp;</em>
        </p>
        <p>
            <strong><em>Estrogen</em></strong>
            <em> is harmful to mitochondria,</em>
            <strong><em> progesterone</em></strong>
            <em> is beneficial.</em>
        </p>
        <p>
            <strong><em>Progesterone's brain-protective</em></strong>
            <em> and restorative effects involve mitochondrial actions.</em>
        </p>
        <p>
            <strong><em>Thyroid hormone, palmitic acid, and light </em></strong>
            <em>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.</em>
        </p>
        <p>
            <strong><em>Heart failure, shock,</em></strong>
            <em>
                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.</em>
        </p>
        <p><strong><em>SOME DEFINITIONS</em></strong></p>
        <p>
            <strong><em>Glycolysis:</em></strong>
            <em>
                The conversion of glucose to lactic acid, providing some usable energy, but many times less than
                oxidation provides.</em>
        </p>
        <p>
            <strong><em>Lactic acid,</em></strong>
            <em>
                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.&nbsp;</em>
        </p>
        <p>
            <strong><em>Crabtree effect:</em></strong>
            <em>
                Inhibition of cellular respiration by an excess of glucose; excess of glucose promotes calcium uptake by
                cells.</em>
        </p>
        <p>
            <strong><em>Pasteur effect:</em></strong>
            <em> Inhibition of glycolysis (fermentation) by oxygen.</em>
        </p>
        <p>
            <strong><em>Randle effect:</em></strong>
            <em>
                The inhibition of the oxidation of glucose by an excess of fatty acids.&nbsp; This lowers metabolic
                efficiency. Estrogen promotes this effect.</em>
        </p>
        <p>
            <em>&nbsp;</em>
            <strong><em>Lactated Ringer's solution:</em></strong>
            <em>
                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,</em>
        </p>
        <p>
            <strong><em>Estrogenic phytotoxins</em></strong>
            <em> damage mitochondria, kill brain cells; tofu is associated with dementia.</em>
        </p>
        <p><em><hr /></em></p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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 <em>cause</em> of respiratory defects, or whether a respiratory defect
            causes the mutations. Recent research seems to show that physiological problems precede and cause the
            mutations.
        </p>
        <p>
            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? &nbsp; 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&nbsp; case, &nbsp; because&nbsp; thyroid&nbsp; stimulates&nbsp; its production, in the other, because
            the Haldane effect limits its loss from the lungs.
        </p>
        <p>
            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 <em>could</em> happen. &nbsp; 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?&nbsp; 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? &nbsp; How did mitochondria originate? &nbsp; "Germs.")
        </p>
        <p>
            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.
        </p>
        <p>
            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.
            &nbsp; 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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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. &nbsp; 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. &nbsp; 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.
        </p>
        <p>
            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.
        </p>
        <p>
            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 <em>cause</em> of the
            respiratory defect in cancer, just as it is usually the immediate cause of the respiratory derangement of
            hyperventilation on the organismic level.
        </p>
        <p>
            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.
        </p>
        <p>
            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. &nbsp; 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,
        </p>
        <p>
            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&nbsp;
            explains&nbsp; women's&nbsp; higher incidence of diabetes.&nbsp; 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.
        </p>
        <p>
            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.
        </p>
        <p>
            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. &nbsp; 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.
        </p>
        <p>
            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.&nbsp; 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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            The stressful conditions that physiologically harm mitochondria are now being seen as the probable cause for
            the mitochondrial genetic defects that accumulate with aging. &nbsp; Stressful exercise, which has been
            known to cause breakage of the nuclear chromosomes, is now seen to damage mitochondrial genes, too. &nbsp;
            Providing energy, while reducing stress, seems to be all it takes to reverse the accumulated mitochondrial
            genetic damage.
        </p>
        <p>
            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.
        </p>
        <p>
            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,&nbsp; and consequently urea synthesis,&nbsp; are depressed, and other synthetic processes are
            changed.
        </p>
        <p>
            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.&nbsp; 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,&nbsp; 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.
        </p>
        <p>
            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.
            &nbsp; &nbsp; The growth of new mitochondria probably occasionally leaves behind such useless materials,
            combining soaps, iron, and porphyrins remaining from damaged respiratory enzymes.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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:<strong
            >
                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.</strong>
            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.
        </p>
        <p>&nbsp;</p>
        <p>&nbsp;</p>
        <p><strong><h3>REFERENCES</h3></strong></p>
        <p>
            Biochim Biophys Acta 1999 Feb 9;1410(2):171-82 <strong>Mitochondrial &nbsp; &nbsp; involvement &nbsp; &nbsp;
                in &nbsp; &nbsp; Alzheimer's
            </strong>disease.Bonilla E, Tanji K, Hirano M, Vu TH, DiMauro S, Schon EA.
        </p>
        <p>
            Rev Pneumol Clin 1986;42(5):238-41.<strong>
                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.
            </strong>Quatrini U, Licciardi A.
        </p>
        <p>
            Muscle Nerve 1999 Feb;22(2):258-61.<strong>
                Acute exercise causes mitochondrial DNA deletion in rat skeletal muscle.</strong> Sakai Y, Iwamura Y,
            Hayashi J, Yamamoto N, Ohkoshi N, Nagata H.
        </p>
        <p>
            HumMol Genet 1999 Jun;8(6): 1047-52.<strong> Gene shifting:</strong>
            <strong>a novel therapy for mitochondrial myopathy.</strong> Taivassalo T, Fu K<em>,</em> Johns T, Arnold D,
            Karpati G, Shoubridge EA.
        </p>
        <p>
            Brain Dev 1989;11(3):195-7.<strong> Effect of sodium dichloroacetate on human pyruvate metabolism.</strong>
            Naito E, Kuroda Y, Toshima K, Takeda E, Saijo T, Kobashi H, Yokota I, Ito M.
        </p>
        <p>
            Mech Ageing Dev 1987 Aug;39(3):281-8.<strong>
                Lack of age-dependent changes in rat heart mitochondria.
            </strong>Manzelmann MS, Harmon HJ.
        </p>
        <p>
            Adv Shock Res 1978,1:105-16.<strong>
                The effect of mitochondrial dysfunction on glucose metabolism during shock.</strong> Rhodes RS.
        </p>
        <p>
            Biochem J 1982 Dec 15;208(3):695-701<strong>&nbsp; Exercise-induced alterations of hepatic mitochondrial
                function.
            </strong>Tate CA, Wolkowicz PE, McMillin-Wood, J.
        </p>
        <p>
            Am J Physiol 1997 Dec;273(6 Pt 2):F869-76. <strong>Neurosteroid inhibition of cell death.</strong> Waters
            SL, Miller GW, Aleo MD, Schnellmann RG.
        </p>
        <p>
            J Pharmacol Exp Ther 1990. May;253(2):628-35. <strong>Protection against hypoxic injury in isolated-perfused
                rat heart by ruthenium red.</strong> Park Y, Bowles DK, Kehrer JP.
        </p>
        <p>
            Environ Health Perspect 1984, Aug;57:281-7.<strong> Cell calcium, cell injury and cell death.</strong> Trump
            BF, Berezesky IK, Sato T, Laiho KU, Phelps PC, DeClaris N.
        </p>
        <p>
            Anesth Analg 1996 Oct;83(4):782-8.<strong>
                Small-volume resuscitation using hypertonic saline improves organ perfusion in burned rats.</strong>
            Kien ND, Antognini JF, Reilly DA, Moore PG.
        </p>
        <p>
            Respir&nbsp; Physiol &nbsp; 1977&nbsp; Dec;31(3):387-95.<strong>
                &nbsp; Post-hypercapnia recovery in the dog: arterial blood acid-base equilibrium and
                glycolysis.</strong> Saunier C, Horsky P, Hannhart B, Garcia-Carmona T, Hartemann D.
        </p>
        <p>
            Am J Physiol 1997 Nov;273(5 Pt 1):C1732-8<strong>
                Glycolysis inhibition by palmitate in renal cells cultured in a two-chamber system.</strong> Bolon C;
            Gauthier C; Simonnet H.
        </p>
        <p>
            Can J Appi Physiol 1998 Dec;23(6):558-69.<strong>
                The role of glucose in the regulation of substrate interaction during exercise.</strong> Sidossis LS.
        </p>
        <p>
            Am J Clin Nutr 1998 Mar;67(3 Suppl):527S-530S. <strong>Effect of lipid oxidation on glucose utilization in
                humans.</strong> JequierE.
        </p>
        <p>
            Ann N Y Acad Sci 1998 Nov 20;854:224-38. <strong>Mitochondrial free radical production and aging in mammals
                and birds.</strong> Barja G.
        </p>
        <p>
            <strong>Science 1999 Aug</strong> 27;285(5432): 1390-3.<strong>
                Gene expression profile of aging and its retardation by caloric restriction.</strong> Lee CK, Klopp RG,
            Weindruch R, Prolla TA.
        </p>
        <p>
            Nucleic Acids Res 1999 Nov 15;27(22):4510-6.<strong>
                Nitric oxide-induced damage to mtDNA and its subsequent repair.</strong> Grishko VI, Druzhyna N, LeDoux
            SP, Wilson GL.
        </p>
        <p>
            Am J Physiol 1998 Jun;274(6 Pt 1):G978-83.<strong>
                Neural injury, repair and adaptation in the GI tract. I. New insights into neuronal injury:
            </strong>a cautionary tale. Hall KE, Wiley JW.
        </p>
        <p>
            Proc Nati Acad Sci U S A 1999 Dec 21;96(26): 14706-14711.<strong>
                Structural details of an interaction between cardiolipin and an integral membrane protein.</strong>
            McAuley KE, Fyfe PK, Ridge JP, Isaacs NW, Cogdell RJ, Jones MR.
        </p>
        <p>
            J. Appi Physiol 1991 Apr;70(4): 1720-30..<strong>
                .Metabolic and work efficiencies during exercise in Andean natives.
            </strong>Hochachka PW, Stanley C, Matheson GO, McKenzie DC, Allen PS, Parkhouse WS.
        </p>
        <p>
            JDev Physiol 1990 Sep;14(3): 139-46.<strong>
                Effect of lactate and beta-hydroxybutyrate infusions on brain metabolism in the fetal sheep.</strong>
            Harding JE, Charlton VE.
        </p>
        <p>
            J Trauma 1999 Feb;46(2):286-91,<strong>
                The effects of diaspirin cross-linked hemoglobin on hemodynamics, metabolic acidosis, and survival in
                burned rats.:</strong> Soltero RG; Hansbrough JF.
        </p>
        <p>
            J Trauma 1999 Apr;46(4):582-8; discussion 588-9, <strong>Resuscitation with lactated Ringer's solution in
                rats with hemorrhagic shock induces immediate apoptosis.</strong> Deb S; Martin B; Sun L; Ruff P; Burris
            D; Rich N; DeBreux S; Austin B; Rhee P.
        </p>
        <p>
            Am J Physiol 1996 Oct;271(4 Pt 1):C1244-9,<strong>
                Glucose and pyruvate regulate cytokine-induced nitric oxide production by cardiac myocytes.</strong>
            Oddis CV; Finkel MS.
        </p>
        <p>
            Biochim Biophys Acta 1999 Feb 9;1410(2):171-82. <strong>Mitochondrial involvement in Alzheimer's disease.
            </strong>Bonilla E, Tanji K, Hirano M, Vu TH, DiMauro S, Schon EA.
        </p>
        <p>
            Adv Exp Med Biol 1995,384:185-94.<strong>
                Metabolic correlates of fatigue from different types of exercise in man.</strong> Vollestad NK.
        </p>
        <p>
            J Biol Chem 1995 Jun 23;270(25): 14855-8. <strong>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.
            </strong>GrossRW<strong>;</strong> Rudolph AE; Wang<strong> J;</strong> Sommers CD; Wolf MJ.
        </p>

        © Ray Peat Ph.D. 2016. All Rights Reserved. www.RayPeat.com
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    <head><title>Multiple sclerosis, protein, fats, and progesterone</title></head>
    <body>
        <h1>
            Multiple sclerosis, protein, fats, and progesterone
        </h1>

        <p>
            <hr />
            <hr />
            <hr />
        </p>

        <p>
            We are always subjected to antigenic burdens. The important question has to do with our ability to limit the
            inflammatory response to these burdens.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            Depression, lupus, migraine, menopause, diabetes, and aging have several important metabolic features in
            common with MS.
        </p>

        <p>
            Popular therapies are illogical, and are likely to cause disease progression.
        </p>
        <p>
            High quality protein, thyroid, pregnenolone and progesterone tend to correct the underlying pathology. These
            are antiinflammatory, but they are not immunosuppressive or catabolic.
        </p>
        <p>
            High altitude and sunny climate are associated with a low incidence of MS.
        </p>
        <p>
            <hr />
            <hr />
            <hr />
        </p>
        <p>
            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).
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            In the excessively sensitive condition produced by hypoglycemia, several things happen that contribute to
            the maladaptive exaggerated inflammatory response.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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).
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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).
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>

        <p>
            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.
        </p>
        <p>
            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).
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p><h3>REFERENCES</h3></p>
        <p>
            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."
        </p>

        <p>
            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."
        </p>
        <p>
            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 &lt; 0.01). During
            high-frequency stimulation, EDL muscles from the EFAD rats fatigued 32% more quickly (ANOVA, P &lt; 0.01)].
            Also, twitch contraction and half-relaxation times were significantly 5-7% reduced in the EFAD group (ANOVA,
            P &lt; 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 &lt; 0.01), but in EDL muscles from the EFAD group,
            endurance was 20% greater than in the High (n-6) group (ANOVA, P &lt; 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.
        </p>

        <p>
            Endocr Res 1999 May;25(2):207-14. Prolactin secretion is increased in patients with multiple sclerosis. Azar
            ST, Yamout B
        </p>
        <p>
            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."
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>

        <p>
            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."
        </p>
        <p>
            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."
        </p>
        <p>
            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."
        </p>
        <p>
            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."
        </p>

        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            J Neuroimmunol 2000 Nov 1;111(1-2):77-85. Female sex steroids: effects upon microglial cell activation. Drew
            PD, Chavis JA.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>

        <p>
            Am J Gastroenterol 1977 Dec;68(6):560-5. Multiple sclerosis and malabsorption. Gupta JK, Ingegno AP, Cook
            AW, Pertschuk LP.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>

        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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
        </p>
        <p>
            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."
        </p>

        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>

        <p>
            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.
        </p>
        <p>
            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
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>
        <p>
            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."
        </p>

        <p>
            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."
        </p>
        <p>
            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."
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>

        <p>
            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."
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>
        <p>
            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
        </p>

        <p>
            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."
        </p>
        <p>
            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."
        </p>
        <p>
            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."
        </p>

        <p>
            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)."
        </p>
        <p>
            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...."
        </p>
        <p>
            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.
        </p>
        <p>
            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.
        </p>

        <p>
            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."
        </p>
        <p>
            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."
        </p>
        <p>
            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.
        </p>

        <p>
            Arthritis Rheum 1981 Aug;24 (8):1054-6. Sex steroid hormones and systemic lupus erythematosus. Talal N.
        </p>
        <p>
            Clin Rheum Dis 1982 Apr;8(1):23-8. Sex hormones and modulation of immune response in SLE. Talal N.
        </p>
        <p>
            Ann N Y Acad Sci 1986;475:320-8. Hormonal approaches to immunotherapy of autoimmune disease. Talal N, Ahmed
            SA, Dauphinee M.
        </p>
        <p>
            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."
        </p>
        <p>
            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."
        </p>

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