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<head><title>Multiple sclerosis, protein, fats, and progesterone</title></head>
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Multiple sclerosis, protein, fats, and progesterone
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We are always subjected to antigenic burdens. The important question has to do with our ability to limit the
inflammatory response to these burdens.


In MS, it is clear that the inflammatory process itself is destructive, and that estrogen is a major
predisposing factor. Unsaturated fatty acids, and dietary imbalance of amino acids interact closely with
hyperestrogenism and hypothyroidism to produce the autoimmune degenerative diseases.


Reduction of the mediators of inflammation is better than augmenting a single antiinflammatory agent such as
cortisol. Although immunosuppressive drugs, including the "essential fatty acids," do alleviate inflammatory
symptoms temporarily, they probably contribute to the underlying pathology.


People with MS have chronically increased production of cortisol. This creates a distortion of protein
assimilation, resembling a nutritional protein deficiency. Excessive serotonin and estrogen cause a
relatively uncontrolled production of cortisol. A vicious circle of inflammatory mediators and amino acid
imbalance can result.


Depression, lupus, migraine, menopause, diabetes, and aging have several important metabolic features in
common with MS.

Popular therapies are illogical, and are likely to cause disease progression.


High quality protein, thyroid, pregnenolone and progesterone tend to correct the underlying pathology. These
are antiinflammatory, but they are not immunosuppressive or catabolic.


High altitude and sunny climate are associated with a low incidence of MS.


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Multiple sclerosis (MS), like other autoimmune diseases, affects women more often than men (about 2 to 1),
has its onset during the reproductive years (especially after the age of 30, when estrogen is very high), is
often exacerbated premenstrually, and is sometimes alleviated by pregnancy (Drew and Chavez, 2000), when
progesterone is very high. Women with a high ratio of estrogen to progesterone have been found to have the
most active brain lesions (Bansil, et al., 1999). Most of the mediators of inflammation that are involved in
MS--mast cells, nitric oxide (NO), serotonin, prolactin, lipid peroxidation, free fatty acids,
prostaglandins and isoprostanes, and the various cytokines (IL, TNF)--are closely associated with estrogen's
actions, and in animals, autoimmune diseases can be brought on by treatment with estrogen (Ahmed and Talal).

The strong association of MS with estrogen has led to an illogical, but popular and well-publicized medical
conclusion that estrogen is protective against MS, and some have claimed that estrogen has beneficial
therapeutic effects. This strange way of thinking has its equivalent in the idea that, since women are much
more likely than men to develop Alzheimer's disease, estrogen is protective against it; or that, since women
have more fragile bones than men do, and their progressive bone loss occurs during the times of their
greatest exposure to estrogen, estrogen prevents osteoporosis.


In this medical environment, close associations between estrogen and degenerative diseases are acknowledged,
but they are given a meaning contrary to common sense by saying that the association occurs because there
isn't enough estrogen. The stove burns you because it isn't hot enough.


As Dave Barry would say, I'm not making this up. Recently well publicized articles have suggested that
estrogen protects the brain (even against stroke!) because it increases serotonin and NO. There is something
almost esthetically pleasing when so many major errors are concentrated into a single article. Nitric oxide
and serotonin are both neurotoxic (Joseph, et al., 1991; Skaper, et al., 1996; Parkinson, et al., 1997;
Santiago, et al., 1998; Barger, et al., 2000), as a result of suppressing mitochondrial respiration. NO
plays a major role in lipid peroxidation and demyelination. It's interesting to see serotonin and NO openly
associated with estrogen, whose mitochondrial toxicity has been carefully hidden from public view.


There are several theories about the cause of MS, old theories about genes and viruses, and newer theories
about bacteria, vitamin deficiencies, oil deficiencies, poisons, and reactions to vaccinations (especially
for hepatitis B and influenza). The only theory that has been abandoned is the 19th century psychiatric
theory about "hysterical paralysis," though occasionally someone does still talk about emotional causes of
multiple sclerosis; the term "female hysteria" has evolved into "conversion disorder."


Each of the main theories has a few facts that seem to support it, but neglects to account for many other
facts. Everyone agrees that the immune system is involved in MS in some way, but that's really where the
problem starts, because of the idea that inflammation is an intrinsic part of immunity. If "inflammation is
necessary and good," then it becomes a problem to define exactly where the boundary is between an
appropriate reaction and a degenerative process. Edema, reduced cellular respiration, loss of normal
functions, fibrosis in its various degrees, each component of inflammation can be seen in a good light, as
part of a "defensive immune reaction." When tissue injury leads to repair, it "must" be seen as beneficial,
even if it leads to the formation of a scar in place of functional tissue, because the comparison is between
an imagined worst possible outcome, and an imperfect recovery, rather than comparing the inflammatory
process with the possibility that a potentially noxious agent might have done no harm at all.


The simplest illustration of how inflammation relates to the organism's resources was an experiment in which
blood glucose was varied, while an animal was exposed to chemicals that varied from mildly irritating to
potentially deadly. When the animal had very low blood sugar, the mildest irritant could be deadly, but when
its blood glucose was kept very high, even the deadly antigens were only mildly irritating. Varying the
blood sodium concentration had similar, but weaker, effects.


There is a tendency to see inflammation not only as a normal part of immunity, but to see it as being
proportional to the nature of the antigen, except when the immune system has been primed for it by previous
contact, in which case the organism will either not react at all (because it has become immune), or it will
react much more violently than it did on the first exposure, because it has become allergic. But, in
reality, the mere concentration of glucose and sodium in the blood (and of thyroid, and many other
substances that aren't considered to be part of the immune system) can make a tremendous difference in the
degree of "immunological" reaction.


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


Adrenaline increases in hypoglycemia, and, if the adrenaline fails to convert glycogen into glucose, it will
provide an alternative fuel by liberating free fatty acids from fat cells.

If the liberated fatty acids are unsaturated, they will cause serotonin to be secreted, and both serotonin
and the unsaturated fatty acids will suppress mitochondrial respiration, exacerbating the hypoglycemia. They
will stimulate the release of cytokines, activating a variety of immunological and inflammatory processes,
and they will cause blood vessels to become leaky, creating edema and starting the first stages of fibrosis.
Both adrenaline and serotonin will stimulate the release of cortisol, which mobilizes amino acids from
tissues such as the large skeletal muscles. Those muscles contain a large amount of cysteine and tryptophan,
which, among other effects, suppress the thyroid. The increased tryptophan, especially in the presence of
free fatty acids, is likely to be converted into additional serotonin, since fatty acids release tryptophan
from albumin, increasing its entry into the brain. Free fatty acids and increased serotonin reduce metabolic
efficiency (leading to insulin resistance, for example) and promote an inflammatory state.


Fats in the blood-stream have easy access to the brain, and the unsaturated free fatty acids produce brain
edema (Chan, et al., 1983, 1988). When brain edema is caused by vascular leakage, proteins that are normally
excluded can enter. The stimulated, excited and fatigued brain exchanges glutamine for tryptophan,
accelerating its uptake from the blood.


When a tissue is injured or stressed, antibodies are formed in response to the altered components of that
tissue. Therefore, we could call a bruise or a sprain an autoimmune condition, but there are no commercial
tests for bruised-shin antibodies. The availability of tests for specific antibodies seems to be the
essential factor in classifying a condition as autoimmune, as in "autoimmune thyroiditis." Unfortunately,
this way of using language is nested in a culture that is full of unrealistic ideas of causality, and
thousands of people build their careers on the search for the "mutated genes that are responsible for the
disease," and for the drugs that will correct the defect.


Early in the study of immunology, the focus was on antibodies. Even earlier, inflammation had been
conceptualized in terms of the "humors," and other prescientific ideas. As soon as multiple
sclerosis/hysterical paralysis was classified as an autoimmune disease, primitive ideas about the nature of
the immune system, interacting with primitive ideas about the nature of the brain and the structure of
cells, blended into the various theories of what the disease is.


Rather than seeing immunological nerve damage as the cause of all the other features of multiple sclerosis,
I think it's important to look at some of the general features of the condition, as contexts in which to
interpret the events in the nerves.


It has been known for a long time that the incidence of MS tends to increase with distance from the equator.
Incidence is low in sunny dry climates, and at high altitudes. Two clear dietary influences have been found:
eating pork, and horsemeat.


People with MS don't regulate their body temperature very well. Their nerve conduction is slow, and in
normal people, conduction is faster at higher temperatures, but in people with MS the conduction is slower
at the normal temperature of 98.6O F than at lower temperatures. A subnormal temperature is also associated
with old age, and with the hot flashes of menopause.


Brain metabolism of glucose is very low in multiple sclerosis, and in my own observations, the general
metabolic rate is subnormal. However, some people reason that the hypometabolism is caused by the lesions,
rather than vice versa.

Animals that lack the unsaturated fatty acids have a higher metabolic rate and ability to use glucose,
converting it to CO2 more readily, have a greater resistance to toxins (Harris, et al., 1990; even cobra
venom: Morganroth, et al., 1989), including endotoxin (Li, et al., 1990)--preventing excessive vascular
leakage--and to immunological damage (Takahashi, et al., 1992), and to trauma, and their neuromuscular
response is accelerated while fast twitch muscles are less easily fatigued (Ayre and Hulber, 1996).


In people with MS, the blood is more viscous, and the platelets tend to clump together more easily. Their
cortisol level is higher than normal, and their pituitary adrenal-cortex-stimulating hormone is harder to
suppress. This is a condition that is also seen in depression and old age. Despite the chronically elevated
cortisol, people with MS typically have hypoglycemia. They are occasionally found to have low blood sodium,
hyponatremia, but this is hard to determine when the blood's water content is variable. Their prolactin is
likely to be high, and this can result from high estrogen, high serotonin, low sodium, or low thyroid.
Drinking too much water can increase prolactin, and can damage the nerves' myelin enclosures; too much
serotonin tends to cause excessive drinking. Disturbances of blood glucose, sodium, and water content can
disrupt the brain's myelin structure. High estrogen disturbs the blood osmotically, making it retain too
much water in relation to the solutes, and this relates to many of estrogen's effects; since simple osmotic
variations can damage the myelin structures, it seems that this mechanism should be investigated thoroughly
before it is assumed that the immunological events are primary.


Mast cells, which promote inflammation by releasing substances such as histamine and serotonin (and make
blood vessels leaky), are more numerous in the brain in multiple sclerosis than in normal brains. Since
platelet clumping releases serotonin, and also because serotonin excess is suggested by so many other
features of MS, serotonin antagonists (ondansetron and ketanserin, for example) have been used
therapeutically with success.


Estrogen causes mast cells to release their inflammatory mediators, and it causes platelets to aggregate,
releasing their serotonin. Since estrogen dominance is closely associated with the presence of active brain
lesions, antiestrogen therapy would seem obvious in MS. Progesterone counteracts estrogen's effects on both
mast cells and platelets.

Aspirin protects against a variety of inflammatory processes, but it's most famous for the inhibition of
prostaglandins. While aspirin is often used to relieve pain in MS, and another inhibitor of prostaglandin
synthesis, indomethacin, has been used therapeutically in MS, it would seem appropriate to investigate more
carefully aspirin's possible role in preventing or relieving MS.


A simple protein deficiency has many surprising effects. It lowers body temperature, and suppresses the
thyroid, but it increases inflammation and the tendency of blood to clot. Since the brain and heart and
lungs require a continuous supply of essential amino acids if they are to continue functioning, in the
absence of dietary protein, cortisol must be produced continuously to mobilize amino acids from the
expendable tissues, which are mainly the skeletal muscles. These muscles have a high concentration of
tryptophan and cysteine, which suppress the thyroid. Cysteine is excitoxic, and tryptophan is the precursor
for serotonin. Presumably, their presence in, and stress-induced release from, the muscles is one of the
mechanisms that reduce metabolic activity during certain types of stress.


When pregnant animals are deprived of protein, the newborn animals have abnormally high levels of serotonin,
and the enzymes responsible for that excess tend to maintain the serotonin excess even when they are grown
and have adequate protein. This is analogous to the effect of excess estrogen early in life, which creates a
tendency to develop breast or prostate cancer in adulthood. It would be interesting to study the gestational
experience, e.g., length of gestation and birth weight, of the people who later develop MS.


Although people in the northern countries aren't normally protein-starved, they do tend to get a large part
of their protein from the muscle meats. In traditional cultures, all parts of the food animals were
eaten--chicken feet, heads, and necks, animals' ears and eyeballs, etc.--and so the amino acid balance was
favorable for maintaining a high metabolic rate and preventing stress.

The observation that multiple sclerosis is associated with the consumption of pork and horsemeat, but not
beef, lamb, or goat, is very interesting, since the fat of those animals is essentially like the fats of the
plant materials that they eat, meaning that it is extremely high in linoleic and linolenic acids. The rumen
of cows, sheep, and goats contains bacteria that convert the polyunsaturated fats into more saturated fats.
Unsaturated fats inhibit the enzymes that digest protein, and MS patients have been reported to have poor
digestion of meat (Gupta, et al., 1977).


The polyunsaturated fats are in themselves toxic to mitochondria, and suppress glucose oxidation, and
inhibit the thyroid function, with the same suppressive effect on the ability to oxidize glucose, but they
are also turned, enzymically, into the prostaglandins, and non-enzymically, by spontaneous lipid
peroxidation, into the toxic isoprostanes. The isoprostanes, and some of the prostaglandins, are elevated in
the brain and other tissues of people with MS.


Lipid peroxidation is very high in multiple sclerosis. Nitric oxide (whose synthesis is promoted by estrogen
in most parts of the brain) is a free radical that activates peroxidation.


Lipid peroxidation selectively destroys, naturally, the unstable polyunsaturated fats. In atherosclerosis,
the blood vessel plaques contain very little unsaturated fat. This is because they are peroxidized so
rapidly, but their high ratio of saturated to unsaturated fats has been used to argue that the
polyunsaturated oils are "heart protective." Similar arguments are often made in MS, though some studies
don't support the idea that there is a lack of any of the unsaturated fats. Since lipid peroxidation is very
high, it would be reasonable to assume that there was an abundance of polyunsaturated fats being peroxidized
through reactions with catalysts such as iron (S.M. LeVine, 1997) and nitric oxide and peroxynitrile.


I believe that an important aspect of the intolerance for heat so often reported in people with MS could be
the tendency of relative hyperthermia to release increased amounts of free fatty acids into the blood
stream. Women, because of estrogen's effects, usually have much higher levels of free fatty acids in the
blood than men do. Estrogen increases the release of free fatty acids from stored fat, and the unsaturated
fats synergize with both estrogen and prolactin, increasing their effects.


Temperature regulation apparently involves some nerve cells that sense temperature very accurately, and
change their activity accordingly. Water has a remarkably high heat capacity, meaning that it takes a
relatively large amount of heat to change its temperature. The "disappearing heat" is being consumed by
structural changes in the water. Proteins have the same sort of structural complexity as water, and together
they can make effective temperature transducers, "thermometers." (Other substances tend to undergo major
structural changes only as they melt or vaporize. The famous "liquid crystals" have a few distinct
structural phases, but cytoplasm is like a very subtle liquid crystal.) The "thermostat cells" are actually
responding to a degree of internal structure, not to the temperature in the abstract. So things that change
their internal structure will modify their temperature "set-point."

Increased estrogen causes an animal to lower its temperature, and it probably does this by increasing the
"structural temperature" of the thermostat cells, "melting" their internal structure. Progesterone causes
the animal to increase its temperature, and it apparently does this by increasing the structure/decreasing
the structural temperature of the thermostat cells. If you put ice in the thermostat, the room gets hot.


A cell's internal structure is equivalent to its readiness to work. Fatigue represents a slightly "melted"
state of the cell, in which structure appears to have been consumed along with the chemical energy reserves.
Experiments that demonstrated this effect were very clear, but they were ignored because they didn't fit
people's stereotyped idea of the cell. With a very sensitive thermometer, it's possible to measure the heat
produced by a nerve when it is stimulated. That's not surprising. But it's surprising that, when the nerve
is recovering from the stimulation, it absorbs heat from its environment, lowering the temperature locally.
That even violated some people's conception of "entropy," but it can easily be demonstrated that changing
the form of some materials changes their heat capacity, as when a rubber band is stretched (it gets hot), or
contracts (it gets cooler).


The excitants, estrogen and cortisol, slow the conduction of nerves, because they cause its internal
structure to be dissipated. They create a "pre-fatigued" state in the cell.


In experiments with rabbit hearts, Szent-Gyorgyi showed that estrogen decreased the heart's readiness to
work, and that progesterone increased its readiness to work, and he said it did this by "building
structure." He pointed out that, for a given drug or other stimulus, cells have a characteristic response,
becoming either more activated or more inhibited, but he showed that, outside the normal concentration or
intensity range of the stimulus, a cell's response is often reversed.


If this is the situation in the nerves in MS, it explains the strange behavior, in which warming the nerve
reduces its function. The implication is that internal structure (and energy) must be restored to the
nerves. In experiments that I have described in previous newsletters, increasing sodium, ATP, carbon
dioxide, and progesterone, and increasing the ratio of magnesium to calcium, have been found to increase
cellular energy and structure. The thyroid hormone is ultimately responsible for maintaining cells' energy
and structure, and responsiveness, but if it is increased suddenly without allowing all the other factors to
adjust, it will raise the temperature too suddenly. It needn't take a long time, but all the factors have to
be present at the same time.

Serotonin, melatonin, estrogen, and polyunsaturated fats all tend to lower body temperature. Since estrogen
and the unsaturated fats are cellular excitants, the actual decrease in body temperature helps to offset
their excitatory effects.


Both bright light and high altitude tend to reduce serotonin's effects. The tissue carbon dioxide retained
at high altitude reduces the incidence of many diseases, and multiple sclerosis might be affected as heart
disease and cancer are. It is known that carbon dioxide is involved in myelin's regulation of its own water
content. Hyperventilation, by causing a loss of carbon dioxide, releases both histamine and serotonin,
making blood more viscous, while making blood vessels more permeable, and causing them to constrict.


If people with MS have developed it through the interactions of excessive estrogen, serotonin, unsaturated
fats, iron, and water, and deficient thyroid, and deficient pregnenolone produced in the myelin-forming
cells (oligodendrocytes), there are many things that can be done to stop its progress, and possibly to
reverse it.


Since a sudden increase in temperature will release increased amounts of the pro-inflammatory fats, things
should be changed gradually. Increased salt is thermogenic, but increased magnesium is protective against
hyperthermia, so increased magnesium (epsom salts baths, for example, coffee, fruits, some vegetables and
meats) would be helpful. Magnesium is rapidly lost from cells in hypothyroidism. Sugar, when accompanied by
fats and minerals, as in milk, is needed to lower cortisol, and to maintain thyroid activity. Balanced
proteins, such as cheese, potatoes, eggs, and beef- or lamb-broth (for the gelatin and mineral content in
particular) will prevent the tryptophan excess that suppresses the thyroid and is potentially a nerve toxin.
Saturated fats, used regularly, reduce the immediate toxic antimetabolic effects of the stored unsaturated
fats, but it takes a long time to change the balance of stored fats.


Since aspirin lowers temperature, is antiinflammatory, in some situations antiestrogenic, and is a powerful
antioxidant, it is likely that it would alleviate symptoms and prevent progression of MS, as it does in
other degenerative diseases. Since platelet aggregation is likely to be involved in the focuses of
inflammation, aspirin might help to prevent the formation of new areas of damage.

While the glucocorticoids are useful for their antiinflammatory actions, cortisol is known to promote the
killing of brain cells by excitotoxicity. Since estrogen decreases GABA, and both estrogen and serotonin
activate the excitatory amino acid transmitters, the addition of synthetic glucocorticoids to the
pre-existing cortisol excess is likely to damage parts of the brain in addition to the inflamed areas.


The excess cortisol of depression, old age, and hyperestrogenism often comes down with use of a thyroid
supplement, but pregnenolone has a very direct action (in opposition to serotonin) that can quiet the
pituitary, reducing ACTH and cortisol. Progesterone has some similar effects, and is protective against
excess cortisol, and is a major factor in nerve and brain restoration. Thyroid, progesterone, and
pregnenolone are all involved in the formation of new myelin, and in the prevention of the edema that
damages it.


Since thyroid and progesterone decrease the formation of estrogen in inflamed tissue, while cortisol
stimulates its formation, it would seem wise to use thyroid and progesterone for their immediate
antiinflammatory effects, which include the inhibition of NO formation (Drew and Chavez, 2000), and their
lack of the excitotoxic, estrogen-stimulating effects of the glucocorticoids. While the glucocorticoids are
catabolic and liberate cysteine and tryptophan from muscles, thyroid and progesterone are not catabolic, and
protect against the toxic consequences of those amino acids.

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multiple sclerosis. Greco A, Minghetti L, Sette G, Fieschi C, Levi G "The CSF level of the isoprostane
8-epi-prostaglandin (PG)-F2alpha (a reliable marker of oxidative stress in vivo) was three times higher in
subjects with definite MS than in a benchmark group of subjects with other neurologic diseases."


J Intern Med 1989 Oct;226(4):241-4. Serum sex hormone and gonadotropin concentrations in premenopausal women
with multiple sclerosis. Grinsted L, Heltberg A, Hagen C, Djursing H.

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


Free Radic Res 1997 Apr;26(4):351-62. Toxicity of polyunsaturated fatty acid esters for human
monocyte-macrophages: the anomalous behaviour of cholesteryl linolenate. Hardwick SJ, Carpenter KL, Law NS,
Van Der Veen C, Marchant CE, Hird R, Mitchinson MJ. "The triglycerides showed a direct relationship between
toxicity and increasing unsaturation, which in turn correlated with increasing susceptibility to oxidation."
"Triarachidonin (20:4; omega-6), trieicosapentaenoin (20:5; omega-3) and tridocosahexaenoin (22:6; omega-3)
were profoundly and rapidly toxic. There was a similar relationship between toxicity and increasing
unsaturation for most of the cholesterol esters, but cholesteryl linolenate was apparently anomalous, being
non-toxic in spite of possessing three double bonds and being extensively oxidised." "The toxicity of
triglycerides suggests that polyunsaturated fatty acid peroxidation products are also toxic."


J Clin Invest 1990 Oct;86(4):1115-23. Essential fatty acid deficiency ameliorates acute renal dysfunction in
the rat after the administration of the aminonucleoside of puromycin. Harris KP, Lefkowith JB, Klahr S,
Schreiner GF.


Mikrobiyol Bul 1989 Oct;23(4):342-7. [Leukotrienes and neurological diseases]. [Article in Turkish] Irkec C,
Ercan S, Irkec M "LTC4 levels were found to be elevated in MS and Behcet patient in comparison with
controls. Augmentation of LTC4 levels underlines the fact that leukotrienes may be held responsible the
pathogenesis of these disorders."

Lancet 1982 Feb 13;1(8268):380-6. Evidence for subacute fat embolism as the cause of multiple sclerosis.
James PB "The neurological features of decompression sickness, which is thought to be due to gas embolism,
are similar to those of multiple sclerosis (MS). This similarity suggested the re-examination of a concept,
first proposed in 1882, that the demyelination in MS is due to venous thrombosis. Unfortunately, although
the plaques of MS are often perivenular, thromboses are not always present. Nevertheless, vascular theories
can explain the topography of the lesions in MS." "There is also evidence in man that fat may lodge in the
microcirculation of the nervous system and cause distal perivenous oedema with the loss of myelin from
axons."


J Clin Pathol 1979 Oct;32(10):1025-9. Antithrombin activities in childhood malnutrition. Jimenez RA, Jimenez
E, Ingram GI, Mora LA, Atmetlla F, Carrillo JM, Vargas W.


Arch Latinoam Nutr 1980 Dec;30(4):580-9. [Prethrombosis in child malnutrition]. Jimenez R, Jimenez E, Mora
LA, Vargas W, Atmetlla F, Carrillo JM


Stroke 1991 Nov;22(11):1448-51. Platelet secretory products may contribute to neuronal injury. Joseph R,
Tsering C, Grunfeld S, Welch KM "The view that certain endogenous substances, such as glutamate, may also
contribute to neuronal injury is now reasonably well established. Blood platelets are known to contain and
secrete a number of substances that have been associated with neuronal dysfunction. Therefore, we
hypothesize that a high concentration (approximately several thousand-fold higher than in plasma, in our
estimation) of locally released platelet secretory products derived from the causative thrombus may
contribute to neuronal injury and promote reactive gliosis." "We further observed that serotonin, a major
platelet product, has neurotoxic properties."

Zh Nevropatol Psikhiatr Im S S Korsakova 1985;85(2):198-206. [Role of disorders of the hemostatic system in
the pathogenesis of multiple sclerosis and ways of correcting them]. [Article in Russian] Karlov VA, Makarov
VA, Savina EB, Seleznev AN, Savin AA The changes in the hemostatic system were studied in 77 patients with
different patterns of disseminated sclerosis (DS). The studies demonstrated activation of both
vasculothrombocytic and coagulation components of hemostasis as well as of fibrinolytic blood properties.
The latent course of the disseminated intravascular coagulation was revealed in 20.7% of cases. The role of
hemostatic disorders in the pathogenetic mechanisms of DS is discussed. The patients with DS received
pathogenetic treatment including drugs eliminating hemostatic disorders, which was beneficial for most
patients.


Zh Nevropatol Psikhiatr Im S S Korsakova 1990;90(11):47-50. [Changes in rheological properties of blood in
multiple sclerosis and their correction]. [Article in Russian] Karlov VA, Savin AA, Smertina LP, Redchits
EG, Seleznev AN, Svetailo LI, Margosiuk NV, Stulin ID As many as 45 patients with multiple sclerosis were
examined for rheological blood properties. As compared to controls, the group under examination manifested
the rise of plasma viscosity, acceleration of red blood cell aggregation. 26.2% of patients demonstrated an
appreciable increase of blood viscosity. It is assumed that these changes contribute to the deterioration of
microcirculation and aggravate the demyelinating process. Correction of the rheological properties of the
blood by plasmapheresis coupled with other methods of pathogenetic therapy turned out effective.


Brain Res 1997 Jun 20;760(1-2):298-303 Iron deposits in multiple sclerosis and Alzheimer's disease brains.
LeVine SM "In summary, the localization of iron deposition in MS and AD brains indicates potential sites
where iron could promote oxidative damage in these disease states."


Circ Shock 1990 Jun;31(2):159-70. Resistance of essential fatty acid-deficient rats to endotoxin-induced
increases in vascular permeability. Li EJ, Cook JA, Spicer KM, Wise WC, Rokach J, Halushka PV.


FEBS Lett 1978 Nov 1;95(1):181-4. Selective inactivation of the NADH-ubiquinone segment of the respiratory
chain of submitochondrial particles by endogenous free fatty acids during hyperthermia. Ludwig P, Bartels M,
Schewe T, Rapoport S.

J Pain Symptom Manage 2000 Nov;20(5):388-91. Ondansetron in multiple sclerosis. Macleod AD. "Two young women
with chronic nausea and vertigo caused by multiple sclerosis responded to the introduction and maintenance
of the 5HT3 receptor antagonist, ondansetron."


Am J Phys Med Rehabil 1994 Jul-Aug;73(4):283-5. Intracranial venous thrombosis in a patient with multiple
sclerosis. A case report and review of contraceptive alternatives in patients with disabilities. Malanga GA,
Gangemi E.


Folia Biol (Praha) 1999;45(4):133-41. Essential fatty acids and related molecular and cellular mechanisms in
multiple sclerosis: new looks at old concepts. Mayer M.


J Clin Endocrinol Metab 1994 Sep;79(3):848-53. Multiple sclerosis is associated with alterations in
hypothalamic-pituitary-adrenal axis function. Michelson D, Stone L, Galliven E, Magiakou MA, Chrousos GP,
Sternberg EM, Gold PW "Compared to matched controls, patients with MS had significantly higher plasma
cortisol levels at baseline. Despite this hypercortisolism and in contrast to patients with depression who
had similar elevations in plasma cortisol levels, patients with MS showed normal, rather than blunted,
plasma ACTH responses to ovine CRH, suggesting that the pathophysiology of hypercortisolism in MS is
different from that in depression." "Taken together, these findings are compatible with data from studies of
experimental animals exposed to chronic inflammatory stress, which showed mild increased activation of the
HPA axis with increased relative activity of AVP in the regulation of the pituitary-adrenal axis."


Exp Neurol 1977 Oct;57(1):142-57. Tryptophan availability: relation to elevated brain serotonin in
developmentally protein-malnourished rats. Miller M, Leahy JP, Stern WC, Morgane PJ, Resnick O.

Am J Physiol 1989 Oct;257(4 Pt 2):H1192-9. Lung injury caused by cobra venom factor is reduced in rats
raised on an essential fatty acid-deficient diet. Morganroth ML, Schoeneich SO, Till GO, Pickett W, Ward PA.


Eur J Haematol 2000 Jul;65(1):82-3. More on the relationship between cystic fibrosis and venous thrombosis.
Mori PG, Acquila M, Bicocchi MP, Bottini F, Romano L. Letter


Acta Neurol Scand 1982 Oct;66(4):497-504, Platelet aggregation and multiple sclerosis. Neu IS, Prosiegel M,
Pfaffenrath V Measurements of blood platelet aggregation were carried out in 30 patients suffering from
multiple sclerosis (MS) and in 15 healthy individuals. Compared with the control group, the MS patients
showed an increase in both spontaneous and induced (ADP and serotonin) platelet aggregation. The possible
pathogenetic significance of these results is discussed.


Neurology 1975 Aug;25(8):713-6. Schwann cells and regenerated peripheral myelin in multiple sclerosis: an
ultrastructural study. Ogata J, Feigin I Tissue of a multiple sclerosis plaque in the brachium conjunctivum
of the pons known to contain peripheral myelin by light microscopic studies were removed from the paraffin
block and processed for electron microscopic studies. The cells related to the peripheral myelin possessed
the ultrastructural characteristics of Schwann cells, with basement membranes and associated collagen
fibers. No continuity was seen with the peripheral within the central nervous tissues by selective
maturation of multipotential primitive reticular cells, a phenomenon consistent with the view that Schwann
cells are mesenchymal in character.


Tohoku J Exp Med 1999 Dec;189(4):259-65. Elevated plasma level of plasminogen activator inhibitor-1 (PAI-1)
in patients with relapsing-remitting multiple sclerosis. Onodera H, Nakashima I, Fujihara K, Nagata T,
Itoyama Y "Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system
and one of the earliest changes in inflammatory focus involves the activation of vascular endothelial
cells." "The level of plasma PAI-1 was significantly higher in active MS cases when compared to stable MS
and controls." "These results suggested that PAI-1 plasma levels are associated with MS disease activity and
is a good marker for MS relapse."

J Mol Med 1997 Mar;75(3):174-86. The role of nitric oxide in multiple sclerosis. Parkinson JF, Mitrovic B,
Merrill JE "Elevated nitric oxide bio-synthesis has been associated with nonspecific immune-mediated
cellular cytotoxicity and the pathogenesis of chronic, inflammatory autoimmune diseases including rheumatoid
arthritis, insulin-dependent diabetes, inflammatory bowel disease, and multiple sclerosis."


Fed Proc 1987 Jan;46(1):91-6. Role of the clotting system in the pathogenesis of neuroimmunologic disease.
Paterson PY, Koh CS, Kwaan HC "Our studies of the clotting system and ensuing fibrinolysis implicate
coagulation and cleavage of fibrin within or on the luminal surface of the cerebrovasculature as events
initiating the inflammation characterizing EAE." "We postulate that the critical event precipitating EAE is
binding of circulating MBP-reactive immune effector cells to MBP immunodeterminants on the surface of
cerebrovascular endothelial cells. Coagulation and ensuing fibrinolysis occur at sites of binding of
effector cells to cerebrovascular endothelium. Release of biologically active peptides cleaved from fibrin
open the BBB, thereby setting the stage for the cascade of inflammatory events culminating in clinical
manifestations of EAE."


Neurotoxicology 1998 Aug-Oct;19 (4-5):599-603. In vitro effect of the cysteine metabolites homocysteic acid,
homocysteine and cysteic acid upon human neuronal cell lines. Parsons RB, Waring RH, Ramsden DB, Williams AC
"Cysteine (CYS) is a non-essential amino acid which elicits excitotoxic properties via the
N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor.. CYS levels are known to be elevated in
association with neurological disease such as Alzheimers Disease (AD) and Parkinsons Disease (PD)." "These
results show that toxic responses are cell-type specific for CYS and its metabolites and this may be
reflected in the patterns of neurodegeneration observed in such diseases as AD and PD."


WMJ 1983 Mar-Apr;55(2):146-50. [Effect of tryptophan excess in a diet on amino acid composition of skin
collagen and on an initial stage of protein biosynthesis in rat liver]. Pechenova TN, Sushkova VV, Solodova
EV, Gulyi MF Protein deficiency and tryptophane load against its background lead to the acid-soluble
collagen synthesis in the rat skin. The amino acid composition of the collagen differs from the norm. This
is accompanied by changes in the free amino acid pool of blood serum and liver, under tryptophane load the
free amino acids pool of the liver increasing twice as high. At the same time protein deficiency increases
and tryptophane load decreases the level of tRNA amino acylation with tryptophane in the animal liver. Thus,
protein deficiency and tryptophane load against its background cause deep changes in the protein
biosynthesis.

Fed Proc 1987 Jan;46(1):91-6. Role of the clotting system in the pathogenesis of neuroimmunologic disease.
Paterson PY, Koh CS, Kwaan HC "Our studies of the clotting system and ensuing fibrinolysis implicate
coagulation and cleavage of fibrin within or on the luminal surface of the cerebrovasculature as events
initiating the inflammation characterizing EAE." "We postulate that the critical event precipitating EAE is
binding of circulating MBP-reactive immune effector cells to MBP immunodeterminants on the surface of
cerebrovascular endothelial cells. Coagulation and ensuing fibrinolysis occur at sites of binding of
effector cells to cerebrovascular endothelium. Release of biologically active peptides cleaved from fibrin
open the BBB, thereby setting the stage for the cascade of inflammatory events culminating in clinical
manifestations of EAE."


Rev Esp Fisiol 1983 Mar;39(1):39-44. Intralipid and free plasmatic tryptophan in vitro. Pena JM, Aulesa C,
Vinas O, Bosch J, Farriol M, Schwartz S "In an attempt to investigate the role of the lipidic emulsion
Intralipid in the development of metabolic encephalopathy in a patient showing high free tryptophan levels,
the relationship between lipidic emulsion and free tryptophan was examined in in vitro experiments. The
addition of intralipid to normal serum produces an immediate increase in non-esterified fatty acids and a
parallel rise in free tryptophan. Moreover, when serum with intralipid is incubated at 37 degrees C, the
lipases release new non-esterified fatty acids and the free tryptophan increases proportionally." "It is
concluded that intralipid causes an increase in free tryptophan levels. It is known that in vivo free
tryptophan modulates 5-hydroxytryptamine synthesis and thus may be considered a possible causal agent for
encephalopathy."


Med Hypotheses 1980 May;6(5):545-557. Fatty acids, fibrinogen and blood flow: a general mechanism for
hyperfibrinogenemia and its pathologic consequences. Pickart LR, Thaler MM Plasma fibrinogen is elevated in
various stressful states and conditions in which active mobilization of free fatty acids (FFA) occurs.
Reduction of plasma FFA by an assortment of hypolipidemic drugs is consistently followed by a decrease in
the accompanying hyperfibrinogenemia. A direct link between FFA and fibrinogen has been demonstrated in
animals, and in experiments employing incubated liver slices. Based on these clinical and experimental
observations, we postulate that hepatic fibrinogen synthesis is stimulated by FFA. Since fibrinogen is a
major determinant of whole blood viscosity, erythrocyte aggregation, and sludging of red cells in terminal
and pre-terminal blood vessels, we propose that microcirculatory blood flow may be impaired in the presence
of chronically elevated plasma FFA levls. Consequently, hypolipidemic drugs may be effective in prevention
of circulatory complications associated with FFA-induced hyperfibrinogenemia.


Neurologia 1996 Aug-Sep;11(7):272. [Exacerbation of spasticity induced by serotonin reuptake inhibitors.
Letter]. del Real MA, Hernandez A, Vaamonde J, Gudin M

J Neurol Neurosurg Psychiatry 1997 Mar;62(3):282-4. Ondansetron, a 5-HT3 antagonist, improves cerebellar
tremor. Rice GP, Lesaux J, Vandervoort P, Macewan L, Ebers GC. "It has been previously shown that
ondansetron, a 5-HT3 antagonist, can ameliorate vertigo in patients with acute brainstem disorders. A
coincidental benefit was the improvement of cerebellar tremor in some patients with both vertigo and tremor.
To further evaluate this effect, a placebo controlled, double blind, crossover study was conducted of a
single dose of intravenous ondansetron in 20 patients with cerebellar tremor caused by multiple sclerosis,
cerebellar degeneration, or drug toxicity." "Thirteen of 19 patients were deemed to have improved spiral
copying after treatment with ondansetron when compared with baseline performance."


Neurologia 1993 Oct;8(8):252-5. [Retinal periphlebitis in multiple sclerosis. A prospective study]. Rio J,
Colin A, Salvador F, Tintore M, Viguera ML, Montalban J, Codina A "In three cases (12.5%) retinal
periphlebitis was observed." "Given the absence of myelin in the retina, the presence of retinal
periphlebitis suggests the existence of a vascular mechanism in the pathogenesis of multiple sclerosis."


Int J Neurosci 1995 Dec;83(3-4):187-98. Premenstrual exacerbation of symptoms in multiple sclerosis is
attenuated by treatment with weak electromagnetic fields. Sandyk R. "The present report concerns two women
with chronic progressive stage MS who experienced, coincident with increasing functional disability, regular
worsening of their symptoms beginning about a week before menstruation and abating with the onset of
menstruation. These symptoms resolved two months after the initiation of treatment with EMFs."

J Physiol Biochem 1998 Dec;54(4):229-37. The role of nitric oxide in the pathogenesis of multiple sclerosis.
Santiago E, Perez-Mediavilla LA, Lopez-Moratalla N "The inducible NOS (iNOS) is associated with the
development of a number of autoimmune diseases." "Induction of the enzyme is effected by proinflammatory
cytokines, immunomodulating peptides, and even beta-endorphin through a mechanism involving an increase in
cAMP. An excessive production of NO has been implicated in the severe lesions observed in multiple sclerosis
(MS)."


J Neurol 1980 Jan;222(3):177-82. Cerebrospinal fluid lipids in demyelinating disease. II. Linoleic acid as
an index of impaired blood-CSF barrier. Seidel D, Heipertz R, Weisner B "The linoleic acid content of
control CSF (1.6 +/- 0.8 nMol/ml) is considerably lower than the corresponding serum value (2.5--4.1
muMol/ml). Although CSF from MS patients contains a significantly higher linoleic acid concentration than
controls the close correlation between CSF linoleic acid and CSF albumin is maintained. The high CSF
concentration of cholesterol esters rich in linoleic acid, which are abundant in serum but represent only
traces in CNS lipids, points towards an impaired BBB function as the cause of CSF linoleic increase. We are
able to show that both albumin and linoleic acid are suitable as "serum markers...."


J Neurol Sci 1987 Feb;77(2-3):147-52. Chronic periphlebitis retinae in multiple sclerosis. A
histopathological study. Shaw PJ, Smith NM, Ince PG, Bates D Retinal periphlebitis in multiple sclerosis is
of particular interest in relation to our understanding of the pathogenesis of the demyelinating central
nervous system plaques. Previous studies have largely been clinical, and there is little detailed
histopathological information relating to this condition. We present the first detailed report in the
neurological literature on the histological findings in chronic periphlebitis retinae associated with
multiple sclerosis. The most significant abnormalities of the affected retinal veins were the presence of
thick laminated collagen in the wall, associated with a scanty infiltration of plasma cells.


Am Heart J 2000 Aug;140(2):212-8. Low intracellular magnesium levels promote platelet-dependent thrombosis
in patients with coronary artery disease. Shechter M, Merz CN, Rude RK, Paul Labrador MJ, Meisel SR, Shah
PK, Kaul S.

J Neurochem 1996 Mar;66(3):1157-66. Mast cell activation causes delayed neurodegeneration in mixed
hippocampal cultures via the nitric oxide pathway. Skaper SD, Facci L, Romanello S, Leon A. "Neurotoxicity
required a prolonged period (12 h) of mast cell incubation, and appeared to depend largely on elaboration of
the free radical nitric oxide by astrocytes." "Myelin basic protein and 17 beta-estradiol had a synergistic
action on the induction of mast cell-associated neuronal injury." "Further, palmitoylethanolamide, which has
been reported to reduce mast cell activation by a local autacoid mechanism, decreased neuron loss resulting
from mast cell stimulation in the mixed cultures but not that caused by direct cytokine induction of
astrocytic nitric oxide synthase." "These results support the notion that brain mast cells could participate
in the pathophysiology of chronic neurodegenerative and inflammatory diseases of the nervous system, and
suggest that down-modulation of mast cell activation in such conditions could be of therapeutic benefit."


International Journal of Microcirculation--Clinical and Experimental, 1996, Vol 16, Iss 5, pp 266-270.
Hyperventilation enhances transcapillary diffusion of sodium fluorescein. J Steurer, D Schiesser, C Stey, W
Vetter, MV Elzi, JP Barras, UK Franzeck. "Voluntary hyperventilation (HV) provokes hemoconcentration due to
a loss of fluid from the intravascular space." "The exact, mechanism of enhanced transcapillary diffusion of
Na fluorescein is not known, The distinct increase in FLI without a significant change in microvascular skin
flux suggests an HV-induced increase in capillary pressure or an enhancement in capillary permeability for
water and small solutes."


Kidney Int 1992 May;41(5):1245-53. Essential fatty acid deficiency normalizes function and histology in rat
nephrotoxic nephritis. Takahashi K, Kato T, Schreiner GF, Ebert J, Badr KF.

Arthritis Rheum 1981 Aug;24 (8):1054-6. Sex steroid hormones and systemic lupus erythematosus. Talal N.


Clin Rheum Dis 1982 Apr;8(1):23-8. Sex hormones and modulation of immune response in SLE. Talal N.


Ann N Y Acad Sci 1986;475:320-8. Hormonal approaches to immunotherapy of autoimmune disease. Talal N, Ahmed
SA, Dauphinee M.


Ann Nucl Med 1998 Apr;12(2):89-94. Clinical significance of reduced cerebral metabolism in multiple
sclerosis: a combined PET and MRI study. Sun X, Tanaka M, Kondo S, Okamoto K, Hirai S "The severity of
cerebral hypometabolism was also related to the number of relapses." "Our results suggest that measurement
of cerebral metabolism in MS has the potential to be an objective marker for monitoring disease activity and
to provide prognostic information."


Fed Proc 1987 Jan;46(1):118-26. Pathway to carrageenan-induced inflammation in the hind limb of the rat.
Vinegar R, Truax JF, Selph JL, Johnston PR, Venable AL, McKenzie KK "Antiserotonin agents inhibited the
hypoalgesia and part of the edema. These findings and histological observations suggested that dermal mast
cells were injured by C. The hyperalgesia and part of the edema were sensitive to arachidonate
cyclooxygenase inhibitors (AACOIs). It is speculated that injured mast cells metabolize arachidonic acid and
reactive intermediates, not prostaglandins, mediate the NPIR hyperalgesia and part of the edema."
"Arachidonic acid metabolism by neutrophils is speculated to produce the mediators of phagocytic
inflammatory (PI) edema and hyperalgesia."