by Raymond Peat

We are always subjected to antigenic burdens. The important question has to do with our ability to limit the inflammatory response to these burdens.

我们总是承受抗原负担。重要的问题与我们限制炎症反应的能力有关。

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.

在多发性硬化症中，很明显炎症过程本身是破坏性的，而雌激素是一个主要的诱发因素。不饱和脂肪酸和饮食中氨基酸的不平衡与雌激素过高和甲状腺功能减退密切相关，从而产生自身免疫性退行性疾病。

减少炎症介质比增加单一的抗炎药物(如皮质醇)要好。虽然免疫抑制药物，包括“必需脂肪酸”，确实能暂时缓解炎症症状，但它们可能有助于潜在的病理。

患有多发性硬化症的人会长期增加皮质醇的分泌。这就造成了蛋白质同化的扭曲，类似于营养蛋白质的缺乏。过量的血清素和雌激素导致相对不受控制的皮质醇的产生。炎症介质和氨基酸失衡的恶性循环可能会导致。

抑郁症、狼疮、偏头痛、更年期、糖尿病和衰老与多发性硬化症有几个共同的重要代谢特征。

流行的治疗方法是不合逻辑的，而且可能导致疾病进展。

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.

高质量的蛋白质、甲状腺、孕烯酮和孕酮有助于纠正潜在的病理。它们是抗炎的，但不具有免疫抑制或分解代谢作用。

高海拔和阳光充足的气候与多发性硬化症的低发病率有关。

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.

多发性硬化(MS),就像其他自身免疫性疾病,影响女性比男性更频繁(约2比1),都有其发生在生育年龄(特别是在30岁之后,当雌激素很高),往往加剧了经前,和有时是缓解怀孕(Drew和查韦斯,2000),当孕酮是非常高的。雌激素与孕激素比例高的女性被发现有最活跃的脑损伤(Bansil, et al.， 1999)。大多数参与MS的炎症介质——肥大细胞，一氧化氮(NO)，血清素，催乳素，脂质过氧化，游离脂肪酸，前列腺素和异前列腺素，以及各种细胞因子(IL, TNF)——都与雌激素的作用密切相关，在动物中，自身免疫性疾病可由雌激素治疗引起(艾哈迈德和塔拉勒)。

多发性硬化症和雌激素的紧密联系导致了一个不合逻辑的，但流行和广为宣传的医学结论，雌激素是预防多发性硬化症，有些人声称雌激素有有益的治疗效果。这种奇怪的思考方式也有类似的想法，因为女性比男性更容易患阿尔茨海默病，雌激素可以预防它;或者，由于女性的骨骼比男性更脆弱，她们的渐进性骨质流失发生在她们接触雌激素最多的时期，雌激素可以预防骨质疏松症。

在这种医学环境中，雌激素和退行性疾病之间的密切联系是公认的，但它们被赋予了一种与常识相反的意义，即这种联系是因为没有足够的雌激素。炉子烧到你了，因为它不够热。

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.

正如戴夫·巴里(Dave Barry)会说的，这不是我编的。最近一些广为宣传的文章认为雌激素可以保护大脑(甚至是防止中风!)因为它能增加血清素和一氧化氮。如此多的主要错误集中在一篇文章中，这几乎是一件赏心悦目的事情。一氧化氮和血清素都是神经毒性物质(Joseph等，1991;Skaper等，1996;帕金森等，1997;圣地亚哥等，1998;Barger等，2000)，作为抑制线粒体呼吸的结果。NO在脂质过氧化和脱髓鞘中起主要作用。有趣的是，血清素和一氧化氮公开与雌激素有关，而雌激素的线粒体毒性一直被小心翼翼地隐藏在公众视野中。

关于多发性硬化症的病因有几种理论，旧的关于基因和病毒的理论，新的关于细菌、维生素缺乏、油缺乏、毒素和疫苗反应(尤其是乙型肝炎和流感)的理论。唯一被抛弃的理论是19世纪关于“癔病性瘫痪”的精神病学理论，尽管偶尔仍有人谈论多发性硬化症的情感原因;“女性歇斯底里症”这个词已经演变成了“转化障碍”。

每一个主要的理论都有一些似乎支持它的事实，但忽略了许多其他的事实。每个人都同意，免疫系统在某种程度上与多发性硬化症有关，但这才是问题的根源，因为炎症是免疫系统固有的一部分。如果“炎症是必要的，也是好的”，那么如何准确界定适当反应和退化过程之间的界限就成了一个问题。水肿，细胞呼吸减少，正常功能丧失，不同程度的纤维化，炎症的每个组成部分都可以在良好的光线下看到，作为“防御性免疫反应”的一部分。当组织损伤导致修复时，它“必须”被视为是有益的，即使它导致功能性组织形成瘢痕，因为这是在一个想象的最坏的可能结果和一个不完美的恢复之间进行比较，而不是将炎症过程与潜在有毒物质可能根本没有伤害的可能性进行比较。

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.

炎症与有机体资源之间的关系最简单的例子是一个实验，在这个实验中，当动物暴露在从轻度刺激性到潜在致命的化学物质中，血糖会发生变化。当动物的血糖很低时，最温和的刺激物可能是致命的，但当它的血糖保持很高时，即使是致命的抗原也只是轻度刺激。改变血钠浓度也有类似但较弱的效果。

有一种倾向,将看到免疫炎症不仅作为一个正常的一部分,但看到它正比于抗原的性质,除了当免疫系统已被先前的准备它接触,在这种情况下,有机体要么不反应(因为它已成为免疫),或者它会比第一次接触时反应更剧烈，因为它已经过敏了。但是，实际上，仅仅是血液中葡萄糖和钠的浓度(以及甲状腺和许多其他不被认为是免疫系统一部分的物质)就可以对“免疫”反应的程度产生巨大的影响。

在由低血糖产生的过度敏感的情况下，一些事情会导致不适应的过度炎症反应。

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.

低血糖时肾上腺素增加，如果肾上腺素不能将糖原转化为葡萄糖，它将通过从脂肪细胞中释放游离脂肪酸提供替代燃料。

如果释放出来的脂肪酸是不饱和的，就会引起血清素的分泌，血清素和不饱和脂肪酸都会抑制线粒体呼吸，加剧低血糖。它们会刺激细胞因子的释放，激活各种免疫和炎症过程，并会导致血管渗漏，造成水肿，并开始纤维化的第一阶段。肾上腺素和血清素都会刺激皮质醇的释放，皮质醇会调动组织中的氨基酸，比如大骨骼肌。这些肌肉含有大量的半胱氨酸和色氨酸，它们的作用之一是抑制甲状腺。增加的色氨酸，特别是在游离脂肪酸存在的情况下，很可能转化为额外的血清素，因为脂肪酸从白蛋白中释放色氨酸，增加了它进入大脑的数量。游离脂肪酸和增加的血清素会降低代谢效率(例如导致胰岛素抵抗)，并促进炎症状态。

血液中的脂肪容易进入大脑，不饱和游离脂肪酸导致脑水肿(Chan, et al.， 1983, 1988)。当血管渗漏引起脑水肿时，通常被排除在外的蛋白质就会进入。受刺激、兴奋和疲劳的大脑会用谷氨酰胺交换色氨酸，加速其从血液中吸收。

当一个组织受到损伤或压力时，抗体就会对该组织改变的成分做出反应。因此，我们可以把擦伤或扭伤称为自身免疫疾病，但目前还没有针对擦伤胫骨抗体的商业测试。可用的特异性抗体检测似乎是将一种疾病分类为自身免疫性疾病的关键因素，如“自身免疫性甲状腺炎”。不幸的是，这种使用语言的方式被嵌套在一种文化中，这种文化充满了对因果关系不切实际的想法，成千上万的人把他们的职业生涯建立在寻找“导致疾病的突变基因”和纠正缺陷的药物上。

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.

在免疫学的早期研究中，重点是抗体。甚至更早的时候，炎症已经被定义为“体液”和其他科学之前的概念。一旦多发性硬化症/癔病性瘫痪被归类为一种自身免疫疾病，关于免疫系统本质的原始观点，与关于大脑本质和细胞结构的原始观点相互作用，融入关于疾病本质的各种理论中。

与其把免疫神经损伤看作是多发性硬化症其他特征的原因，我认为重要的是看看这种疾病的一些一般特征，作为解释神经事件的背景。

众所周知，多发性硬化症的发病率随着离赤道的距离增加而增加。在阳光干燥的气候和高海拔地区发病率较低。两种明显的饮食影响已经被发现:吃猪肉和马肉。

患有多发性硬化症的人不能很好地调节体温。他们的神经传导很慢，而在正常人中，在较高的温度下，神经传导更快，但在多发性硬化症患者中，在98.6的正常温度下，神经传导比在较低温度下要慢。体温过低也与老年和更年期潮热有关。

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.

在多发性硬化症中，葡萄糖的脑代谢非常低，而且在我自己的观察中，总体代谢率低于正常水平。然而，有些人认为低代谢是由病变引起的，而不是相反。

缺乏不饱和脂肪酸的动物有更高的代谢率和利用葡萄糖的能力，更容易将葡萄糖转化为二氧化碳，对毒素有更强的抵抗力(Harris, et al.， 1990;甚至眼镜蛇毒液:Morganroth, et al.， 1989)，包括内毒素(Li, et al.， 1990)——防止过多的血管渗漏——以及免疫损伤(Takahashi, et al.， 1992)和创伤，它们的神经肌肉反应加快，而快速抽动肌肉不那么容易疲劳(Ayre和Hulber, 1996)。

多发性硬化症患者的血液更粘稠，血小板更容易凝结在一起。他们的皮质醇水平高于正常水平，他们的垂体肾上腺皮质刺激激素更难抑制。这种情况在抑郁症和老年人中也会出现。尽管皮质醇水平长期升高，但多发性硬化症患者通常会出现低血糖。他们偶尔会出现低钠，低钠血症，但当血液中的含水量变化时，这很难确定。她们的催乳素可能很高，这可能是由于高雌激素、高血清素、低钠或低甲状腺所致。喝太多水会增加催乳素，破坏神经的髓鞘膜;过多的血清素会导致过量饮酒。血糖、钠和水含量的紊乱会破坏大脑的髓鞘结构。高雌激素会渗透地扰乱血液，使血液中保留了过多的水分，这与雌激素的许多作用有关;由于简单的渗透变化可以破坏髓鞘结构，在假定免疫事件是主要的之前，似乎应该对这种机制进行彻底的研究。

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.

肥大细胞通过释放组织胺和血清素等物质促进炎症(并使血管渗漏)，在多发性硬化症患者的大脑中比正常大脑中数量更多。由于血小板聚集释放血清素，也因为血清素过量是由多发性硬化的许多其他特征所暗示的，血清素拮抗剂(例如昂丹西酮和酮坦瑟林)已被成功地用于治疗。

雌激素导致肥大细胞释放炎症介质，并导致血小板聚集，释放血清素。由于雌激素优势与活跃的脑损伤的存在密切相关，抗雌激素治疗在ms中似乎很明显。孕酮抵消了雌激素对肥大细胞和血小板的影响。

阿司匹林可以防止多种炎症过程，但它最著名的是抑制前列腺素。阿司匹林常被用于缓解多发性硬化症的疼痛，而另一种前列腺素合成抑制剂吲哚美辛已被用于治疗多发性硬化症，似乎更仔细地研究阿司匹林在预防或缓解多发性硬化症中的可能作用是合适的。

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.

简单的蛋白质缺乏会有许多令人惊讶的影响。它会降低体温，抑制甲状腺，但它会增加炎症和血液凝结的倾向。由于大脑、心脏和肺需要持续的必需氨基酸供应才能继续运作，在缺乏膳食蛋白质的情况下，必须不断产生皮质醇来调动消耗性组织(主要是骨骼肌)中的氨基酸。这些肌肉含有高浓度的色氨酸和半胱氨酸，它们会抑制甲状腺。半胱氨酸是兴奋性的，而色氨酸是血清素的前体。据推测，它们在肌肉中的存在，以及由压力引起的肌肉释放，是在某些类型的压力下减少代谢活动的机制之一。

当怀孕的动物缺乏蛋白质时，新生的动物血清素水平异常高，而导致血清素过量的酶倾向于维持血清素过量，即使它们长大了，有足够的蛋白质。这类似于生命早期过量的雌激素的影响，它会导致成年后患乳腺癌或前列腺癌的倾向。研究后来患多发性硬化症的人的妊娠经历，例如妊娠时间和出生体重，将是很有趣的。

虽然北方国家的人通常不缺乏蛋白质，但他们确实倾向于从肌肉肉中获取大部分蛋白质。在传统文化中，食用动物的所有部位——鸡爪、头、脖子、动物的耳朵和眼睛等——因此氨基酸平衡有利于维持高代谢率和防止压力。

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.

多发性硬化症的观察与猪肉和马肉的消费,而不是牛肉,羊肉,或者山羊,非常有趣,因为脂肪的动物本质上是喜欢他们吃的脂肪的植物材料,这意味着它非常高在亚麻油酸和亚麻酸。牛、绵羊和山羊的瘤胃中含有将多不饱和脂肪转化为更多饱和脂肪的细菌。不饱和脂肪会抑制消化蛋白质的酶，据报道，多发性硬化症患者对肉类的消化不良(Gupta等人，1977)。

多不饱和脂肪本身是有毒的线粒体,并抑制葡萄糖氧化,抑制甲状腺功能,用同样的抑制影响氧化葡萄糖的能力,但他们也转过身来,酶促,前列腺素,非酶促,通过自发的脂质过氧化作用,为有毒花生四烯酸(Arachidonic Acid) 氧化反应過程中的主要产物。异前列腺素和一些前列腺素在多发性硬化症患者的大脑和其他组织中升高。

脂质过氧化在多发性硬化症中非常高。一氧化氮(在大脑的大部分区域雌激素促进其合成)是一种自由基，能激活过氧化作用。

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.”

脂质过氧化自然地选择性破坏不稳定的多不饱和脂肪。在动脉粥样硬化中，血管斑块含有很少的不饱和脂肪。这是因为它们的氧化速度非常快，但它们饱和脂肪和不饱和脂肪的高比率被用来证明多不饱和油是“保护心脏的”。类似的论点在多发性硬化症中也经常出现，尽管一些研究并不支持任何不饱和脂肪的缺乏。由于脂质过氧化性非常高，可以合理地假设有大量的多不饱和脂肪通过与催化剂如铁(S.M. LeVine, 1997)、一氧化氮和过氧腈的反应被过氧化。

我认为，多发性硬化症患者热不耐受的一个重要方面可能是相对热疗的趋势，释放更多的自由脂肪酸进入血液。由于雌激素的作用，女性血液中游离脂肪酸的含量通常比男性高得多。雌激素增加了储存脂肪中自由脂肪酸的释放，而不饱和脂肪与雌激素和催乳素协同作用，增加了它们的作用。

温度调节显然涉及一些神经细胞，它们能非常准确地感知温度，并相应地改变它们的活动。水有非常高的热容，这意味着它需要相当大的热量来改变它的温度。“消失的热量”被水的结构变化所消耗。蛋白质具有和水一样的结构复杂性，它们结合在一起可以制成有效的温度传感器，即“温度计”。(其他物质只有在熔化或蒸发时才会发生重大结构变化。著名的“液晶”有几个不同的结构相，但细胞质就像一个非常微妙的液晶。)“恒温细胞”实际上是对某种程度的内部结构做出反应，而不是抽象的温度。所以改变它们内部结构的物质会改变它们的温度“设定点”。

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.

增加的雌激素会导致动物体温降低，这可能是通过增加恒温细胞的“结构温度”，“熔化”它们的内部结构来实现的。黄体酮使动物体温升高，这显然是通过增加/降低恒温细胞的结构温度来实现的。如果你把冰放进恒温器里，房间就会变热。

一个细胞的内部结构相当于它的工作准备。疲劳代表细胞的一种轻微的“熔化”状态，在这种状态下，细胞的结构似乎与化学能量储备一起被消耗掉了。证明这种效应的实验非常清楚，但它们被忽略了，因为它们不符合人们对细胞的刻板印象。有了一个非常灵敏的温度计，就可以测量神经受到刺激时产生的热量。这并不奇怪。但令人惊讶的是，当神经从刺激中恢复时，它会从环境中吸收热量，降低局部温度。这甚至违背了一些人的“熵”概念，但这很容易证明，改变某些材料的形式会改变它们的热容，就像橡皮筋拉伸(变热)或收缩(变冷)一样。

兴奋剂，雌激素和皮质醇，会减缓神经的传导，因为它们会使神经的内部结构耗散。它们在细胞中创造一种“预疲劳”状态。

在兔子心脏的实验中，圣捷尔吉表明雌激素降低了心脏工作的准备程度，而孕酮则提高了它工作的准备程度，他说这是通过“构建结构”实现的。他指出，对于给定的药物或其他刺激，细胞会有一种特征性的反应，要么变得更活跃，要么变得更受抑制，但他指出，在刺激的正常浓度或强度范围之外，细胞的反应往往是相反的。

如果这是多发性硬化症患者神经的情况，就可以解释神经受热会降低其功能的奇怪行为。这意味着神经的内部结构(和能量)必须恢复。在我之前的通讯中描述过的实验中，增加钠、ATP、二氧化碳和孕酮，以及增加镁和钙的比例，已经被发现可以增加细胞的能量和结构。甲状腺激素最终负责维持细胞的能量、结构和反应能力，但如果它在不允许其他所有因素调整的情况下突然增加，它会突然提高体温。这并不需要很长时间，但所有因素必须同时出现。

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.

血清素、褪黑素、雌激素和多不饱和脂肪都倾向于降低体温。由于雌激素和不饱和脂肪是细胞兴奋剂，体温的实际下降有助于抵消它们的兴奋作用。

强光和高海拔都会降低血清素的作用。留在高海拔的组织二氧化碳降低了许多疾病的发病率，多发性硬化症可能会像心脏病和癌症一样受到影响。众所周知，二氧化碳参与了髓磷脂自身水分含量的调节。

过度通气，通过造成二氧化碳的损失，释放组胺和血清素，使血液更粘稠，同时使血管更通透，并导致血管收缩。

如果通过交互女士已经开发出它的人过多的雌激素,血清素,不饱和脂肪,铁,和水,和缺乏甲状腺和缺乏孕烯醇酮生产myelin-forming细胞(寡树突胶质细胞),可以做很多事情来阻止其进展,并可能逆转。

因为温度的突然升高会释放更多的促炎脂肪，所以应该逐渐改变。增加盐是产热的，但是增加镁可以防止体温升高，所以增加镁(泻盐浴，例如咖啡，水果，一些蔬菜和肉类)是有帮助的。甲状腺机能减退时，镁会从细胞中迅速流失。糖，当与脂肪和矿物质，如牛奶，是需要降低皮质醇，维持甲状腺活动。均衡的蛋白质，如奶酪、土豆、鸡蛋和牛肉或羊肉汤(特别是明胶和矿物质含量)，将防止色氨酸过量，抑制甲状腺，并可能是一种神经毒素。经常使用饱和脂肪可以立即降低储存的不饱和脂肪的毒性抗代谢作用，但要改变储存脂肪的平衡需要很长时间。

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.

由于阿司匹林能降低体温，抗炎，在某些情况下抗雌激素，是一种强大的抗氧化剂，它可能会缓解症状，防止MS的进展，就像它在其他退行性疾病中所做的那样。由于血小板聚集可能与炎症的焦点有关，阿司匹林可能有助于防止新的损伤区域的形成。

糖皮质激素有助于抗炎作用，而皮质醇则通过兴奋毒性促进脑细胞的死亡。由于雌激素能减少GABA，而且雌激素和血清素都能激活兴奋性氨基酸递质，在已有的皮质醇过量的基础上添加合成糖皮质激素可能会损伤大脑的部分区域，以及炎症区域。

抑郁、老年和雌激素分泌过多的皮质醇通常通过甲状腺补充剂来降低，但孕烯醇酮有一个非常直接的作用(与血清素相反)，可以安静垂体，减少ACTH和皮质醇。孕酮也有类似的作用，可以防止皮质醇过量，是神经和大脑恢复的主要因素。甲状腺、孕酮和孕烯酮都参与了新的髓磷脂的形成，并在防止损害髓磷脂的水肿中发挥作用。

由于甲状腺和孕酮减少炎症组织中雌激素的形成，而皮质醇刺激其形成，使用甲状腺和孕酮似乎是明智的，因为它们的直接抗炎作用，包括抑制NO的形成(Drew和Chavez, 2000)，以及它们缺乏兴奋毒性，糖皮质激素的雌激素刺激作用。糖皮质激素可分解代谢并从肌肉中释放半胱氨酸和色氨酸，而甲状腺和孕酮则不能分解代谢，并可防止这些氨基酸的毒性后果。

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

Acta Neurol Scand 1999 Feb;99(2):91-4. Correlation between sex hormones and magnetic resonance imaging lesions in multiple sclerosis. Bansil S, Lee HJ, Jindal S, Holtz CR, Cook SD “Patients with high estradiol and low progesterone levels had a significantly greater number of Gd enhancing lesions than those with low levels of both these hormones. Patients with a high estrogen to progesterone ratio had a significantly greater number of active MRI lesions than those with a low ratio.”

J Neuroimmunol 1996 Mar;65(1):75-81. Circulating antibodies directed against conjugated fatty acids in sera of patients with multiple sclerosis. Boullerne A, Petry KG, Geffard M “These results suggest that in MS and RA, autoepitopes on cell membranes that are normally hidden from the immune system become immunogenic. This may arise because of previous membrane disruption by oxidative processes.”

J Neurosci Res 2000 Nov 15;62(4):503-9. Dehydroepiandrosterone inhibits microglial nitric oxide production in a stimulus-specific manner. Barger SW, Chavis JA, Drew PD.

J Exp Med 1984 Nov 1;160(5):1532-43. Inhibition of autoimmune neuropathological process by treatment with an iron-chelating agent. Bowern N, Ramshaw IA, Clark IA, Doherty PC “Iron is believed to influence both the migration and function of immune effector cells. It can also act as a catalyst in the formation of free radicals, which are highly toxic agents causing tissue damage in sites of inflammation.”

J Neurol Neurosurg Psychiatry 1981 Apr;44(4):340-3. Rheological and fibrinolytic findings in multiple sclerosis. Brunetti A, Ricchieri GL, Patrassi GM, Girolami A, Tavolato B. “The whole blood viscosity was found to be increased in multiple sclerosis.”

J Neurochem 1988 Apr;50(4):1185-93. Induction of intracellular superoxide radical formation by arachidonic acid and by polyunsaturated fatty acids in primary astrocytic cultures. Chan PH, Chen SF, Yu AC “Other PUFAs, including linoleic acid, linolenic acid, and docosahexaenoic acid, were also effective in stimulating NBF formation in astrocytes, whereas saturated palmitic acid and monounsaturated oleic acid were ineffective. Similar effects of these PUFAs were observed in malondialdehyde formation in cells and lactic acid accumulation in incubation medium. These data indicate that both membrane integrity and cellular metabolism were perturbed by arachidonic acid and by other PUFAs.”

Ann Neurol 1983 Jun;13(6):625-32. Induction of brain edema following intracerebral injection of arachidonic acid. Chan PH, Fishman RA, Caronna J, Schmidley JW, Prioleau G, Lee J “Intracerebral injection of polyunsaturated fatty acids (PUFAs), including linolenic acid (18:3) and arachidonic acid (20:4), caused significant increases in cerebral water and sodium content concomitant with decreases in potassium content and Na+- and K+- dependent adenosine triphosphatase activity. There was gross and microscopic evidence of edema. Saturated fatty acids and monounsaturated fatty acid were not effective in inducing brain edema. The [125I]-bovine serum albumin spaces increased twofold and threefold at 24 hours with 18:3 and 20:4, respectively, indicating vasogenic edema with increased permeability of brain endothelial cells” “These data indicate that arachidonic acid and other PUFAs have the ability to induce vasogenic and cellular brain edema and further support the hypothesis that the degradation of phospholipids and accumulation of PUFAs, particularly arachidonic acid, initiate the development of brain edema in various disease states.”

Med Sci Sports Exerc 1997 Jan;29(1):58-62. Effects of acute physical exercise on central serotonergic systems. Chaouloff F “Works from the 1980's have established that acute running increases brain serotonin (5-hydroxytryptamine: 5-HT) synthesis in two ways. Lipolysis-elicited release of free fatty acids in the blood compartment displaces the binding of the essential amino acid tryptophan to albumin, thereby increasing the concentration of the so-called “free tryptophan” portion, and because exercise increases the ratio of circulating free tryptophan to the sum of the concentrations of the amino acids that compete with tryptophan for uptake at the blood-brain barrier level, tryptophan enters markedly in the brain compartment.” “Indirect indices of 5-HT functions open the possibility that acute exercise-induced increases in 5-HT biosynthesis are associated with (or lead to) increases in 5-HT release.”

Med Hypotheses 1995 Nov;45(5):455-8. Melanin, melatonin, melanocyte-stimulating hormone, and the susceptibility to autoimmune demyelination: a rationale for light therapy in multiple sclerosis. Constantinescu CS “The hypothesis formulated here is based on the observation that resistance to multiple sclerosis and experimental autoimmune encephalomyelitis is associated with dark skin pigmentation. While this may signify a protective role for melanin against environmental factors producing oxidative damage, the mechanism postulated here is that susceptibility to autoimmune demyelination is influenced by hormonal factors, i.e. the neurohormones melatonin and melanocyte stimulating hormone, which have opposing effects on immune functions and, the same time, are important determinants of the individual's production of melanin.”

Neurosci Lett 1989 Nov 6;105(3):246-50. Presence of Schwann cells in neurodegenerative lesions of the central nervous system. Dusart I, Isacson O, Nothias F, Gumpel M, Peschanski M Ultrastructural analysis of neurodegenerative CNS lesions produced by an excitotoxic substance revealed that the majority of cells ensheathing axons were not oligodendrocytes. By their morphology and the presence of both a basal lamina and collagen fibers they were identified as Schwann cells. The presence of Schwann cells, whose growth-promoting role in the peripheral nervous system has been largely documented, may account for the development of regenerating growth cones which have been observed in the excitotoxically lesioned central nervous system. Further support for this hypothesis came from the analysis of fetal neural transplants implanted into the lesioned area. Schwann cells ensheathing axons were indeed numerous in the neuron-depleted area surrounding the transplants, where neurite outgrowth of graft origin occurred.

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

Neurology 1999 Nov 10;53(8):1876-9 Cerebrospinal fluid isoprostane shows oxidative stress in patients with multiple sclerosis. Greco A, Minghetti L, Sette G, Fieschi C, Levi G “The CSF level of the isoprostane 8-epi-prostaglandin (PG)-F2alpha (a reliable marker of oxidative stress in vivo) was three times higher in subjects with definite MS than in a benchmark group of subjects with other neurologic diseases.”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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