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    <head><title>BSE - mad cow - scrapie, etc.: Stimulated amyloid degeneration and the toxic fats</title></head>
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        <h1>
            BSE - mad cow - scrapie, etc.: Stimulated amyloid degeneration and the toxic fats
        </h1>

        <article class="posted">
            <p>
                I have written before about the protective effects of carbon dioxide and progesterone, especially for
                the brain, and how the structure of cell water is affected by adsorbed and dissolved materials, and by
                metabolic energy. In the high energy (rested) state, cell water behaves as if it were colder than its
                real temperature, and this affects the behavior of proteins and fats in the cell, allowing “oily”
                surfaces to remain in contact with the more orderly water. Carbon dioxide spontaneously combines with
                the amino groups in proteins, stabilizing the normal functional conformation. The loss of carbon dioxide
                affects the structure of all proteins in the body, and the loss of cellular energy affects the structure
                of the intracellular proteins and their associated molecules.
            </p>
            <p>
                In scrapie and many other degenerative diseases (the amyloidoses), proteins condense into fibrils that
                tend to keep enlarging, with a variety of very harmful effects. The condensation of the “amyloid”
                proteins is sensitive to temperature, and a slight increase in the disorder of the water can induce
                functional proteins to change their conformation so that they spontaneously associate into fibrous
                masses. In the absence of sufficient carbon dioxide, all proteins are susceptible to structural
                alteration by the addition of sugars and fats and aldehydes, especially under conditions that favor
                lipid peroxidation.
            </p>
            <p>
                The amyloidoses affect different tissues in different ways, but when they occur in the brain, they
                produce progressive loss of function, with the type of protein forming the fibrils determining the
                nature of the functional loss. The protein which carries thyroid hormone and vitamin A, transthyretin,
                can produce nerve and brain amyloid disease, but it can also protect against other amyloid brain
                diseases; in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and the “prion diseases”
                (scrapie, kuru, CJD, BSE, etc.) amyloid particles are formed by different proteins. The transthyretin
                protein which is binding small molecules resists condensation into the amyloid fibrils, but without its
                normal vitamin A and thyroid hormone, it can create toxic fibrils. (Raghu, et al., 2002.)
            </p>
            <p>
                Around 1970 I read E. J. Field’s suggestion that aging tissues and tissues affected by viral diseases
                showed some similar structures (“inclusion bodies”) under the electron microscope. In following up those
                observations, it turned out that old tissues appeared to develop antigens “identical with, or similar
                to,” scrapie-infected young tissues. The premature aging caused by removal of the thymus gland in
                newborn animals produced similar results.
            </p>
            <p>
                Field’s group and others (e.g., Alpers) were clearly showing that the scrapie infection involved
                proteins, but not viruses with nucleic acids. In one of Field’s last publications (1978), he even
                suggested that the infectious process might depend on a structural rearrangement of the host’s
                molecules, similar to the idea which is now known as the “prion hypothesis.” Field’s suggestion was an
                important advance in the theory of aging, and the evidence supporting it is now voluminous, but that
                work has been omitted from the official histories.
            </p>
            <p>
                Although phenomena of “imprinting” and non-genetic inheritance had been established earlier, the
                dogmatism of genetics led the scientific establishment to reject everything that challenged the primacy
                of DNA. When I mentioned to my professors (in 1971) the evidence that scrapie was transmitted without
                nucleic acid, I could see from their reactions that it would be a very long time before much progress
                would be made in understanding the degenerative brain diseases. When the exact structure of the
                “infectious” protein was later worked out, and the 1997 Nobel Prize awarded (to Stanley Prusiner), I was
                surprised that no one from Field’s group was included. (In 1976, a nobel prize had been awarded to D.C.
                Gajdusek, for his promotion of the idea of “slow viruses” in general, and particularly for arguing that
                scrapie, CJD and kuru were caused by slow viruses.)
            </p>
            <p>
                In reading Prusiner’s autobiographical statements, I was even more surprised to see that he claimed to
                have been puzzled to find out, around 1983, that the infectious agent was a protein. I had thought that
                my professors were lethargic authoritarians when they refused to look at the evidence in 1970-72, but
                Prusiner’s expression of puzzlement so many years later over the absence of nucleic acid in the
                infectious agent is hard to account for.
            </p>
            <p>
                In my own research in 1971, I was interested in another kind of age-related “inclusion body,” which was
                variously called lipofuscin, age pigment, and ceroid pigment. This brown (yellow autofluorescent)
                pigment contained proteins and metals, as well as polyunsaturated lipids, and overlapped in many ways
                with the amyloid bodies. All of these inclusion bodies were known to be associated with radiation
                injury, aging, and hormonal-nutritional imbalances. Excess of estrogen, polyunsaturated fatty acids, and
                oxidative metals were major factors in the development of lipofuscin, and estrogen was also known to
                cause other types of “inclusion bodies” to develop in cells.
            </p>
            <p>
                Although very little was known about the composition of the inclusion bodies (they were usually thought
                to be organelles damaged by free radical activity, or antibodies resulting from autoimmunity), their
                involvement in aging and degenerative disease was clear<strong>,</strong> and it was widely known that
                ionizing radiation accelerated their formation. But it was just at this time that the national research
                priorities of the U.S. were redirected toward genetic explanations for all major diseases, with for
                example the “war on cancer” centering on the concepts of the “oncogene” and the cancer virus. Since the
                “slow virus” of cancer, or the viral oncogene, requires activation by something in the environment, its
                function is to distract the public’s attention from those environmental causes of disease, viz.,
                radiation and chemical pollution.
            </p>
            <p>
                The U.S. Public Health Service has historically been one of the branches of the military, and currently
                has 6000 commissioned officers. It has been intimately involved in all aspects of chemical, biological,
                and nuclear warfare, and it has participated in many covert projects, including experimentation on
                people without their knowledge. For decades, information on radiation injury to the public was hidden,
                classified, altered, or destroyed by the PHS. During the radiation disaster at Three Mile Island, they
                calmly defended the interests of the nuclear industry.
            </p>
            <p>
                After the April, 1986 catastrophe at the reactor in Chernobyl, some of the food being imported into the
                U.S. was so highly radioactive that the FDA secretly seized it, to prevent the public from being
                concerned. The first cow found to have BSE in England was in November, 1986, several months after
                England’s pastures had been heavily contaminated by rainfall carrying radioactive material from
                Chernobyl, which soaked into the soil and continued to contaminate crops for years (and will continue,
                for centuries). The number of sick cows increased rapidly to a peak in 1992. Human deaths from the
                similar disease (“variant CJD”) began a few years later.
            </p>
            <p>
                In June, 2000, a wildfire burned across southern Washington, turning the radioactive vegetation on the
                Hanford Nuclear Site into radioactive smoke, contaminating a wide area, including farms, dairies, and
                orchards. In 2003, the first cow in the U.S. with BSE was reported, from a dairy a few miles from the
                Hanford Site.
            </p>
            <p>
                Beginning in 1946, Bikini Island was used to test atomic bombs. In 1954, they began to test hydrogen
                bombs in the Pacific<strong>;</strong> some of the bombs were deliberately designed to vaporize whole
                islands, so that the effects of radioactive fallout could be studied. In 1954, the first child with kuru
                was reported in the rainy highlands of New Guinea.
            </p>
            <p>
                Within two years, hundreds of people in that area (of the Fore tribe) were dying from kuru, with the
                mortality highest among the women<strong>;</strong> in some villages, the majority of the women died
                from the disease, but by 1957 the mortality was falling rapidly. Between 1957 and 1964, 5% of the
                population of the Fore tribe died of the disease, according to D.C. Gajdusek, who had been sent by the
                U.S. Army to investigate the disease. Although Gajdusek graduated in 1946 from Harvard medical school as
                a pediatrician, in his autobiography he said that when he was drafted in 1951, the army assigned him to
                work in virology. In 1958, Gajdusek became director of the NIH laboratories for neurological and
                virological research. This was a remarkable achievement for someone who had supposedly only done some
                scattered field-work in infectious diseases, and whose purpose in going to New Guinea had been to study
                ''child growth and development in primitive cultures.'' The only published reason I have found that
                might be a basis for making him head of neurology, was his sending a diseased Fore brain to Fort Detrick
                in 1957.
            </p>
            <p>
                Gajdusek claimed to have seen the Fore people eating dead relatives, but his figures show that the
                disease was already in rapid decline when he arrived. He took photographs which were widely published in
                the US, supposedly showing cannibalism, but 30 years later, he said the photographs showed people eating
                pork, and that he had seen no cannibalism. (At the time Gajdusek was observing kuru in New Guinea, the
                influence of “cannibalism” on brain function was already in the news, because of the discovery by J.V.
                McConnell that the behavior of “trained” flatworms could be transmitted to other worms by chopping them
                up and feeding them to the naive worms.)
            </p>
            <p>
                Harvard medical school, in association with the military program centered at Fort Detrick,
                Fredericksburg, Maryland, was active in biological warfare in the 1940s, and I think it’s more plausible
                to see Gajdusek as a trouble-shooter for the biological warfare establishment, than as a biological
                researcher. One of his biographers has written that the idea of associating kuru with scrapie was
                suggested to him by a veterinarian, and that Gajdusek had responded by claiming to have experiments in
                progress to test that theory, four years before the experiments were actually made.
            </p>
            <p>
                In other words, the slow virus theory for which Gajdusek was given the Nobel Prize is scientific junk,
                which Gajdusek has repeatedly reinterpreted retrospectively, making it seem to have been anticipatory of
                the prion theory. Whatever actually caused kuru, I think the army was afraid that it was the result of
                radioactive fallout from one of its bomb tests, and that Gajdusek’s job was to explain it away.
            </p>
            <p>
                I suspect that kuru was the result of an unusual combination of malnutrition (the women were vegetarian)
                and radiation. In the very short time that Gajdusek spent in New Guinea, he claimed to have done studies
                to eliminate all of the alternative causes, nutritional, toxic, anthropological, bacterial causes,
                studies that would normally have required several years of well organized work. I don’t think he
                mentioned the possibility of radiation poisoning.
            </p>
            <p>
                In 1998 Congress commissioned a study of the health effects of radiation from bomb testing, and although
                the study examined the effects of only part of the bomb tests, it concluded that they had killed 15,000
                Americans. No one has tried to accurately estimate the numbers killed in other countries.
            </p>
            <p>
                Even very low doses of ionizing radiation create an inflammatory reaction (Vickers, et al., 1991), and
                there is evidence that the inflammatory state can persist as long as the individual lives<strong>;
                </strong>in Japan, the “acute phase” proteins are still elevated in the people who were exposed to
                radiation from the atomic bombs. The acute phase proteins that are increased by malnutrition and
                radiation increase the tendency to form amyloid deposits. Strong radiation can even cause, after a delay
                of more than a year, the development of vacuoles, which are the most obvious feature of the “prion”
                brain diseases. The persistent inflammatory reaction eventually produces cellular changes, but these
                were originally overlooked because of the theory that radiation is harmful only when it produces
                immediate changes in the DNA.
            </p>
            <p>
                Radiation damage to the brain is most visible early in life, and in old age. In 1955, Alice Stewart
                showed that prenatal x-rays increase the incidence of brain cancer, leukemia, and other cancers. In
                1967, a study in Japanese bomb survivors found that prenatal exposure to radiation had reduced their
                head size and brain size. In 1979, Sternglass and Bell showed extremely close correspondence between
                scores on the SAT and prenatal exposure to radiation.
            </p>
            <p>
                Serum amyloid A, which can increase 1000-fold under the influence of proinflammatory cytokines,
                resulting from irradiation, stress, trauma, or infection, is an activator of phospholipase A2 (PLA2),
                which releases fatty acids. Some of the neurodegenerative states, including amyloid-prion diseases,
                involve activated PLA2, as well as increases in the toxic breakdown products of the polyunsaturated
                fatty acids, such as 4-hydroxynonenal. The quantity of PUFA in the tissues strongly determines the
                susceptibility of the tissue to injury by radiation and other stresses. But a diet rich in PUFA will
                produce brain damage even without exceptional stressors, when there aren’t enough antioxidants, such as
                vitamin E and selenium, in the diet.
            </p>
            <p>
                Amyloidosis has traditionally been thought of as a condition involving deposits mainly in blood vessels,
                kidneys, joints and skin and in extracellular spaces in the brain, and the fact that the “amyloid”
                stained in a certain way led to the idea that it was a single protein. But as more proteins--currently
                about 20--were identified in amyloid deposits, it was gradually realized that the deposits can be
                identified inside cells of many different tissues, before the larger, very visible, extracellular
                deposits are formed.
            </p>
            <p>
                There is evidence of a steady increase in the death rate from amyloidosis. It kills women at a younger
                age than men, often at the age of 50 or 60.
            </p>
            <p>
                Serum amyloid P is called “the female protein” in hamsters, because of its association with
                estrogen<strong>;</strong> castrated (or estrogen treated) males also produce large amounts of it, and
                its excess is associated with the deposition of amyloid (Coe and Ross, 1985). It can bind other amyloid
                proteins together, accelerating the formation of fibrils, but this function is probably just a variation
                of a normal function in immunity, tissue repair, and development.
            </p>
            <p>
                Estrogen increases the inflammation-associated substances such as IL-6, C-reactive protein, and amyloid,
                and liberates fatty acids, especially the unstable polyunsaturated fatty acids. It also increases
                fibrinogen and decreases albumin, increasing the leakiness of capillaries. The decrease of albumin
                increases the concentration of free fatty acids and tryptophan, which would normally be bound to
                albumin.
            </p>
            <p>
                In the U.S. and Europe, livestock are fed large amounts of high-protein feeds, and currently these
                typically contain fish meal and soybeans. The estrogenic materials in soybeans increase the animals’
                tendency toward inflammation (with increased serum amyloid).
            </p>
            <p>
                Officially, BSE appeared because cows were fed slaughter-house waste containing tissues of sheep that
                had died of scrapie. Scrapie was a nerve disease of sheep, first reported in Iceland in the 18th
                century. When I was studying the digestive system and nutrition of horses, I learned that it was common
                for horses in Norway to be fed dried fish during the winter. This abundant food was probably used for
                sheep, as well as for horses. The extra protein provided by fish meal is still important for sheep in
                areas where pastures are limited, but it has now become common to use it to increase productivity and
                growth throughout the lamb, beef, and dairy industries, as well as in most lab chows fed to experimental
                animals, such as the hamsters used for testing the infectivity of the diseased tissues.
            </p>
            <p>
                Increased dietary polyunsaturated fatty acids (PUFA) suppress the activity of the ruminal bacteria which
                are responsible for the hydrogenation-detoxication of PUFA in the animal’s diet. This allows the
                unstable fats, 98% of which are normally destroyed, to pass into the animals’ tissues and milk.
            </p>
            <p>
                The polyunsaturated fats in fish are very unstable, and when they get past the bacterial saturases
                (biohydrogenases) in the rumen that normally protect ruminants from lipid peroxidation, they are likely
                to cause their toxic effects more quickly than in humans, whose antioxidant systems are highly
                developed. The toxic effects of polyunsaturated fats involve altered (immunogenic) protein structure,
                decreased energy metabolism, and many inflammatory effects produced by the prostaglandin-like
                substances. Marine fish are now so generally polluted with dioxin, that in Japan there is a clear
                association between the amount of fish in a person’s diet (their body content of EPA and DHA) and the
                amount of dioxin in their body.
            </p>
            <p>
                Radiation and many kinds of poisoning cause early peroxidation of those highly unsaturated fats, and the
                breakdown products accelerate the changes in the folding and chelating behavior of proteins. The
                accumulation of altered proteins is associated with the degenerative diseases. The role of toxic metals
                in brain inflammation is well established (e.g., aluminum, lead, mercury<strong>: </strong>Campbell, et
                al., 2004<strong>; </strong>Dave, et al., 1994<strong>; </strong>Ronnback and Hansson, 1992<strong
                >)</strong>.
            </p>
            <p>
                The “prion hypothesis” has the value of weakening the fanaticism of the DNA-genetics doctrine, but it
                has some problems. There are now several examples in which other degenerative diseases have been
                transmitted by procedures similar to those used to test the scrapie agent. (e.g., Goudsmit, et al.,
                1980; Xing, et al., 2001; Cui, et al., 2002.) Experimental controls haven’t been adequate to distinguish
                between the pure prion and its associated impurities. Gajdusek burned a sample of the infective hamster
                brain to ash, and found that it still retained “infectivity.” He argued that there was a mineral
                template that transmitted the toxic conformation to normal proteins. Others have demonstrated that the
                active structure of the infective agent is maintained by a carbohydrate scaffolding, or that the
                infectivity is destroyed by the frequency of ultraviolet light that destroys the active lipid of
                bacterial endotoxin, lipopolysaccharide.
            </p>
            <p>
                But simply injuring the brain or other organ (by injecting anything) will sometimes activate a series of
                reactions similar to those seen in aging and the amyloidoses. When a slight trauma leads to a prolonged
                or expanding disturbance of structure and function, the process isn’t essentially different from
                transmitting a condition to another individual. The problem is being “transmitted” from the initial
                injury, recruiting new cells, and passing the disturbed state on to daughter cells in a disturbed form
                of regeneration. Keloids, hypertrophic scars, are analogous to the dementias in their overgrowth of
                connective tissue cells<strong>:</strong> In the aging or injured brain, the glial cells (mainly
                astrocytes) proliferate, in reparative processes that sometimes become exaggerated and harmful.
            </p>
            <p>
                When tissue phospholipids contain large amounts of polyunsaturated fatty acids, large amounts of
                prostaglandins are immediately formed by any injury, including low doses of ionizing radiation. The
                liberated free fatty acids have many other effects, including the formation of highly reactive
                aldehydes, which modify DNA, proteins, and other cell components.
            </p>
            <p>
                Animals which are “deficient” in the polyunsaturated fatty acids have a great resistance to a variety of
                inflammatory challenges. Their tissues appear to be poor allergens or antigens, since they can be easily
                grafted onto other animals without rejection. Something related to this can probably be seen in the data
                of human liver transplants. Women’s livers are subjected to more lipid peroxidation than men’s, because
                of the effects of estrogen (increasing growth hormone and free fatty acids, and selectively mobilizing
                the polyunsaturated fatty acids and increasing their oxidation). Liver transplants from middle-aged
                female donors fail much more often (40 to 45%) than livers from male donors (22 to 25%), and other
                organs show the same effect. The autoimmune diseases are several times as common in women as in men,
                suggesting that some tissues become relatively incompatible with their own body, after prolonged
                exposure to the unstable fatty acids. If we consider the healthy function of the immune system to be the
                removal or correction of injured tissue, it’s reasonable to view the random interactions of oxidized
                fats with proteins as exactly the sort of thing our immune system takes care of.
            </p>
            <p>
                The serum amyloids A and P and the closely related lipoproteins are considered to be important parts of
                our “innate immunity,” operating in a more general way than the familiar system of specific acquired
                immunities.
            </p>
            <p>
                The amyloids and lipoproteins are powerfully responsive to bacterial endotoxin, LPS, and their
                structural feature that binds it, the “pleated sheet” structure, appears to also be what allows the
                amyloids to form amorphous deposits and fibrils under some circumstances. Our innate immune system is
                perfectly competent for handling our normal stress-induced exposures to bacterial endotoxin, but as we
                accumulate the unstable fats, each exposure to endotoxin creates additional inflammatory stress by
                liberating stored fats. The brain has a very high concentration of complex fats, and is highly
                susceptible to the effects of lipid peroxidative stress, which become progressively worse as the
                unstable fats accumulate during aging.
            </p>
            <p>
                More than 60 years ago, a vitamin E deficiency was known to cause a brain disease, sometimes associated
                with sterility and muscular dystrophy. The symptoms of the brain disease were similar to those of “mad
                cow disease,” and the condition is now usually called “crazy chick disease.” Veterinarians are usually
                taught that it is caused by a selenium deficiency, but it is actually the result of an excess of PUFA in
                the diet, and is exacerbated by increased iron or other oxidants, and prevented by increased vitamin E,
                selenium, or substitution of saturated fats for the unsaturated.
            </p>
            <p>
                Terminology, established by tradition and thoughtless memorization, obscures many of the commonalities
                in the various brain diseases. Brain inflammation (Betmouni and Perry, 1999; Perry, et al., 1998),
                myelination disorders, edema, overgrowth of the astroglia, and circulatory changes are common
                occurrences in most of the degenerative encephalopathies, but traditional textbook descriptions have
                created the impression that each disease is pathologically very distinct from the others. The current
                classification of “the prion diseases” is reifying a group of symptoms that aren’t specific to any
                specific known cause. And standard laboratory procedures for preparing brain sections for microscopic
                examination may cause brain cells to shrink to 5% of their original volume (Hillman and Jarman, <strong
                ><em>Atlas of the cellular structure of the human nervous system,</em></strong> 1991), so the
                objectivity of pathological studies shouldn’t be over-estimated.
            </p>
            <p>
                According to a 1989 study (Laura Manuelidis, neuropathology department at Yale), 13% of the people who
                had died from “Alzheimer’s disease” actually had CJD. Between 1979 and 2000, the number of people dying
                annually from Alzheimer’s disease increased 50-fold. Very competent neuropathologists differ radically
                in their descriptions of the dementia epidemic.
            </p>
            <p>
                By some tests, the “prion” resembles the LPS endotoxin. One of the interesting developments of the prion
                theory is that a particular structure that appears when the prion becomes toxic, the “beta pleated
                sheet,” is also a feature of most of the normal proteins that can form amyloid, and that this structure
                is directly related to binding and eliminating the bacterial LPS. If the prion theory is correct about
                the conversion of a normal protein into the pleated sheet, it isn’t necessarily correct about the
                incurability of the condition. The innate immune system should be able to inactivate the prion just as
                it does the bacterial endotoxin, if we remove the conditions that cause the innate immune reaction to
                amplify the inflammation beyond control.
            </p>
            <p>
                In the prion diseases, the severely damaged brain appears to have a “pathological overactivity” of the
                serotonergic systems (Fraser, et al., 2003). This is an interesting parallel to Alzheimer’s disease,
                since it has been known for several years that the blood platelets have an increased tendency to release
                serotonin in that more common form of dementia. Serotonin itself is toxic to nerves, and is part of the
                adaptive system that gets out of control during prolonged inflammation. Serotonin is an important
                activator of the phospholipases.
            </p>
            <p>
                The modification of proteins’ structure by glycosylation is involved in the development of the toxic
                form of the “prionic” protein, as well as in all the degenerative processes of aging. Until the ability
                to use sugar is impaired, cells produce enough carbon dioxide to protect proteins against random
                glycation, but with each exposure to free polyunsaturated fatty acids, the ability to use glucose is
                damaged. In the dementias, the brain has a greatly reduced ability to use glucose.
            </p>
            <p>
                One of estrogen’s central effects is to shift metabolism away from the oxidation of glucose, decreasing
                carbon dioxide production. There is a much higher incidence of Alzheimer’s disease in women, and
                estrogen exposure exacerbates all of the changes that lead to it, such as shifts in nerve transmitters,
                increased vascular leakiness, and the increased production of the acute phase proteins.
            </p>
            <p>
                Everything that is known about the “always fatal” prionic diseases, the diseases of disturbed protein
                folding, suggests that they can be avoided and even reversed by systematically reversing the processes
                that amplify inflammation.
            </p>
            <p>
                People who take aspirin, drink coffee, and use tobacco, have a much lower incidence of Alzheimer’s
                disease than people who don’t use those things. Caffeine inhibits brain phospholipase, making it
                neuroprotective in a wide spectrum of conditions. In recent tests, aspirin has been found to prevent the
                misfolding of the prion protein, and even to reverse the misfolded beta sheet conformation, restoring it
                to the harmless normal conformation. Nicotine might have a similar effect, preventing deposition of
                amyloid fibrils and disrupting those already formed (Ono, et al., 2002). Vitamin E, aspirin,
                progesterone, and nicotine also inhibit phospholipase, which contributes to their antiinflammatory
                action. Each of the amyloid-forming proteins probably has molecules that interfere with its toxic
                accumulation.
            </p>
            <p>
                Thyroid hormone, vitamins A and E, niacinamide (to inhibit systemic lipolysis), magnesium, calcium,
                progesterone, sugar, saturated fats, and gelatin all contribute in basic ways to prevention of the
                inflammatory states that eventually lead to the amyloid diseases. The scarcity of degenerative brain
                disease in high altitude populations is consistent with a protective role for carbon dioxide.
            </p>
            <p>
                The relatively sudden acceptability of the idea of non-genetic transmission doesn't mean that Lamarck
                has been rehabilitated by the scientific establishment; it could just be that it's the most politically
                acceptable way to explain the outbreaks of deadly disease caused by the industrialization of foods and
                the exposure of the population to dangerous levels of radiation.
            </p>
            <p>&nbsp;</p>
            <p><h3>REFERENCES</h3></p>
            <p>
                J Autoimmun. 1989 Aug;2(4):543-52. <strong>Estrogen induces the development of autoantibodies and
                    promotes salivary gland lymphoid infiltrates in normal mice.</strong> Ahmed SA, Aufdemorte TB, Chen
                JR, Montoya AI, Olive D, Talal N. “We hypothesize that an imbalance of the in utero sex hormone
                microenvironment critically influences the<strong>
                    fetal immune system. We have termed this influence immunological imprinting. After birth this
                    imprinting could contribute to immune-mediated disorders. To test this hypothesis, we developed a
                    mouse model in which normal mice were</strong> prenatally exposed to estrogens. In preliminary
                experiments, these mice produced higher numbers of APFC to Br-ME, particularly in the peritoneal cavity
                cell exudates. Furthermore, mice prenatally exposed to <strong>estrogens had accelerated development of
                    autoimmune salivary gland lesions indistinguishable from Sjogren's syndrome
                </strong>(SS) in humans.”
            </p>
            <p>
                J Gen Virol. 1978 Dec;41(3):503-16. <strong>The scrapie agent: evidence against its dependence for
                    replication on intrinsic nucleic acid.</strong> Alper T, Haig DA, Clarke MC. Exposure of the scrapie
                agent to u.v. light at various wavelengths has shown<strong>
                    that light of 237 nm is 4 to 5 times as effective in inactivating it as 'germicidal' wavelengths
                    (250 to 270 nm); whereas with systems that depend on</strong> RNA or DNA for function, inactivation
                is most effective by wavelengths in the germicidal range and there is a minimum of response in the
                wavelength region round 240 nm. The action spectrum for the scrapie agent is reminiscent of the
                absorption spectrum for purified bacterial endotoxin, identified as a lipopolysaccharide complex.
            </p>
            <p>
                Am J Pathol. 1971 Oct; 65(1): 43-50. <strong>Disseminated amyloidosis in germfree mice. Spontaneous
                    prevalence, relationship to ionizing radiation and pathogenetic implications.</strong> Anderson RE.
            </p>
            <p>
                Neurobiol Dis. 2002 Dec; 11(3): 386-93. <strong>Astrocytes accumulate 4-hydroxynonenal adducts in murine
                    scrapie and human Creutzfeldt-Jakob disease.</strong> Andreoletti O, Levavasseur E, Uro-Coste E,
                Tabouret G, Sarradin P, Delisle MB, Berthon P, Salvayre R, Schelcher F, Negre-Salvayre A.
            </p>
            <p>
                Biol Chem. 1999 Nov;380(11):1295-306. <strong>Prion rods contain an inert polysaccharide
                    scaffold.</strong> Appel TR, Dumpitak C, Matthiesen U, Riesner D. “<strong>Only glucose was obtained
                    by acid hydrolysis of the remnant and methylation analysis showed 80% 1,4-, 15% 1,6- and 5%
                    1,4,6-linked glucose units. The physical and chemical properties as well as the absence of terminal
                    glucose units indicate a very high molecular mass of the polysaccharide. No evidence was found for
                    covalent bonds between PrP and the polysaccharide. The polysaccharide certainly contributes to the
                    unusual chemical and physical stability of prion rods, acting like a scaffold.</strong>”
            </p>
            <p>
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                    response in CNS following injection of prion brain homogenate or normal brain homogenate.</strong>
                Betmouni S, Perry VH. “The neuropathological hallmarks of end-stage prion disease are vacuolation,
                neuronal loss, astrocytosis and deposition of PrPSc amyloid. We have also shown that there is an
                inflammatory response in the brains of scrapie-affected mice from 8 weeks post-injection.” <strong>“The
                    well circumscribed inflammatory response seen previously at 8 weeks is therefore a consequence of a
                    disease process rather than a surgical artefact. This disease process may be related to a localized
                    accumulation of PrPSc sufficient to stimulate an inflammatory response which in turn may contribute
                    to neuronal loss.”</strong>
            </p>
            <p>
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                VH.
            </p>
            <p>
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            </p>
            <p>
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                    nervous system of mice with scrapie.</strong> Betmouni S, Perry VH, Gordon JL.
            </p>
            <p>
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            </p>
            <p>
                Neuroscience. 1996 Sep;74(1):1-5. <strong>Evidence for an early inflammatory response in the central
                    nervous system of mice with scrapie.</strong> Betmouni S, Perry VH, Gordon JL. “In Alzheimer's
                disease, the most prevalent of the neurodegenerative diseases, inflammation of the CNS contributes to
                the pathology and is a target for therapy. In contrast, the group of neurodegenerative conditions known
                as the Prion Diseases have been widely reported as lacking any inflammatory elements despite the many
                similarities between the pathologies of Alzheimer's Disease and Prion Diseases We have found evidence
                for an inflammatory component in mouse scrapie, characterized by microglial activation and T-lymphocyte
                recruitment, which appears long before any clinical signs of the disease and spreads along well-defined
                anatomical pathways.”
            </p>
            <p>
                Nat Med. 1999 Jun;5(6):694-7. <strong>Serum amyloid P component controls chromatin degradation and
                    prevents antinuclear autoimmunity.</strong> Bickerstaff MC, Botto M, Hutchinson WL, Herbert J,
                Tennent GA, Bybee A, Mitchell DA, Cook HT, Butler PJ, Walport MJ, Pepys MB. “Serum amyloid P component
                (SAP)<strong> . . .</strong> is the single normal circulating protein that shows specific
                calcium-dependent binding to DNA and chromatin in physiological conditions. The avid binding of SAP
                displaces H1-type histones and thereby solubilizes native long chromatin, which is otherwise profoundly
                insoluble at the physiological ionic strength of extracellular fluids.” “Here we show that mice with
                targeted deletion of the SAP gene spontaneously develop antinuclear autoimmunity and severe
                glomerulonephritis, a phenotype resembling human systemic lupus erythematosus, a serious autoimmune
                disease.” “These findings indicate that SAP has an important physiological role, inhibiting the
                formation of pathogenic autoantibodies against chromatin and DNA, probably by binding to chromatin and
                regulating its degradation.”
            </p>
            <p>
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            </p>
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                    century clearly suggests that inherited variation is not restricted to the changes in genomic
                    sequences.</strong> The prion model, originally based on unusual transmission of certain
                neurodegenerative diseases in mammals, provides a molecular mechanism for the template-like reproduction
                of alternative protein conformations. <strong>Recent data extend this model to protein-based genetic
                    elements in yeast and other fungi</strong>.” “Prion-forming abilities appear to be conserved in
                evolution, despite the divergence of the corresponding amino acid sequences. Moreover, a wide variety of
                proteins of different origins appear to possess the ability to form amyloid-like aggregates, that in
                certain conditions might potentially result in prion-like switches. <strong>This suggests a possible
                    mechanism for the inheritance of acquired traits,</strong> postulated in the Lamarckian theory of
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                    Hamster female protein, a sex-limited pentraxin, is a constituent of Syrian hamster amyloid.</strong
                > Coe JE, Ross MJ.
            </p>
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                Y, Setoguchi M, Gondo T, Ishihara T. “We herein report that experimental murine amyloid A (AA)
                deposition is accelerated by oral administration of semipurified amyloid fibrils extracted from
                different species. Three groups of mice were treated with semipurified murine AA amyloid fibrils,
                semipurified bovine AA amyloid fibrils or semipurified human light chain-derived (A(lambda)) amyloid
                fibrils for 10 days. After 3 weeks, each mouse was subjected to inflammatory stimulation by subcutaneous
                injection with a mixture of complete Freund's adjuvant supplemented with Mycobacterium butyricum.”
                “Amyloid deposits were detected in 14 out of 15 mice treated with murine AA amyloid fibrils, 12 out of
                15 mice treated with bovine AA amyloid fibrils and 11 out of 15 mice treated with human A(lambda)
                amyloid fibrils. No amyloid deposits were detected in control mice receiving the inflammatory stimulant
                alone or in amyloid fibril-treated mice without inflammatory stimulation. Our results suggest that AA
                amyloid deposition<strong>
                    is accelerated by oral administration of semipurified amyloid fibrils when there is a concurrent
                    inflammatory stimulation.”
                </strong>
            </p>
            <p>
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                    blockade of beta-amyloid neurotoxicity.</strong> Dall'lgna OP, Porciuncula LO, Souza DO, Cunha RA,
                Lara DR. “This constitutes the first in vitro evidence to suggest that adenosine A(2A) receptors may be
                the molecular target responsible for the <strong>observed beneficial effects of caffeine consumption in
                    the development of Alzheimer's disease.</strong>”<strong></strong>
            </p>
            <p>
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                    peptide 25-35 and perturbation of lipid bilayers.</strong> Dante S, Hauss T, Dencher NA. “For a very
                long time, the aggregated form of the Abeta was supposed to be responsible for the neurodegeneration
                that occurs in AD. Recently, the attention has been diverted to the monomeric or oligomeric forms of
                Abeta and their interaction with cellular targets.”
            </p>
            <p>
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                ceroid/lipofuscinosis storage in human, canine, and ovine forms of neuronal ceroidlipofuscinosis is
                predominantly in neurons and retinal pigment epithelial cells. Despite problems in identifying
                individual storage materials, it is believed that non-enzymic oxidation of unsaturated fatty acids in
                phospholipids and inhibition of lysosomal proteolysis, leading to massive deposition of autofluorescent
                pigment, is the cause of the disease.” <strong>“We believe that the PLA1 deficiency leads to transient
                    lysosomal storage of phospholipids containing peroxy fatty acids which are then chemically converted
                    to hydroxynonenal, a potent inhibitor of a thiol-dependent enzymes.</strong> Inhibition of proteases
                is believed to be intrinsic to the formation of lipofuscin.”
            </p>
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                </strong>Du Clos TW. “The pentraxins are a family of proteins characterized by cyclic pentameric
                structure, calcium-dependent ligand binding and sequence homology. The two main representatives of this
                family are the serum proteins, C-reactive protein (CRP) and serum amyloid P component (SAP). In man CRP
                is an acute phase reactant which increases up to 1,000 fold during the acute phase<strong></strong
                >response whereas SAP is a constitutive protein expressed at about 30 micrograms/ml. These proteins
                activate complement through the classical pathway and participate in opsonization of particulate
                antigens<strong></strong>and bacteria. In the past several years it has been determined that both of
                these pentraxins interact with nuclear antigens including chromatin and small nuclear ribonucleoproteins
                (snRNPs). Both CRP and SAP have nuclear transport signals which facilitate their entry into the nuclei
                of intact cells. Furthermore, these pentraxins have been shown to affect the clearance of nuclear
                antigens in vivo.”
            </p>
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            </p>
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            </p>
            <p>
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            </p>
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            <p>
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            </p>
            <p>
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            </p>
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            </p>
            <p>
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                    neuroprotective in injured rat optic nerves.</strong>” “The results of this study show that survival
                of RGCs after axonal injury can be<strong>
                    enhanced by vaccination with an appropriate self-antigen.</strong> Furthermore, the use of
                nonencephalitogenic myelin peptides for immunization apparently allows neuroprotection without incurring
                the risk of an autoimmune disease.”
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                    brain, and that the mechanism of toxicity is related to NGF synthesis.”</strong>
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                in the A-bomb survivors have recently been supplemented by reports that non-cancer diseases, including
                cardiovascular disease, may also have <strong>increased in incidence with increasing radiation dose.
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                    such diseases, we undertook a
                </strong>detailed investigation of the long-term effects of ionizing radiation on the levels of the
                inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) in A-bomb survivors.” “Blood
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                <strong><hr /></strong>Higher CRP levels also correlated with age, male gender, body mass index and a
                history of myocardial infarction. After adjustments for these factors, <strong>CRP levels still appeared
                    to have increased significantly with increasing radiation dose (about 28% increase at 1Gy,
                </strong>
                <hr />
                <strong><hr /></strong>
                <hr />
                <strong>“Our results appear to indicate that exposure to A-bomb radiation has caused significant
                    increases in inflammatory activity that are still demonstrable in the blood of A-bomb survivors and
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                using Japanese Vital Statistics for 1969-1985. <strong>The amyloidosis death rate has increased
                    gradually year by year for both sexes.</strong>” “The mean age at death from amyloidosis gradually
                increased year by year for both sexes, although the age was <strong>11-23 years shorter for males and
                    20-25 years shorter for females</strong> than that of the general population.”
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                is critically dependent on the aggregation of the peptide into cross-beta-pleated sheet fibrils. Also,
                in vivo and postmortem NMR studies have shown changes in certain brain membrane phospholipid metabolites
                in normal aging and more extensive alterations in patients with Alzheimer's disease. The finding that
                membrane phospholipids affect the aggregation of A beta suggests that the abnormalities in membrane
                metabolism found in Alzheimer's disease could affect the deposition of A beta in vivo.” “Certain
                metabolites (glycerophosphocholine, glycerophosphoethanolamine, and alpha-glycerophosphate) augment the
                aggregation of A beta. Other membrane phospholipid metabolites (phosphocholine, phosphoethanolamine, and
                inositol-1-phosphate) have no effect.<strong></strong>We conclude that increased membrane phospholipid
                metabolite concentrations may play a role in the deposition of A beta seen in normal aging and the even
                greater deposition of A beta observed in Alzheimer's disease.”<strong></strong>
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                whereas that of the homogenate remained high throughout the entire period of observation and sharply
                increased by the third month.”
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                cytoplasmic inclusions distinct from lipofuscin. In adult rodents, this senescence-dependent glial
                granulation is accelerated by administration of estradiol valerate.” “<strong>Our findings indicate that
                    estrogen elicits a heat shock response and subsequent granulation in astrocytes</strong> residing in
                estradiol receptor-rich brain regions including the arcuate nucleus and the wall surrounding the third
                ventricle but not in estradiol receptor-deficient regions such as the striatum and corpus callosum. The
                heat shock proteins induced by estrogen, namely, the 27, 72, and 90 kDa stress proteins, are upregulated
                in astrocytes in response to oxidative challenge supporting our hypothesis that estrogen mediates
                senescent changes in the rodent hypothalamus through oxidative mechanisms.”
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                increased at 120 and 240 days in the irradiated cord segments when compared to both the nonirradiated
                thoracic and cervical segments (p &lt; 0.01) and age-matched controls (p &lt; 0.03).<strong>”
                </strong>“In the first 24 h after radiation, a 104% increase in microvessel permeability was observed
                which returned to normal by 3 days. Normal permeability was maintained at 14 and 28 days, but at 120 and
                240 days a persistent and significant increase of 98% and 73% respectively above control level was
                noted.”
            </p>
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                deposits was about two times higher in the patients who had received brain radiation therapy (27.8%)
                compared to non-radiated patients (14.8%). Amyloid angiopathy was much more prominent (P &lt; 0.05) with
                radiation therapy (22.2%) than without (8.0%).”
            </p>
            <p>
                Diabetes. 2003 Dec;52(12):2882-7. <strong>Elevation of free fatty acids induces inflammation and impairs
                    vascular reactivity in healthy subjects.</strong> Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim
                H, Aljada A, Dandona P.
            </p>
            <p>
                Arterioscler Thromb Vasc Biol. 2003 Dec 29. <strong>Effect of Lower Dosage of Oral Conjugated Equine
                    Estrogen on Inflammatory Markers and Endothelial Function in Healthy Postmenopausal Women.</strong>
                Wakatsuki A, Ikenoue N, Shinohara K, Watanabe K, Fukaya T. {Oral estrogen) “... <strong>increases plasma
                    C-reactive protein (CRP) and interleukin-6 (IL-6) concentration.</strong> The proinflammatory effect
                of oral ERT may explain the increased risk of coronary heart disease (CHD) associated with this
                treatment.”
            </p>
            <p>
                Am J Pathol. 1997 Jun; 150(6): 2181-95. <strong>Free fatty acids stimulate the polymerization of tau and
                    amyloid beta peptides.</strong>
                <strong>In vitro evidence for a common effector of pathogenesis in Alzheimer's disease.</strong> Wilson
                DM, Binder LI. “We have discovered that free fatty acids (FFAs) stimulate the assembly of both amyloid
                and tau filaments in vitro.” <strong>“Utilizing fluorescence spectroscopy, unsaturated FFAs were also
                    demonstrated to induce beta-amyloid assembly.</strong>” [These results] “...suggest that cortical
                elevations of FFAs may constitute a unifying stimulatory event driving the formation of two of the
                obvious pathogenetic lesions in Alzheimer's disease.”
            </p>
            <p>
                Lab Invest. 2001 Apr; 81(4): 493-9. <strong>Transmission of mouse senile amyloidosis.</strong> Xing Y,
                Nakamura A, Chiba T, Kogishi K, Matsushita T, Li F, Guo Z, Hosokawa M, Mori M, Higuchi K. “In mouse
                senile amyloidosis, apolipoprotein A-II polymerizes into amyloid fibrils (AApoAII) and deposits
                systemically. Peripheral injection of AApoAII fibrils into young mice induces systemic amyloidosis....”
                “We isolated AApoAII amyloid fibrils from the livers of old R1.P1-Apoa2(c) mice and injected them with
                feeding needles into the stomachs of young R1.P1-Apoa2(c) mice for 5 consecutive days. After 2 months,
                all mice had AApoAII deposits in the lamina propria of the small intestine. Amyloid deposition extended
                to the tongue, stomach, heart, and liver at 3 and 4 months after feeding. AApoAII suspended in drinking
                water also induced amyloidosis.” “Amyloid deposition was induced in young mice reared in the same cage
                for 3 months with old mice who had severe amyloidosis. Detection of AApoAII in feces of old mice and
                induction of amyloidosis by the injection of an amyloid fraction of feces suggested the propagation of
                amyloidosis by eating feces. Here, we substantiate the transmissibility of AApoAII amyloidosis and
                present a possible pathogenesis of amyloidosis, ie, oral transmission of amyloid fibril conformation,
                where we assert that exogenous amyloid fibrils act as templates and change the conformation of
                endogenous amyloid protein to polymerize into amyloid fibrils.”
            </p>
        </article>
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