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933 lines
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<head><title>BSE - mad cow - scrapie, etc.: Stimulated amyloid degeneration and the toxic fats</title></head>
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<body>
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<h1>
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BSE - mad cow - scrapie, etc.: Stimulated amyloid degeneration and the toxic fats
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</h1>
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<article class="posted">
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<p>
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I have written before about the protective effects of carbon dioxide and progesterone, especially for
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the brain, and how the structure of cell water is affected by adsorbed and dissolved materials, and by
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metabolic energy. In the high energy (rested) state, cell water behaves as if it were colder than its
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real temperature, and this affects the behavior of proteins and fats in the cell, allowing “oily”
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surfaces to remain in contact with the more orderly water. Carbon dioxide spontaneously combines with
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the amino groups in proteins, stabilizing the normal functional conformation. The loss of carbon dioxide
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affects the structure of all proteins in the body, and the loss of cellular energy affects the structure
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of the intracellular proteins and their associated molecules.
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</p>
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<p>
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In scrapie and many other degenerative diseases (the amyloidoses), proteins condense into fibrils that
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tend to keep enlarging, with a variety of very harmful effects. The condensation of the “amyloid”
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proteins is sensitive to temperature, and a slight increase in the disorder of the water can induce
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functional proteins to change their conformation so that they spontaneously associate into fibrous
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masses. In the absence of sufficient carbon dioxide, all proteins are susceptible to structural
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alteration by the addition of sugars and fats and aldehydes, especially under conditions that favor
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lipid peroxidation.
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</p>
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<p>
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The amyloidoses affect different tissues in different ways, but when they occur in the brain, they
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produce progressive loss of function, with the type of protein forming the fibrils determining the
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nature of the functional loss. The protein which carries thyroid hormone and vitamin A, transthyretin,
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can produce nerve and brain amyloid disease, but it can also protect against other amyloid brain
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diseases; in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and the “prion diseases”
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(scrapie, kuru, CJD, BSE, etc.) amyloid particles are formed by different proteins. The transthyretin
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protein which is binding small molecules resists condensation into the amyloid fibrils, but without its
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normal vitamin A and thyroid hormone, it can create toxic fibrils. (Raghu, et al., 2002.)
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</p>
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<p>
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Around 1970 I read E. J. Field’s suggestion that aging tissues and tissues affected by viral diseases
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showed some similar structures (“inclusion bodies”) under the electron microscope. In following up those
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observations, it turned out that old tissues appeared to develop antigens “identical with, or similar
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to,” scrapie-infected young tissues. The premature aging caused by removal of the thymus gland in
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newborn animals produced similar results.
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</p>
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<p>
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Field’s group and others (e.g., Alpers) were clearly showing that the scrapie infection involved
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proteins, but not viruses with nucleic acids. In one of Field’s last publications (1978), he even
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suggested that the infectious process might depend on a structural rearrangement of the host’s
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molecules, similar to the idea which is now known as the “prion hypothesis.” Field’s suggestion was an
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important advance in the theory of aging, and the evidence supporting it is now voluminous, but that
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work has been omitted from the official histories.
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</p>
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<p>
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Although phenomena of “imprinting” and non-genetic inheritance had been established earlier, the
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dogmatism of genetics led the scientific establishment to reject everything that challenged the primacy
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of DNA. When I mentioned to my professors (in 1971) the evidence that scrapie was transmitted without
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nucleic acid, I could see from their reactions that it would be a very long time before much progress
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would be made in understanding the degenerative brain diseases. When the exact structure of the
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“infectious” protein was later worked out, and the 1997 Nobel Prize awarded (to Stanley Prusiner), I was
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surprised that no one from Field’s group was included. (In 1976, a nobel prize had been awarded to D.C.
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Gajdusek, for his promotion of the idea of “slow viruses” in general, and particularly for arguing that
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scrapie, CJD and kuru were caused by slow viruses.)
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</p>
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<p>
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In reading Prusiner’s autobiographical statements, I was even more surprised to see that he claimed to
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have been puzzled to find out, around 1983, that the infectious agent was a protein. I had thought that
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my professors were lethargic authoritarians when they refused to look at the evidence in 1970-72, but
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Prusiner’s expression of puzzlement so many years later over the absence of nucleic acid in the
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infectious agent is hard to account for.
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</p>
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<p>
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In my own research in 1971, I was interested in another kind of age-related “inclusion body,” which was
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variously called lipofuscin, age pigment, and ceroid pigment. This brown (yellow autofluorescent)
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pigment contained proteins and metals, as well as polyunsaturated lipids, and overlapped in many ways
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with the amyloid bodies. All of these inclusion bodies were known to be associated with radiation
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injury, aging, and hormonal-nutritional imbalances. Excess of estrogen, polyunsaturated fatty acids, and
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oxidative metals were major factors in the development of lipofuscin, and estrogen was also known to
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cause other types of “inclusion bodies” to develop in cells.
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</p>
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<p>
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Although very little was known about the composition of the inclusion bodies (they were usually thought
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to be organelles damaged by free radical activity, or antibodies resulting from autoimmunity), their
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involvement in aging and degenerative disease was clear<strong>,</strong> and it was widely known that
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ionizing radiation accelerated their formation. But it was just at this time that the national research
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priorities of the U.S. were redirected toward genetic explanations for all major diseases, with for
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example the “war on cancer” centering on the concepts of the “oncogene” and the cancer virus. Since the
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“slow virus” of cancer, or the viral oncogene, requires activation by something in the environment, its
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function is to distract the public’s attention from those environmental causes of disease, viz.,
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radiation and chemical pollution.
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</p>
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<p>
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The U.S. Public Health Service has historically been one of the branches of the military, and currently
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has 6000 commissioned officers. It has been intimately involved in all aspects of chemical, biological,
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and nuclear warfare, and it has participated in many covert projects, including experimentation on
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people without their knowledge. For decades, information on radiation injury to the public was hidden,
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classified, altered, or destroyed by the PHS. During the radiation disaster at Three Mile Island, they
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calmly defended the interests of the nuclear industry.
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</p>
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<p>
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After the April, 1986 catastrophe at the reactor in Chernobyl, some of the food being imported into the
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U.S. was so highly radioactive that the FDA secretly seized it, to prevent the public from being
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concerned. The first cow found to have BSE in England was in November, 1986, several months after
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England’s pastures had been heavily contaminated by rainfall carrying radioactive material from
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Chernobyl, which soaked into the soil and continued to contaminate crops for years (and will continue,
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for centuries). The number of sick cows increased rapidly to a peak in 1992. Human deaths from the
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similar disease (“variant CJD”) began a few years later.
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</p>
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<p>
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In June, 2000, a wildfire burned across southern Washington, turning the radioactive vegetation on the
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Hanford Nuclear Site into radioactive smoke, contaminating a wide area, including farms, dairies, and
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orchards. In 2003, the first cow in the U.S. with BSE was reported, from a dairy a few miles from the
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Hanford Site.
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</p>
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<p>
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Beginning in 1946, Bikini Island was used to test atomic bombs. In 1954, they began to test hydrogen
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bombs in the Pacific<strong>;</strong> some of the bombs were deliberately designed to vaporize whole
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islands, so that the effects of radioactive fallout could be studied. In 1954, the first child with kuru
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was reported in the rainy highlands of New Guinea.
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</p>
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<p>
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Within two years, hundreds of people in that area (of the Fore tribe) were dying from kuru, with the
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mortality highest among the women<strong>;</strong> in some villages, the majority of the women died
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from the disease, but by 1957 the mortality was falling rapidly. Between 1957 and 1964, 5% of the
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population of the Fore tribe died of the disease, according to D.C. Gajdusek, who had been sent by the
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U.S. Army to investigate the disease. Although Gajdusek graduated in 1946 from Harvard medical school as
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a pediatrician, in his autobiography he said that when he was drafted in 1951, the army assigned him to
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work in virology. In 1958, Gajdusek became director of the NIH laboratories for neurological and
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virological research. This was a remarkable achievement for someone who had supposedly only done some
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scattered field-work in infectious diseases, and whose purpose in going to New Guinea had been to study
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''child growth and development in primitive cultures.'' The only published reason I have found that
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might be a basis for making him head of neurology, was his sending a diseased Fore brain to Fort Detrick
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in 1957.
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</p>
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<p>
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Gajdusek claimed to have seen the Fore people eating dead relatives, but his figures show that the
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disease was already in rapid decline when he arrived. He took photographs which were widely published in
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the US, supposedly showing cannibalism, but 30 years later, he said the photographs showed people eating
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pork, and that he had seen no cannibalism. (At the time Gajdusek was observing kuru in New Guinea, the
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influence of “cannibalism” on brain function was already in the news, because of the discovery by J.V.
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McConnell that the behavior of “trained” flatworms could be transmitted to other worms by chopping them
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up and feeding them to the naive worms.)
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</p>
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<p>
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Harvard medical school, in association with the military program centered at Fort Detrick,
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Fredericksburg, Maryland, was active in biological warfare in the 1940s, and I think it’s more plausible
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to see Gajdusek as a trouble-shooter for the biological warfare establishment, than as a biological
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researcher. One of his biographers has written that the idea of associating kuru with scrapie was
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suggested to him by a veterinarian, and that Gajdusek had responded by claiming to have experiments in
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progress to test that theory, four years before the experiments were actually made.
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</p>
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<p>
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In other words, the slow virus theory for which Gajdusek was given the Nobel Prize is scientific junk,
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which Gajdusek has repeatedly reinterpreted retrospectively, making it seem to have been anticipatory of
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the prion theory. Whatever actually caused kuru, I think the army was afraid that it was the result of
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radioactive fallout from one of its bomb tests, and that Gajdusek’s job was to explain it away.
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</p>
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<p>
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I suspect that kuru was the result of an unusual combination of malnutrition (the women were vegetarian)
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and radiation. In the very short time that Gajdusek spent in New Guinea, he claimed to have done studies
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to eliminate all of the alternative causes, nutritional, toxic, anthropological, bacterial causes,
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studies that would normally have required several years of well organized work. I don’t think he
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mentioned the possibility of radiation poisoning.
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</p>
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<p>
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In 1998 Congress commissioned a study of the health effects of radiation from bomb testing, and although
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the study examined the effects of only part of the bomb tests, it concluded that they had killed 15,000
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Americans. No one has tried to accurately estimate the numbers killed in other countries.
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</p>
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<p>
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Even very low doses of ionizing radiation create an inflammatory reaction (Vickers, et al., 1991), and
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there is evidence that the inflammatory state can persist as long as the individual lives<strong>;
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</strong>in Japan, the “acute phase” proteins are still elevated in the people who were exposed to
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radiation from the atomic bombs. The acute phase proteins that are increased by malnutrition and
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radiation increase the tendency to form amyloid deposits. Strong radiation can even cause, after a delay
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of more than a year, the development of vacuoles, which are the most obvious feature of the “prion”
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brain diseases. The persistent inflammatory reaction eventually produces cellular changes, but these
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were originally overlooked because of the theory that radiation is harmful only when it produces
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immediate changes in the DNA.
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</p>
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<p>
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Radiation damage to the brain is most visible early in life, and in old age. In 1955, Alice Stewart
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showed that prenatal x-rays increase the incidence of brain cancer, leukemia, and other cancers. In
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1967, a study in Japanese bomb survivors found that prenatal exposure to radiation had reduced their
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head size and brain size. In 1979, Sternglass and Bell showed extremely close correspondence between
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scores on the SAT and prenatal exposure to radiation.
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</p>
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<p>
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Serum amyloid A, which can increase 1000-fold under the influence of proinflammatory cytokines,
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resulting from irradiation, stress, trauma, or infection, is an activator of phospholipase A2 (PLA2),
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which releases fatty acids. Some of the neurodegenerative states, including amyloid-prion diseases,
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involve activated PLA2, as well as increases in the toxic breakdown products of the polyunsaturated
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fatty acids, such as 4-hydroxynonenal. The quantity of PUFA in the tissues strongly determines the
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susceptibility of the tissue to injury by radiation and other stresses. But a diet rich in PUFA will
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produce brain damage even without exceptional stressors, when there aren’t enough antioxidants, such as
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vitamin E and selenium, in the diet.
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</p>
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<p>
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Amyloidosis has traditionally been thought of as a condition involving deposits mainly in blood vessels,
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kidneys, joints and skin and in extracellular spaces in the brain, and the fact that the “amyloid”
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stained in a certain way led to the idea that it was a single protein. But as more proteins--currently
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about 20--were identified in amyloid deposits, it was gradually realized that the deposits can be
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identified inside cells of many different tissues, before the larger, very visible, extracellular
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deposits are formed.
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</p>
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<p>
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There is evidence of a steady increase in the death rate from amyloidosis. It kills women at a younger
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age than men, often at the age of 50 or 60.
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</p>
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<p>
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Serum amyloid P is called “the female protein” in hamsters, because of its association with
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estrogen<strong>;</strong> castrated (or estrogen treated) males also produce large amounts of it, and
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its excess is associated with the deposition of amyloid (Coe and Ross, 1985). It can bind other amyloid
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proteins together, accelerating the formation of fibrils, but this function is probably just a variation
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of a normal function in immunity, tissue repair, and development.
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</p>
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<p>
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Estrogen increases the inflammation-associated substances such as IL-6, C-reactive protein, and amyloid,
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and liberates fatty acids, especially the unstable polyunsaturated fatty acids. It also increases
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fibrinogen and decreases albumin, increasing the leakiness of capillaries. The decrease of albumin
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increases the concentration of free fatty acids and tryptophan, which would normally be bound to
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albumin.
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</p>
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<p>
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In the U.S. and Europe, livestock are fed large amounts of high-protein feeds, and currently these
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typically contain fish meal and soybeans. The estrogenic materials in soybeans increase the animals’
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tendency toward inflammation (with increased serum amyloid).
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</p>
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<p>
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Officially, BSE appeared because cows were fed slaughter-house waste containing tissues of sheep that
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had died of scrapie. Scrapie was a nerve disease of sheep, first reported in Iceland in the 18th
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century. When I was studying the digestive system and nutrition of horses, I learned that it was common
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for horses in Norway to be fed dried fish during the winter. This abundant food was probably used for
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sheep, as well as for horses. The extra protein provided by fish meal is still important for sheep in
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areas where pastures are limited, but it has now become common to use it to increase productivity and
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growth throughout the lamb, beef, and dairy industries, as well as in most lab chows fed to experimental
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animals, such as the hamsters used for testing the infectivity of the diseased tissues.
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</p>
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<p>
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Increased dietary polyunsaturated fatty acids (PUFA) suppress the activity of the ruminal bacteria which
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are responsible for the hydrogenation-detoxication of PUFA in the animal’s diet. This allows the
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unstable fats, 98% of which are normally destroyed, to pass into the animals’ tissues and milk.
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</p>
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<p>
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The polyunsaturated fats in fish are very unstable, and when they get past the bacterial saturases
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(biohydrogenases) in the rumen that normally protect ruminants from lipid peroxidation, they are likely
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to cause their toxic effects more quickly than in humans, whose antioxidant systems are highly
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developed. The toxic effects of polyunsaturated fats involve altered (immunogenic) protein structure,
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decreased energy metabolism, and many inflammatory effects produced by the prostaglandin-like
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substances. Marine fish are now so generally polluted with dioxin, that in Japan there is a clear
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association between the amount of fish in a person’s diet (their body content of EPA and DHA) and the
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amount of dioxin in their body.
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</p>
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<p>
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Radiation and many kinds of poisoning cause early peroxidation of those highly unsaturated fats, and the
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breakdown products accelerate the changes in the folding and chelating behavior of proteins. The
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accumulation of altered proteins is associated with the degenerative diseases. The role of toxic metals
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in brain inflammation is well established (e.g., aluminum, lead, mercury<strong>: </strong>Campbell, et
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al., 2004<strong>; </strong>Dave, et al., 1994<strong>; </strong>Ronnback and Hansson, 1992<strong
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>)</strong>.
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</p>
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<p>
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The “prion hypothesis” has the value of weakening the fanaticism of the DNA-genetics doctrine, but it
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has some problems. There are now several examples in which other degenerative diseases have been
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transmitted by procedures similar to those used to test the scrapie agent. (e.g., Goudsmit, et al.,
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1980; Xing, et al., 2001; Cui, et al., 2002.) Experimental controls haven’t been adequate to distinguish
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between the pure prion and its associated impurities. Gajdusek burned a sample of the infective hamster
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brain to ash, and found that it still retained “infectivity.” He argued that there was a mineral
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template that transmitted the toxic conformation to normal proteins. Others have demonstrated that the
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active structure of the infective agent is maintained by a carbohydrate scaffolding, or that the
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infectivity is destroyed by the frequency of ultraviolet light that destroys the active lipid of
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bacterial endotoxin, lipopolysaccharide.
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</p>
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<p>
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But simply injuring the brain or other organ (by injecting anything) will sometimes activate a series of
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reactions similar to those seen in aging and the amyloidoses. When a slight trauma leads to a prolonged
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or expanding disturbance of structure and function, the process isn’t essentially different from
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transmitting a condition to another individual. The problem is being “transmitted” from the initial
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injury, recruiting new cells, and passing the disturbed state on to daughter cells in a disturbed form
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of regeneration. Keloids, hypertrophic scars, are analogous to the dementias in their overgrowth of
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connective tissue cells<strong>:</strong> In the aging or injured brain, the glial cells (mainly
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astrocytes) proliferate, in reparative processes that sometimes become exaggerated and harmful.
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</p>
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<p>
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When tissue phospholipids contain large amounts of polyunsaturated fatty acids, large amounts of
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prostaglandins are immediately formed by any injury, including low doses of ionizing radiation. The
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liberated free fatty acids have many other effects, including the formation of highly reactive
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aldehydes, which modify DNA, proteins, and other cell components.
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</p>
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<p>
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Animals which are “deficient” in the polyunsaturated fatty acids have a great resistance to a variety of
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inflammatory challenges. Their tissues appear to be poor allergens or antigens, since they can be easily
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grafted onto other animals without rejection. Something related to this can probably be seen in the data
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of human liver transplants. Women’s livers are subjected to more lipid peroxidation than men’s, because
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of the effects of estrogen (increasing growth hormone and free fatty acids, and selectively mobilizing
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the polyunsaturated fatty acids and increasing their oxidation). Liver transplants from middle-aged
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female donors fail much more often (40 to 45%) than livers from male donors (22 to 25%), and other
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organs show the same effect. The autoimmune diseases are several times as common in women as in men,
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suggesting that some tissues become relatively incompatible with their own body, after prolonged
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exposure to the unstable fatty acids. If we consider the healthy function of the immune system to be the
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removal or correction of injured tissue, it’s reasonable to view the random interactions of oxidized
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fats with proteins as exactly the sort of thing our immune system takes care of.
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</p>
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<p>
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The serum amyloids A and P and the closely related lipoproteins are considered to be important parts of
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our “innate immunity,” operating in a more general way than the familiar system of specific acquired
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immunities.
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</p>
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<p>
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The amyloids and lipoproteins are powerfully responsive to bacterial endotoxin, LPS, and their
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structural feature that binds it, the “pleated sheet” structure, appears to also be what allows the
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amyloids to form amorphous deposits and fibrils under some circumstances. Our innate immune system is
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perfectly competent for handling our normal stress-induced exposures to bacterial endotoxin, but as we
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accumulate the unstable fats, each exposure to endotoxin creates additional inflammatory stress by
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liberating stored fats. The brain has a very high concentration of complex fats, and is highly
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susceptible to the effects of lipid peroxidative stress, which become progressively worse as the
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unstable fats accumulate during aging.
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</p>
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<p>
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More than 60 years ago, a vitamin E deficiency was known to cause a brain disease, sometimes associated
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with sterility and muscular dystrophy. The symptoms of the brain disease were similar to those of “mad
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cow disease,” and the condition is now usually called “crazy chick disease.” Veterinarians are usually
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taught that it is caused by a selenium deficiency, but it is actually the result of an excess of PUFA in
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the diet, and is exacerbated by increased iron or other oxidants, and prevented by increased vitamin E,
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selenium, or substitution of saturated fats for the unsaturated.
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</p>
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<p>
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Terminology, established by tradition and thoughtless memorization, obscures many of the commonalities
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in the various brain diseases. Brain inflammation (Betmouni and Perry, 1999; Perry, et al., 1998),
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myelination disorders, edema, overgrowth of the astroglia, and circulatory changes are common
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occurrences in most of the degenerative encephalopathies, but traditional textbook descriptions have
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created the impression that each disease is pathologically very distinct from the others. The current
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classification of “the prion diseases” is reifying a group of symptoms that aren’t specific to any
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specific known cause. And standard laboratory procedures for preparing brain sections for microscopic
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examination may cause brain cells to shrink to 5% of their original volume (Hillman and Jarman, <strong
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||
><em>Atlas of the cellular structure of the human nervous system,</em></strong> 1991), so the
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objectivity of pathological studies shouldn’t be over-estimated.
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</p>
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<p>
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According to a 1989 study (Laura Manuelidis, neuropathology department at Yale), 13% of the people who
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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
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in their descriptions of the dementia epidemic.
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</p>
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<p>
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By some tests, the “prion” resembles the LPS endotoxin. One of the interesting developments of the prion
|
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theory is that a particular structure that appears when the prion becomes toxic, the “beta pleated
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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
|
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the conversion of a normal protein into the pleated sheet, it isn’t necessarily correct about the
|
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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> </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>
|
||
Arch Neurol. 1974 Sep; 31(3): 174-82. <strong>Altered cell membranes in Creutzfeldt-Jakob
|
||
disease.</strong> Microchemical studies. Bass NH, Hess HH, Pope A.
|
||
</p>
|
||
<p>
|
||
Neuropathol Appl Neurobiol. <strong> 1999</strong> Feb;25(1):20-8. <strong>The acute inflammatory
|
||
response in CNS following injection of prion brain homogenate or normal brain homogenate.</strong>
|
||
Betmouni S, Perry VH. “The neuropathological hallmarks of end-stage prion disease are vacuolation,
|
||
neuronal loss, astrocytosis and deposition of PrPSc amyloid. We have also shown that there is an
|
||
inflammatory response in the brains of scrapie-affected mice from 8 weeks post-injection.” <strong>“The
|
||
well circumscribed inflammatory response seen previously at 8 weeks is therefore a consequence of a
|
||
disease process rather than a surgical artefact. This disease process may be related to a localized
|
||
accumulation of PrPSc sufficient to stimulate an inflammatory response which in turn may contribute
|
||
to neuronal loss.”</strong>
|
||
</p>
|
||
<p>
|
||
Neuropathol Appl Neurobiol. 1999 Feb; 25(1): 20-8. <strong>The acute inflammatory response in CNS
|
||
following injection of prion brain homogenate or normal brain homogenate.</strong> Betmouni S, Perry
|
||
VH.
|
||
</p>
|
||
<p>
|
||
Curr Biol. 1999 Sep 23;9(18):R677-9. <strong>Vacuolation in murine prion disease: an informative
|
||
artifact.</strong> Betmouni S, Clements J, Perry VH.
|
||
</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.
|
||
</p>
|
||
<p>
|
||
Ann N Y Acad Sci 1982;396:131-43. <strong>Alzheimer's disease and transmissible virus dementia
|
||
(Creutzfeldt-Jakob disease).</strong> Brown P, Salazar AM, Gibbs CJ Jr, Gajdusek DC.
|
||
</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>
|
||
J Neurosci Res. 2004 Feb 15;75(4):565-72. <strong>Chronic exposure to aluminum in drinking water
|
||
increases inflammatory parameters selectively in the brain.</strong> Campbell A, Becaria A, Lahiri
|
||
DK, Sharman K, Bondy SC.
|
||
</p>
|
||
<p>
|
||
Mutat Res. 2001 Mar; 488(1): 39-64. <strong>Mutation processes at the protein level: is Lamarck
|
||
back?</strong> Chernoff YO. <strong>“The experimental evidence accumulated for the last half of the
|
||
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
|
||
evolution.” J Clin Invest. 1985 Jul;76(1):66-74.<strong>
|
||
Hamster female protein, a sex-limited pentraxin, is a constituent of Syrian hamster amyloid.</strong
|
||
> Coe JE, Ross MJ.
|
||
</p>
|
||
<p>
|
||
Pathol Int. 2002 Jan; 52(1): 40-5. <strong>Acceleration of murine AA amyloidosis by oral administration
|
||
of amyloid fibrils extracted from different species.</strong> Cui D, Kawano H, Takahashi M, Hoshii
|
||
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>
|
||
Br J Pharmacol. 2003 Apr;138(7):1207-9. <strong>Neuroprotection by caffeine and adenosine A2A receptor
|
||
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>
|
||
Biochemistry. 2003 Nov 25; 42(46): 13667-72. <strong>Insertion of externally administered amyloid beta
|
||
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>
|
||
Dev Neurosci. 1994;16(3-4):222-31. <strong>Astrocytes as mediators of methylmercury neurotoxicity:
|
||
effects on D-aspartate and serotonin uptake.</strong> Dave V, Mullaney KJ, Goderie S, Kimelberg HK,
|
||
Aschner M.
|
||
</p>
|
||
<p>
|
||
Adv Exp Med Biol. 1989; 266: 259-70; discussion 271. <strong>Phospholipases and the molecular basis for
|
||
the formation of ceroid in Batten Disease.</strong> Dawson G, Dawson SA, Siakotos AN. “Lysosomal
|
||
ceroid/lipofuscinosis storage in human, canine, and ovine forms of neuronal ceroidlipofuscinosis is
|
||
predominantly in neurons and retinal pigment epithelial cells. Despite problems in identifying
|
||
individual storage materials, it is believed that non-enzymic oxidation of unsaturated fatty acids in
|
||
phospholipids and inhibition of lysosomal proteolysis, leading to massive deposition of autofluorescent
|
||
pigment, is the cause of the disease.” <strong>“We believe that the PLA1 deficiency leads to transient
|
||
lysosomal storage of phospholipids containing peroxy fatty acids which are then chemically converted
|
||
to hydroxynonenal, a potent inhibitor of a thiol-dependent enzymes.</strong> Inhibition of proteases
|
||
is believed to be intrinsic to the formation of lipofuscin.”
|
||
</p>
|
||
<p>
|
||
Ann Rheum Dis. 2001 Jul;60(7):694-5. <strong>Concomitant diagnosis of primary Sjogren's syndrome and
|
||
systemic AL amyloidosis.</strong> Delevaux I, Andre M, Amoura Z, Kemeny JL, Piette JC, Aumaitre O.
|
||
</p>
|
||
<p>
|
||
Mol Biol Rep. 1996;23(3-4):253-60. <strong>The interaction of C-reactive protein and serum amyloid P
|
||
component with nuclear antigens.
|
||
</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>
|
||
<p>
|
||
Am J Pathol. 1996 Oct;149(4):1313-20. <strong>Lipoproteins accumulate in immune deposits and are
|
||
modified by lipid peroxidation in passive Heymann nephritis.</strong> Exner M, Susani M, Witztum JL,
|
||
Hovorka A, Curtiss LK, Spitzauer S, Kerjaschki D.
|
||
</p>
|
||
<p>
|
||
J Med Genet. 1976 Dec;13(6):479-95.<strong>
|
||
Scrapie: a review of its relation to human disease and ageing.</strong> Field EJ.
|
||
</p>
|
||
<p>
|
||
Age Ageing. 1978 Feb;7(1):28-39. <strong>Immunological assessment of ageing: emergence of scrapie-like
|
||
antigens.</strong> Field EJ.
|
||
</p>
|
||
<p>
|
||
Acta Neurol Scand. 1975 Apr;51(4):299-309. <strong>Cellular sensitization in kuru, Jakob-Creutzfeldt
|
||
disease and multiple sclerosis: with a note on the biohazards of slow infection work.</strong> Field
|
||
EJ, Shenton BK.
|
||
</p>
|
||
<p>
|
||
Brain. 1973 Sep;96(3):629-36. <strong>Altered response to scrapie tissues in neurological disease.
|
||
Possible evidence for an antigen associated with reactive astrocytes.</strong> Field EJ, Shenton BK.
|
||
</p>
|
||
<p>
|
||
Nature. 1973 Jul 20;244(5412):174-6. <strong>Scrapie-like antigen(s) in ageing tissues.</strong> Field
|
||
EJ, Shenton BK.
|
||
</p>
|
||
<p>
|
||
Nature. 1973 Jul 13;244(5411):96-7. <strong>Rapid immunological method for diagnosis of natural scrapie
|
||
in sheep.</strong> Field EJ, Shenton BK.
|
||
</p>
|
||
<p>
|
||
Gerontologia. 1973;19(4):203-10.<strong>
|
||
Thymectomy and immunological ageing in mice: precocious emergence of scrapie-like antigen.</strong>
|
||
Field EJ, Shenton BK.
|
||
</p>
|
||
<p>
|
||
Gerontologia. 1973;19(4):211-9. <strong>Emergence of new antigens in ageing tissues.</strong> Field EJ,
|
||
Shenton BK.
|
||
</p>
|
||
<p>
|
||
Nature. 1972 Nov 10;240(5376):104-6. <strong>Rapid diagnosis of scrapie in the mouse.</strong> Field EJ,
|
||
Shenton BK.
|
||
</p>
|
||
<p>
|
||
J Neurol Sci. 1972 Nov;17(3):347-64. <strong>An electron-microscopic study of scrapie in the rat:
|
||
further observations on "inclusion bodies" and virus-like particles.</strong> Field EJ, Narang HK.
|
||
</p>
|
||
<p>
|
||
Lancet. 1970 Oct 10;2(7676):780-1. <strong>Amyloidosis, Alzheimer's disease, and ageing.</strong> Field
|
||
EJ.
|
||
</p>
|
||
<p>
|
||
Nature. 1970 Jun 6;226(249):971-3. <strong>Evidence against transmission of scrapie by animal house
|
||
fomites.</strong> Field EJ, Joyce G.
|
||
</p>
|
||
<p>
|
||
Arch Gesamte Virusforsch. 1970;30(2):224-37. <strong>The incorporation of (3H) thymidine and (14C)
|
||
glucosamine into a DNA-polysaccharide complex in normal and scrapie-affected mouse brain.</strong>
|
||
Adams DH, Caspary EA, Field EJ.
|
||
</p>
|
||
<p>
|
||
Biochem J. 1969 Sep;114(2):19P-20P. <strong> Structural changes in scrapie affected brain.</strong>
|
||
Field EJ, Peat A.
|
||
</p>
|
||
<p>
|
||
J Gen Virol. 1969 Jul;5(1):149-50. <strong>Failure of interferon to modify scrapie in the mouse.</strong
|
||
> Field EJ, Joyce G, Keith A.
|
||
</p>
|
||
<p>
|
||
Nature. 1969 Apr 5;221(188):90-1. <strong>Susceptibility of scrapie agent to ionizing radiation.</strong
|
||
> Field EJ, Farmer F, Caspary EA, Joyce G.
|
||
</p>
|
||
<p>
|
||
Nature. 1969 Mar 29;221(187):1265-6.<strong>
|
||
Neurological illness after inoculation of tissue from tumour bearing animals.</strong> Field EJ,
|
||
Adams DH, Joyce G.
|
||
</p>
|
||
<p>Lancet. 1968 May 4;1(7549):981-2. <strong>Transmission of kuru to mice.</strong> Field EJ.</p>
|
||
<p>
|
||
Br J Exp Pathol. 1967 Dec;48(6):662-4. <strong>Invasion of the mouse nervous system by scrapie
|
||
agent.</strong> Field EJ.
|
||
</p>
|
||
<p>
|
||
Acta Neuropathol (Berl). 1967 Nov 29;9(4):305-15. <strong>Scrapie in the rat: an electron-microscopic
|
||
study. II. Glial inclusions.</strong> Field EJ, Raine CS, Joyce G.
|
||
</p>
|
||
<p>
|
||
J Neurosci. 2001 Jan 1;21(1):136-42.<strong>
|
||
Vaccination for neuroprotection in the mouse optic nerve: implications for optic
|
||
Neuropathies.</strong> Fisher J, Levkovitch-Verbin H, Schori H, Yoles E, Butovsky O, Kaye JF,
|
||
Ben-Nun A, Schwartz M. “<strong>T-cell autoimmunity to myelin basic protein was recently shown to be
|
||
neuroprotective in injured rat optic nerves.</strong>” “The results of this study show that survival
|
||
of RGCs after axonal injury can be<strong>
|
||
enhanced by vaccination with an appropriate self-antigen.</strong> Furthermore, the use of
|
||
nonencephalitogenic myelin peptides for immunization apparently allows neuroprotection without incurring
|
||
the risk of an autoimmune disease.”
|
||
</p>
|
||
<p>
|
||
Neuropathol Appl Neurobiol. 2003 Oct;29(5):482-95. <strong>Neuronal and astrocytic responses involving
|
||
the serotonergic system in human spongiform encephalopathies.</strong> Fraser E, McDonagh AM, Head
|
||
M, Bishop M, Ironside JW, Mann DM.
|
||
</p>
|
||
<p>
|
||
J Neural Transm. 2001;108(2):221-30. <strong>Difference in toxicity of beta-amyloid peptide with aging
|
||
in relation to nerve growth factor content in rat brain.</strong> Fukuta T, Nitta A, Itoh A,
|
||
Furukawa S, Nabeshima T. “NGF levels in the hippocampus were<strong>
|
||
increased only in adult rats. These results suggest that Abeta is toxic only in the matured adult
|
||
brain, and that the mechanism of toxicity is related to NGF synthesis.”</strong>
|
||
</p>
|
||
<p>
|
||
Science 197: 943-960(1977). <strong>Unconventional viruses and the origin and disappearance of
|
||
kuru.</strong> Gajdusek, D.C.
|
||
</p>
|
||
<p>
|
||
Trends Mol Med. 2001 Aug;7(8):336. <strong>Beneficial autoimmunity in traumatic brain injury.</strong>
|
||
Gurwitz D.
|
||
</p>
|
||
<p>
|
||
BMJ 2004; 328 :19, <strong>Effect of low doses of ionising radiation in infancy on cognitive function in
|
||
adulthood: Swedish population based cohort study.</strong> Hall P, Adami HO, Trichopoulos D et al.
|
||
</p>
|
||
<p>
|
||
Arch Pathol. 1966 Oct; 82(4): 353-5.<strong>
|
||
A lipofuscin-like pigment in the kidneys of estrogen-treated rats.</strong> Harris C.
|
||
</p>
|
||
<p>
|
||
Int J Radiat Biol. 2003 Feb; 79(2): 129-36<strong>. Radiation dose-dependent increases in inflammatory
|
||
response markers in A-bomb Survivors.</strong> Hayashi T, Kusunoki Y, Hakoda M, Morishita Y, Kubo Y,
|
||
Maki M, Kasagi F, Kodama K, Macphee DG, Kyoizumi S. “The well-documented increases in malignant tumours
|
||
in the A-bomb survivors have recently been supplemented by reports that non-cancer diseases, including
|
||
cardiovascular disease, may also have <strong>increased in incidence with increasing radiation dose.
|
||
Given that low-level inflammatory responses are widely accepted as a significant risk factor for
|
||
such diseases, we undertook a
|
||
</strong>detailed investigation of the long-term effects of ionizing radiation on the levels of the
|
||
inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6) in A-bomb survivors.” “Blood
|
||
samples were taken from 453 participants in a long-term epidemiological cohort of A-bomb survivors.”
|
||
<strong><hr /></strong>Higher CRP levels also correlated with age, male gender, body mass index and a
|
||
history of myocardial infarction. After adjustments for these factors, <strong>CRP levels still appeared
|
||
to have increased significantly with increasing radiation dose (about 28% increase at 1Gy,
|
||
</strong>
|
||
<hr />
|
||
<strong><hr /></strong>
|
||
<hr />
|
||
<strong>“Our results appear to indicate that exposure to A-bomb radiation has caused significant
|
||
increases in inflammatory activity that are still demonstrable in the blood of A-bomb survivors and
|
||
which may lead to increased risks of cardiovascular disease and other non-cancer diseases.</strong>”
|
||
</p>
|
||
<p>
|
||
Immunol Rev. 2000 Oct;177:52-67. <strong>Chemokines and chemokine receptors in inflammation of the
|
||
nervous system: manifold roles and exquisite regulation.</strong> Huang D, Han Y, Rani MR, Glabinski
|
||
A, Trebst C, Sorensen T, Tani M, Wang J, Chien P, O'Bryan S, Bielecki B, Zhou ZL, Majumder S, Ransohoff
|
||
RM.
|
||
</p>
|
||
<p>
|
||
Am J Med Genet. 1989 Dec;34(4):562-8. <strong>Mortality rate of amyloidosis in Japan: secular trends and
|
||
geographical Variations.</strong> Imaizumi Y. “The death rate in Japan from amyloidosis was analyzed
|
||
using Japanese Vital Statistics for 1969-1985. <strong>The amyloidosis death rate has increased
|
||
gradually year by year for both sexes.</strong>” “The mean age at death from amyloidosis gradually
|
||
increased year by year for both sexes, although the age was <strong>11-23 years shorter for males and
|
||
20-25 years shorter for females</strong> than that of the general population.”
|
||
</p>
|
||
<p>
|
||
Stroke. 1991 Nov;22(11):1448-51. <strong>Platelet secretory products may contribute to neuronal
|
||
injury.</strong> Joseph R, Tsering C, Grunfeld S, Welch KM.
|
||
</p>
|
||
<p>
|
||
J Neurochem. 1997 Jul; 69(1): 266-72.<strong>
|
||
Aggregation of beta-amyloid peptide is promoted by membrane phospholipid metabolites elevated in
|
||
Alzheimer's disease brain.</strong> Klunk WE, Xu CJ, McClure RJ, Panchalingam K, Stanley JA,
|
||
Pettegrew JW. “A beta peptides have been shown to be toxic to neurons in cell culture, and this toxicity
|
||
is critically dependent on the aggregation of the peptide into cross-beta-pleated sheet fibrils. Also,
|
||
in vivo and postmortem NMR studies have shown changes in certain brain membrane phospholipid metabolites
|
||
in normal aging and more extensive alterations in patients with Alzheimer's disease. The finding that
|
||
membrane phospholipids affect the aggregation of A beta suggests that the abnormalities in membrane
|
||
metabolism found in Alzheimer's disease could affect the deposition of A beta in vivo.” “Certain
|
||
metabolites (glycerophosphocholine, glycerophosphoethanolamine, and alpha-glycerophosphate) augment the
|
||
aggregation of A beta. Other membrane phospholipid metabolites (phosphocholine, phosphoethanolamine, and
|
||
inositol-1-phosphate) have no effect.<strong></strong>We conclude that increased membrane phospholipid
|
||
metabolite concentrations may play a role in the deposition of A beta seen in normal aging and the even
|
||
greater deposition of A beta observed in Alzheimer's disease.”<strong></strong>
|
||
</p>
|
||
<p>
|
||
J Pharm Sci. 1971 Feb; 60(2): 167-80. <strong>Experimental modification of the chemistry and biology of
|
||
the aging process.</strong> Kormendy CG, Bender AD.
|
||
</p>
|
||
<p>
|
||
Radiobiologiia. 1990 May-Jun;30(3):317-20. <strong>[Cholesterol and fatty acids of the nuclei and
|
||
chromatin of the rat thymus at long intervals following gamma irradiation]</strong> Kulagina TP.
|
||
“The FFA content in the homogenate, nuclei and chromatin of rat thymus drastically increased 60 min
|
||
after the last exposure. In a month, the FFA content of nuclei and chromatin dropped to control levels,
|
||
whereas that of the homogenate remained high throughout the entire period of observation and sharply
|
||
increased by the third month.”
|
||
</p>
|
||
<p>
|
||
J Neuropathol Exp Neurol. 1968 Jan; 27(1): 157-8.<strong>
|
||
Amyloid in late postradiation necrosis of brain.</strong> Mandybur TJ, Gore y.
|
||
</p>
|
||
<p>
|
||
Hepatology. 1995 Dec;22(6):1754-62. <strong>Effect of donor age and sex on the outcome of liver
|
||
transplantation.</strong> Marino IR, Doyle HR, Aldrighetti L, Doria C, McMichael J, Gayowski T, Fung
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||
JJ, Tzakis AG, Starzl TE.
|
||
</p>
|
||
<p>
|
||
Brain Res. 673(1), 149-152, 1995. <strong>"Glucose deprivation increases aspartic acid release from
|
||
synaptosomes of aged mice,"</strong>M. Martinez, et al., "...in the absence of glucose in the medium
|
||
of incubation aspartate and glutamate release was higher in old than in young animals." "...<strong
|
||
>there is an age-dependent dysfunction in this process linked to energy metabolism disturbance</strong
|
||
>."
|
||
</p>
|
||
<p>
|
||
Neurobiol Aging. 1995 Nov-Dec; 16(6): 977-81. <strong>Estrogen induction of glial heat shock proteins:
|
||
implications for hypothalamic Aging.</strong> Mydlarski MB, Liberman A, Schipper HM. “In the aging
|
||
mammalian hypothalamus, a unique subpopulation of glial cells accumulates peroxidase-positive
|
||
cytoplasmic inclusions distinct from lipofuscin. In adult rodents, this senescence-dependent glial
|
||
granulation is accelerated by administration of estradiol valerate.” “<strong>Our findings indicate that
|
||
estrogen elicits a heat shock response and subsequent granulation in astrocytes</strong> residing in
|
||
estradiol receptor-rich brain regions including the arcuate nucleus and the wall surrounding the third
|
||
ventricle but not in estradiol receptor-deficient regions such as the striatum and corpus callosum. The
|
||
heat shock proteins induced by estrogen, namely, the 27, 72, and 90 kDa stress proteins, are upregulated
|
||
in astrocytes in response to oxidative challenge supporting our hypothesis that estrogen mediates
|
||
senescent changes in the rodent hypothalamus through oxidative mechanisms.”
|
||
</p>
|
||
<p>
|
||
Proc. Natl. Acad. Sci. USA, vol. 44, pp. 712-717 (1958): <strong>"Epigenetic Control Systems".</strong>
|
||
D. L. Nanney.
|
||
</p>
|
||
<p>
|
||
Journal of the Neurological Sciences 1995;134:61-6.<strong>
|
||
Mortality from motor neuron disease in Japan, 1950-1990: association with radioactive fallout from
|
||
atmospheric weapons testing.
|
||
</strong>Neilson S, Robinson I, Rose FC.
|
||
</p>
|
||
<p>
|
||
Biol Psychiatry. 2002 Nov 1;52(9):880-6. <strong>Nicotine breaks down preformed Alzheimer's beta-amyloid
|
||
fibrils in vitro.</strong> Ono K, Hasegawa K, Yamada M, Naiki H. “The antiamyloidogenic effect of
|
||
nicotine may be exerted not only by the inhibition of fAbeta formation but also by the disruption of
|
||
preformed fAbeta.”
|
||
</p>
|
||
<p>
|
||
Res Immunol. 1998 Sep-Oct; 149(7-8): 721-5. <strong>The contribution of inflammation to acute and
|
||
chronic neurodegeneration.</strong> Perry VH, Bolton SJ, Anthony DC, Betmouni S.<strong></strong>
|
||
</p>
|
||
<p>
|
||
<strong>
|
||
Neurology. 1966 Oct;16(10):957-62. Myxedema and ataxia. Cerebellar alterations and "neural myxedema
|
||
bodies".
|
||
</strong> Price TR, Netsky MG.
|
||
</p>
|
||
<p>
|
||
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1580-5. Epub 2003 Feb 03. <strong>
|
||
Short-term administration of omega 3 fatty acids from fish oil results in increased transthyretin
|
||
transcription in old rat hippocampus.</strong> Puskas LG, Kitajka K, Nyakas C, Barcelo-Coblijn G,
|
||
Farkas T.
|
||
</p>
|
||
<p>
|
||
Arch Biochem Biophys. 2002 Apr 1;400(1):43-7. <strong>Inhibition of transthyretin amyloid fibril
|
||
formation by 2,4-dinitrophenol through tetramer stabilization.
|
||
</strong>Raghu P, Reddy GB, Sivakumar B.
|
||
</p>
|
||
<p>
|
||
Br J Ind Med. 1992 Apr;49(4):233-40. <strong>Chronic encephalopathies induced by mercury or lead:
|
||
aspects of underlying cellular and molecular mechanisms.</strong> Ronnback L, Hansson E.
|
||
</p>
|
||
<p>
|
||
Radiat Res. 1967 Mar; 30(3): 640-53. <strong>Radiation studies on mice of an inbred tumor-resistant
|
||
strain. The alteration of endogenous susceptibility to amyloidosis by x-irradiation.</strong>
|
||
Rosenblum WI, Goldfeder A, Ghosh AK.
|
||
</p>
|
||
<p>
|
||
Neurotoxicology 15(3), 493-502, 1994.<strong>"Phosphoinositide second messengers in cholinergic
|
||
excitotoxicity,"</strong> K. Savolainen, et al. "Acetylcholine is a powerful excitotoxic
|
||
neurotransmitter in the brain. By stimulating calcium-mobilizing receptors, acetylcholine, through
|
||
G-proteins, stimulates phospholipase C and cause the hydrolysis of a membrane phospholipid...."Female
|
||
sex and senescence increase the sensitivity of rats to cholinergic excitotoxicity."
|
||
</p>
|
||
<p>
|
||
Int J Radiat Oncol Biol Phys. 1995 Jan 1;31(1):57-64. <strong>Radiation-induced changes in the profile
|
||
of spinal cord serotonin, prostaglandin synthesis, and vascular permeability.</strong> Siegal T,
|
||
Pfeffer MR. “Serotonin levels were unchanged at 2, 14,<strong></strong>and 56 days after radiation but
|
||
increased at 120 and 240 days in the irradiated cord segments when compared to both the nonirradiated
|
||
thoracic and cervical segments (p < 0.01) and age-matched controls (p < 0.03).<strong>”
|
||
</strong>“In the first 24 h after radiation, a 104% increase in microvessel permeability was observed
|
||
which returned to normal by 3 days. Normal permeability was maintained at 14 and 28 days, but at 120 and
|
||
240 days a persistent and significant increase of 98% and 73% respectively above control level was
|
||
noted.”
|
||
</p>
|
||
<p>
|
||
Annual Meeting of the American Psychological Association, New York, New York, September 3, 1979, <strong
|
||
>"Fallout and the Decline of Scholastic Aptitude Scores,"</strong> Ernest Sternglass and Stephen Bell.
|
||
</p>
|
||
<p>
|
||
Acta Neuropathol (Berl). 1995; 90(2): 135-41. <strong>Cerebral beta amyloid deposition in patients with
|
||
malignant neoplasms: its prevalence with aging and effects of radiation therapy on vascular
|
||
amyloid.</strong> Sugihara S, Ogawa A, Nakazato Y, Yamaguchi H. “The prevalence of cerebral A beta
|
||
deposits was about two times higher in the patients who had received brain radiation therapy (27.8%)
|
||
compared to non-radiated patients (14.8%). Amyloid angiopathy was much more prominent (P < 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>
|
||
</body>
|
||
</html>
|