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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> </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
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</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.
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<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
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>
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