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486 lines
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<head><title>The Great Fish Oil Experiment</title></head>
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<h1>
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The Great Fish Oil Experiment
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</h1>
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Reading medical journals and following the mass media, it's easy to get the idea that fish oil is something any
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sensible person should use. It's rare to see anything suggesting that it could be dangerous. During the recent
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years in which the U.S. government has gone from warning against the consumption of too much of these omega-3
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oils
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<em>("to assure that the combined daily intake of two fatty acids that are components" "(i.e., eicosapentaenoic
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acid (EPA) and docosahexaenoic acid (DHA)) would not exceed 3 grams per person per day (g/p/d)")</em> to
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sponsoring biased industry claims, there has been considerable accumulation of information about the dangers of
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fish oils and omega-3 fatty acids. But there has been an even greater increase in the industry's promotional
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activities. The US government and the mass media selectively promote research that is favorable to the fish oil
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industry. The editorial boards of oil research journals often include industry representatives, and their
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editorial decisions favor research conclusions that promote the industry, in the way that editorial decisions in
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previous decades favored articles that denied the dangers of radiation and reported that estrogen cures almost
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everything. Marcia Angell, former editor of the NEJM, has observed that the "significant results" reported in
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published studies can be properly interpreted only by knowing how many studies reporting opposite results were
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rejected by the editors. One way to evaluate published studies is to see whether they tell you everything you
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would need to know to replicate the experiment, and whether the information they provide is adequate for drawing
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the conclusions they draw, for example whether they compared the experimental subjects to proper control
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subjects. With just a few minimal critical principles of this sort, most "scientific" publications on nutrition,
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endocrinology, cancer and other degenerative diseases are seen to be unscientific. In nutritional experiments
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with fish oil, controls must receive similar amounts of vitamins A, D, E, and K, and should include fat free or
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"EFA" deficient diets for comparison. In declaring EPA and DHA to be safe, the FDA neglected to evaluate their
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antithyroid, immunosuppressive, lipid peroxidative (Song et al., 2000), light sensitizing, and antimitochondrial
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effects, their depression of glucose oxidation (Delarue et al., 2003), and their contribution to metastatic
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cancer (Klieveri, et al., 2000), lipofuscinosis and liver damage, among other problems. <hr />
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<hr />
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<hr />
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"Houston-based Omega Protein Inc.'s bottom line may get a little fatter. The publicly traded company, which
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produces an Omega-3 fatty acid product called OmegaPure, has signed an agreement to provide its fish oil in
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school lunches in 38 school districts in South Texas beginning this month. The 500-person company, which has
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ties to former President George Bush's Zapata Corp., will distribute the product through an agreement with
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Mercedes-based H&H Foods. Although the dollar amount of the contract between Omega Protein and H&H Foods
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hinges on future sales, the company is poised to cash in as school administrators and parents refocus their
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attention on the nutritional content of student diets. Omega Protein President and CEO Joseph von Rosenberg says
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the company's recent investment of $16.5 million for a fish oil refinery in Reedville, Va., scheduled for
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completion in May, and an increased awareness of the benefits of Omega-3 in human food, positions Omega to
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capitalize on predicted demand." Jenna Colley Houston Business Journal
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<hr />
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<hr />
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<hr />
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Andrew Weil was on the radio recently recommending DHA (usually found in fish oil*) to treat depression, and I
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think that means that a lot of people are buying it and eating it. A few years ago the government declared that
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it was "generally regarded as safe" and approved its use in baby formula, and a few months ago Texas school
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districts contracted with Omega Protein (which grew out of the Bush family's Zapata Corporation) to provide
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menhaden fish oil for school lunches. Between the 1950s and the 1970s, people were assured that eating
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polyunsaturated seed oils would protect them against heart disease. There's no evidence that the bad outcome of
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that campaign decreased the gullibility of the public. They are happily joining in the latest public health
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experiment.<p></p>
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<p>
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<em>*Weil recommends eating "oily fish"--"wild Alaskan salmon, mackerel, sardines, or herring"--. "If you do
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take supplements, fish oil is a better source of DHA than algae"
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</em>
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When a group of people in government and industry decide on a policy, they can use carrots (good jobs,
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grants, and prestige) and sticks (loss of jobs and grants, organized slander, and worse) to make their
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guidelines clear, and most people will choose to follow those cues, even if they know that the policy is
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wrong. Historically, policy makers have told the public that "radiation is good for you," "estrogen will
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make you fertile (or safely infertile) and feminine and strong and intelligent," "starchy foods will prevent
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diabetes and obesity," "using diuretics and avoiding salt will make pregnancy safer," and that the
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polyunsaturated fatty acids are "nutritionally essential, and will prevent heart disease."
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<strong><em> </em></strong>The original "essential fatty acids" were linoleic, linolenic, and arachidonic
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acids. Now that the toxic effects of those are coming to be recognized, new "essential fatty acids," the
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omega-3 fatty acids, including those with long chains, found in fish oils, are said to make babies more
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intelligent, to be necessary for good vision, and to prevent cancer, heart disease, obesity, arthritis,
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depression, epilepsy, psychosis, dementia, ulcers, eczema and dry skin. With just a normal amount of vitamin
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E in the diet, cod liver oil is certain to be highly oxidized in the tissues of a mammal that eats a lot of
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it, and an experiment with dogs showed that it could increase their cancer mortality from the normal 5% to
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100%. Although fish oils rapidly destroy vitamin E in the body, some of them, especially the liver oils, can
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provide useful vitamins, A and D. In studies comparing fish oil diets with standard diets, these nutrients,
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as well as any toxins besides fatty acids (Huang, et al., 1997; Miyazaki, et al., 1998) in either type of
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oil, should be taken into account, but they seldom are.
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</p>
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<p>
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Despite the nutritional value of those vitamins, fish oils are generally much more immunosuppressive than
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the seed oils, and the early effects of fish oil on the "immune system" include the suppression of
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prostaglandin synthesis, because the more highly unsaturated long chain fats interfere with the conversion
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of linoleic acid into arachidonic acid and prostaglandins. The prostaglandins are so problematic that their
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suppression is helpful, whether the inhibition is caused by aspirin or vitamin E, or by fish oil.
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</p>
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<p>
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Some of the important antiinflammatory effects of fish oil result from the oxidized oils, rather than the
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unchanged oils (Sethi, 2002; Chaudhary, et al., 2004). These oils are so unstable that they begin to
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spontaneously oxidize even before they reach the bloodstream.
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</p>
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<p>
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In experiments that last just a few weeks or months, there may not be time for cancers to develop, and on
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that time scale, the immunosuppressive and antiinflammatory effects of oxidized fish oil might seem
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beneficial. For a few decades, x-ray treatments were used to relieve inflammatory conditions, and most of
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the doctors who promoted the treatment were able to retire before their patients began suffering the fatal
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effects of atrophy, fibrosis, and cancer. (But a few people are still advocating x-ray therapy for
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inflammatory diseases, e.g., Hildebrandt, et al., 2003.) The fish oil fad is now just as old as the x-ray
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fad was at its peak of popularity, and if its antiinflammatory actions involve the same mechanisms as the
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antiinflammatory immunosuppressive x-ray treatments, then we can expect to see another epidemic of fibrotic
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conditions and cancer in about 15 to 20 years. Around 1970 researchers reported that animals given fish oil
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in their food lived longer than animals on the standard diet. Alex Comfort, who was familiar with the
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research showing that simple reduction of food intake increased longevity, observed that the animals were
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very reluctant to eat the food containing smelly fish oil, and were eating so little food that their
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longevity could be accounted for by their reduced caloric intake. Even when "fresh" deodorized fish oil is
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added to the diet, its spontaneous oxidation before it reaches the animal's tissues reduces its caloric
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value. Without antioxidants, fish oil is massively degraded within 48 hours, and even with a huge amount of
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antioxidant there is still considerable degradation (Gonzalez, 1988; Klein, et al., 1990). Fish oil has been
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used for hundreds of years as varnish or for fuel in lamps, and the fatty fish have been used as fertilizer
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and animal feed, and later the hydrogenated solid form of the oil, which is more stable, has been used in
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Europe as a food substitute for people. When whale hunting was reduced around 1950, fish oil was substituted
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for whale oil in margarine production. Like the seed oils, such as linseed oil, the fish oils were mostly
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replaced by petroleum derivatives in the paint industry after the 1960s.
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</p>
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<p>
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Although by 1980 many animal diseases were known to be caused by eating oily fish, and the unsaturated oils
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were known to accelerate the formation of the "age pigment," lipofuscin, many "beneficial effects" of
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dietary fish oil started appearing in research journals around that time, and the mass media, responding to
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the industry's public relations campaign, began ignoring studies that showed harmful effects from eating
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fish oil.
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</p>
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<p>
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When reviewers in professional journals begin to ignore valid research whose conclusions are harmful to the
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fish oil industry, we can see that the policy guidelines set by the industry and its agents in government
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have become clear. Around the end of the century, we begin to see a strange literary device appearing, in
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which research reports on the toxic effects of omega-3 oils are prefaced by remarks to the effect that "we
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all know how great these oils are for good health." I think I detect groveling and shuffling of the feet by
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authors who want to get their work published. If you are willing to say that your work probably doesn't mean
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what it seems to mean, maybe they will publish it.
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</p>
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<p>
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For more than 50 years, the great majority of the medical publications on estrogen were part of the drug
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industry's campaign to fraudulently gain billions of dollars, and anyone who cared to analyze them could see
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that the authors and editors were part of a cult, rather than seekers of useful knowledge. Likewise, the
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doctrine of the harmlessness of x-rays and radioactive fallout was kept alive for several decades by
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demonizing all who challenged it. It now looks as though we are in danger of entering another period of
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medical-industrial-governmental cultism, this time to promote the universal use of polyunsaturated fats as
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both drugs and foods. In 2004, a study of 29,133 men reported that the use of omega-3 oil or consumption of
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fish didn't decrease depression or suicide, and in 2001, a study of 42,612 men and women reported that after
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more than 9 years the use of cod liver oil showed no protective effect against coronary heart disease
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(Hakkarainen, et al., 2004; Egeland, et al., 2001).
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</p>
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<p>
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The most popular way of arguing that fish oil will prevent heart disease is to show that it lowers blood
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lipids, continuing the old approach of the American Heart Association's "heart protective diet."
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Unfortunately for that argument, it's now known that the triglycerides in the blood are decreased because of
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the fish oil's toxic effects on the liver (Hagve and Christophersen, 1988; Ritskes-Hoitinga, et al., 1998).
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In experiments with rats, EPA and DHA lowered blood lipids only when given to rats that had been fed, in
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which case the fats were incorporated into tissues, and suppressed mitochondrial respiration (Osmundsen, et
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al., 1998).
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</p>
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<p>
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The belief that eating cholesterol causes heart disease was based mainly on old experiments with rabbits,
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and subsequent experiments have made it clear that it is <strong><em>oxidized</em></strong> cholesterol that
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damages the arteries (Stapran, et al., 1997). Since both fish oil and oxidized cholesterol damage rabbits'
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arteries, and since the lipid peroxides associated with fish oil attack a great variety of biological
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materials, including the LDL lipoproteins carrying cholesterol, the implications<strong> </strong>of the
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rabbit experiments now seem very different.
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</p>
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<p>
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Another way of arguing for the use of fish oil or other omega-3 fats is to show a correlation between
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disease and a decreased amount of EPA, DHA, or arachidonic acid in the tissues, and to say "these oils are
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deficient, the disease is caused by a deficiency of essential fatty acids." Those oils are extremely
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susceptible to oxidation, so they tend to spontaneously disappear in response to tissue injury, cellular
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excitation, the increased energy demands of stress, exposure to toxins or ionizing radiation, or even
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exposure to light. That spontaneous oxidation is what made them useful as varnish or paint medium. But it is
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what makes them sensitize the tissues to injury. Their "deficiency" in the tissues frequently corresponds to
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the intensity of oxidative stress and lipid peroxidation; it is usually their presence, rather than their
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deficiency, that created the disposition for the disease.
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</p>
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<p>
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One of the earliest harmful effects of polyunsaturated fatty acids, PUFA, to be observed was their
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acceleration of the formation of lipofuscin or ceroid, the "age pigment," during oxidative stress or vitamin
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E deficiency. Associated with the formation of lipofuscin, the PUFA were discovered to cause degeneration of
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the gonads and brain, and the fact that vitamin E could prevent some of their toxic effects led to the idea
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that vitamin E was essentially an antioxidant. Unfortunately, the protective effect of vitamin E against the
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PUFA is only partial (Allard, et al., 1997).
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</p>
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<p>
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The degenerative diseases are all associated with disturbances involving fat metabolism and lipid
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peroxidation. Alzheimer's disease, alcoholic and nonalcoholic liver disease, retinal degeneration, epilepsy,
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AIDS, diabetes, and a variety of circulatory problems involve breakdown products of the PUFA. The products
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of PUFA decomposition include acrolein, malondialdehyde, hydroxynonenal, crotonaldehyde, ethane, pentane,
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and the neuroprostanes, which are prostaglandin-like molecules formed from DHA by free radical lipid
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peroxidation products, especially in the brain and at a higher level in Alzheimer's disease.
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</p>
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<p>
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The reactions of three types of cell--vascular endothelium, nerve cells, and thymus cells--to the PUFA will
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illustrate some of the important processes involved in their toxicity.
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</p>
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<p>
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When the body doesn't have enough glucose, free fatty acids are released from the tissues, and their
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oxidation blocks the oxidation of glucose even when it becomes available from the breakdown of protein
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caused by cortisol, which is released during glucose deprivation. Cells of the thymus are sensitive to
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glucose deprivation, and even in the presence of glucose, cortisol prevents them from using glucose, causing
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them to take up fatty acids. The thymic cells die easily when exposed either to excess cortisol, or
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deficient glucose. The polyunsaturated fatty acids<strong> </strong>linoleate, arachidonate, and
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eicosapentaenoic, are especially toxic to thymic cells by preventing their inactivation of cortisol,
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increasing its action. (Klein, et al., 1987, 1989, 1990). Lymphocytes from people with AIDS and leukemia are
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less able to metabolize cortisol. An extract of serum from AIDS patients caused lymphocytes exposed to
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cortisol to die 7 times faster than cells from healthy people. AIDS patients have high levels of both
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cortisol and free polyunsaturated fatty acids (Christeff, et al., 1988). The cytotoxicity caused by EPA and
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its metabolites (15 mg. of EPA per liter killed over 90% of a certain type of macrophage) isn't inhibited by
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vitamin E (Fyfe and Abbey, 2000). Immunological activation tends to kill T cells that contain PUFA (Switzer,
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et al., 2003).
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</p>
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<p>
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When animals are fed fish oil and then exposed to bacteria, their immunosuppressed thymic (T) cells cause
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them to succumb to the infection more easily than animals fed coconut oil or a fat free diet. Natural killer
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cells, which eliminate cancer cells and virus infected cells, are decreased after eating fish oil, and T
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suppressor cells are often increased. More subtle interference with immunity is produced by the actions of
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PUFA on the "immune synapse," a contact between cells that permits the transmission of immunological
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information. The immunosuppressive effect of fish oil is recognized as a useful aid in preventing the
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rejection of transplanted organs, but some studies are showing that survival a year after transplantation
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isn't improved.
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</p>
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<p>
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Polyunsaturated fatty acids, especially those that can be turned into prostaglandins, are widely involved in
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causing inflammation and vascular leakiness. EPA and DHA don't form ordinary prostaglandins, though the
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isoprostanes and neuroprostanes they produce during lipid peroxidation behave in many ways like the more
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common prostaglandins, and their enzymically formed eicosanoids have some functions similar to those of the
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common prostaglandins. The brain contains a very high concentration of these unstable fatty acids, and they
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are released in synapses by ordinary excitatory process.
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</p>
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<p>
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Chan, et al., 1983, found that polyunsaturated fats caused brain swelling and increased blood vessel
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permeability. In 1988, Chan's group found that DHA and other polyunsaturated fatty acids added to cultured
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cells from the cerebral cortex produced free radicals and stimulated production of malondialdehyde and
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lactate, and inhibited the uptake of glutamic acid, which suggests that they would contribute to prolonged
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excitation of the nerves (Yu, et al., 1986). In brain slices, the polyunsaturated fatty acids caused the
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production of free radicals and swelling of the tissue, and the saturated fatty acids didn't (Chan and
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Fishman, 1980). The PUFA inhibited the respiration of mitochondria in brain cells (Hillered and Chan, 1988),
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and at a higher concentration, caused them to swell (Hillered and Chan, 1989), but saturated fatty acids
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didn't produce edema. Free radical activity was shown to cause the liberation of free fatty acids from the
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cellular structure (Chan, et al., 1982, 1984). The activation of lipases by free radicals and lipid
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peroxides, with the loss of potassium from the cells, suggests that excitation can become a self-stimulating
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process, leading to cellular destruction.
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</p>
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<p>
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DHA itself, rather than its decomposition products, facilitates excitatory (glutamate) nerve transmission
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(Nishikawa, et al., 1994), and that excitatory action causes the release of arachidonic acid (Pellerin and
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Wolfe, 1991).
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</p>
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<p>
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Considering just one of the products of fish oil peroxidation, acrolein, and a few of its effects in cells,
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we can get an idea of the types of damage that could result from increasing the amount of omega-3 fats in
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our tissues. The "barrier" between the brain and blood stream is one of the most effective vascular barriers
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in the body, but it is very permeable to oils, and lipid peroxidation disrupts it, damaging the ATPase that
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regulates sodium and potassium (Stanimirovic, et al., 1995). Apparently, anything that depletes the cell's
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energy, lowering ATP, allows an excess of calcium to enter cells, contributing to their death (Ray, et al.,
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1994). Increasing intracellular calcium activates phospholipases, releasing more polyunsaturated fats
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(Sweetman, et al., 1995) The acrolein which is released during lipid peroxidation inhibits mitochondrial
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function by poisoning the crucial respiratory enzyme, cytochrome oxidase, resulting in a decreased ability
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to produce energy (Picklo and Montine, 2001). (In the retina, the PUFA contribute to light-induced damage of
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the energy producing ability of the cells [King, 2004], by damaging the same crucial enzyme.) Besides
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inhibiting the ability of nerve cells to produce energy from the oxidation of glucose, acrolein inhibits the
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ability of cells to regulate the excitatory amino acid glutamate (Lovell, et al., 2000), contributing to the
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excitatory process. High levels of acrolein (and other products of PUFA degradation) are found in the brain
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in Alzheimer's disease (Lovell, et al., 2001).
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</p>
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<p>
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The "prion" diseases, CJD and TSE/BSE (mad cow disease) have many features in common with Alzheimer's
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disease, and several studies have shown that the "prion" protein produces its damage by activating the
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lipases that release polyunsaturated fatty acids and produce lipid peroxides (Bate, et al., 2004, Stewart,
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et al., 2001). Acrolein reacts with DNA, causing "genetic" damage, and also reacts with the lysine in
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proteins, for example contributing to the toxicity of oxidized low density lipoproteins (LDL), the proteins
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that carry cholesterol and that became famous because of their involvement in the development of
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atherosclerosis that was supposedly caused by eating saturated fats.
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</p>
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<p>
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My newsletter on mad cow disease discussed the evidence incriminating the use of fish meal in animal feed,
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as a cause of the degenerative brain diseases, and earlier newsletters (glycemia, and glycation) discussed
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the reasons for thinking that inappropriate glycation of lysine groups in proteins, as a result of a lack of
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protective carbon dioxide/carbamino groups, produces the amyloid (or "prion") proteins that characterize the
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dementias. Acrolein, produced from the decomposing "fish oils" in the brain, is probably the most reactive
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product of lipid peroxidation in the brain, and so would be likely to cause the glycation of lysine in the
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plaque-forming proteins. These toxic effects of acrolein in the brain are analogous to the multitude of
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toxic effects of the omega-3 fatty acids and their breakdown products in all of the other organs and tissues
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of the body. Cancer cells are unusual in their degree of resistance to the lethal actions of the lipid
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peroxides, but the inflammatory effects of the highly unsaturated fatty acids are now widely recognized to
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be essentially involved in the process of cancerization (my newsletters on cancer and leakiness discuss some
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of the ways the fats are involved in tumor development). The fats that we synthesize from sugar, or coconut
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oil, or oleic acid, the omega-9 series, are protective against the inflammatory PUFA, in some cases more
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effective even than vitamin E.
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</p>
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<p>
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In Woody Allen's 1973 movie, <strong><em>Sleeper,</em></strong> the protagonist woke up after being frozen
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for 200 years, to find that saturated fats were health foods. At the time the movie was made, that had
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already been established (e.g., Hartroft and Porta, 1968 edition of<em>
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Present Knowledge in Nutrition</em>, who showed that adequate saturated fat in the diet helped to
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protect against the formation of lipofuscin). PS: Royal Society for the Protection of Birds says 2004 has
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been the most catastrophic breeding season on record for seabirds along UK coasts. It says industrial
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fishing to supply fish meal and oil is barely sustainable and imperils the whole marine food web. "The UK
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has suffered serious seabird disasters this year already. In Shetland and Orkney, entire colonies of birds
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failed to produce any young because of severe food shortages. "On top of that, hundreds of seabirds have
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been washing ashore having perished at sea. Again, lack of food is thought to be one of the reasons." The
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report, Assessment Of The Sustainability Of Industrial Fisheries Producing Fish Meal And Fish Oil, was
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compiled for the RSPB by Poseidon Aquatic Resource Management Ltd and the University of Newcastle-upon-Tyne.
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<h3>REFERENCES</h3>
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Neuroreport. 2002 Oct 28;13(15):1933-8. <strong>Cyclo-oxygenase inhibitors protect against prion-induced
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neurotoxicity in vitro.</strong> Bate C, Rutherford S, Gravenor M, Reid S, Williams A. Neuroreport. 2004
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Mar 1;15(3):509-13.<strong>
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The role of platelet activating factor in prion and amyloid-beta neurotoxicity.</strong> Bate C, Salmona
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M, Williams A. J Biol Chem. 2004 Aug 27;279(35):36405-11. <strong>Phospholipase A2 inhibitors or
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platelet-activating factor antagonists prevent prion replication.</strong>
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Bate C, Reid S, Williams A. J Neurochem 1980 Oct;35(4):1004-7.<strong>
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Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling.</strong
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> Chan PH, Fishman RA. Brain Res. 1982 Sep 23;248(1):151-7. <strong>Alterations of membrane integrity and
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cellular constituents by arachidonic acid in neuroblastoma and glioma cells.</strong> Chan PH, Fishman
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RA. J Neurochem. 1982 Feb;38(2):525-31. <strong>Phospholipid degradation and cellular edema induced by free
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radicals in brain cortical slices.</strong>
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Chan PH, Yurko M, Fishman RA. Ann Neurol. 1983 Jun;13(6):625-32. <strong>Induction of brain edema following
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intracerebral injection of arachidonic acid.</strong> Chan PH, Fishman RA, Caronna J, Schmidley JW,
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Prioleau G, Lee J. J Neurosci Res. 1984;12(4):595-605. <strong>Release of polyunsaturated fatty acids from
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</p>
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