-Caveat Lector- Sent: Monday, October 02, 2000 3:15 PM Subject: [firebase-news] Fw: gwvm Toxins Producing Chronic Fatigue Syndrome > > Gulf War help > http://www.gulfweb.org > > Paralyzed Veterans of America > http://www.pva.org > > VA-Help > http://www.egroups.com/group/VA-problems > ----- Original Message ----- > From: "Rich Van Konynenburg" <[EMAIL PROTECTED]> > To: <[EMAIL PROTECTED]>; <[EMAIL PROTECTED]> > Sent: Monday, October 02, 2000 1:01 PM > Subject: Re: gwvm Toxins Producing Chronic Fatigue Syndrome > > > > Thanks to Jim Moss for posting this abstract, and yes, Craig, > > "mitochondrial dysfunction" is exactly what gives rise to chronic fatigue > > syndrome, in my opinion. > > > > Below is a write-up of my metabolic pathogenesis hypothesis for chronic > > fatigue syndrome. My view of Gulf War Illnesses is that the variety of > > toxins to which the troops were subjected overloaded their Phase II > > glutathione detoxication subsystem, and this allowed the toxins to build > up > > in their bodies. Depending on which toxins an individual received, he or > > she exhibits a different subset of symptoms, because the various toxins > > operate on the body at different locations and in different ways. Attacks > > on the enzymes in the mitochondria will put partial blockades in the Krebs > > cycle (Dr. Edward Conley in his book "America Exhausted" calls them > > "functional blocks." It's the same concept.) This produces "mitochondrial > > dysfunction," a lowering in the production of ATP below what the cells > > need, and fatigue and other symptoms ensue. > > > > Here's the write-up: > > > > May 22, 2000 > > > > Metabolic Pathogenesis Hypothesis for > > Chronic Fatigue Syndrome and Fibromyalgia > > > > Rich Van Konynenburg, Ph.D. > > > > E-mail: [EMAIL PROTECTED] > > > > > > [Disclaimer: The author is not licensed to diagnose or treat disease. > > This paper is intended for information only, and is directed toward > medical > > professionals and researchers. Anyone considering using this information > > for diagnosis or treatment does so at their own risk, and should first > > consult with a licensed health care provider.] > > > > In discussing chronic fatigue syndrome (CFS) and fibromyalgia (FM), as is > > true for other disorders, it is important to distinguish between the root > > cause (etiology), the development of the disease (pathogenesis) and the > > abnormal function of the body after the disease has become established > > (pathophysiology). The main emphasis of this paper is the pathogenesis of > > these disorders, but there is also discussion of some etiologies proposed > > by others. > > > > The essential idea of the Metabolic Pathogenesis Hypothesis for these > > disorders is that the onset of CFS/FM occurs when a chronic partial > > blockade is inserted somewhere in the chain of reactions that make up the > > Intermediary Metabolism. The Intermediary Metabolism is involved in using > > nutrients from food as fuel and forming ATP (adenosine triphosphate) for > > use in powering many different reactions in the cells, including the > > contraction of muscle fibers and the generation of electrical potentials > to > > power the nerve impulses (action potentials). The Intermediary Metabolism > > is composed of glycolysis, the pyruvate dehydrogenase complex, the Krebs > or > > citric acid cycle, and the respiratory chain. > > > > According to this hypothesis, the population of people who have been > > diagnosed with CFS or FM (PWCs) using the CDC case definition [1] or the > > American College of Rheumatology criteria [2] did not all have the same > > root cause for their disorder. Rather, there are several subsets of PWCs. > > Each subset has a different etiology, but all the etiologies have in > common > > the fact that they impact the Intermediary Metabolism by inserting one or > > more chronic partial blockades somewhere within it. Since the reactions > of > > Intermediary Metabolism are dependent on one another, a partial blockade > > anywhere within this series causes a decrease in the production of ATP, > and > > this in turn leads to many of the observed symptoms. > > > > According to this hypothesis, different etiologies insert the partial > > blockades at different places in the intermediary metabolism. This > explains > > why subsets of PWCs differ in terms of their history of triggering > factors, > > speed of onset, biochemical indicators, and response to various > treatments, > > while at the same time they generally share a more or less common set of > > symptoms. > > > > The common set of symptoms arises from the common pathogenesis and > > pathophysiology, which flow from the various etiologies, but the > individual > > etiologies are different. As an analogy, consider a chain of mechanical > > gears performing some useful work. It is possible to throw a monkey > wrench > > into the gears at several different places, but the end result is the > same: > > the gear train will slow or stop, and the useful work will not be done at > > the same rate as before. > > > > One major etiology (perhaps applying to the largest subset of PWCs) > appears > > to be the depletion of reduced glutathione, as suggested by Dr. Paul > Cheney > > in recent talks [3] and by Dr. Gustavo Bounous and Mr. John Molson in a > > recent paper [4]. Reduced glutathione (GSH) is the chemically reduced form > > of the tripeptide glutathione, which is made up of cysteine, glycine and > > glutamate. GSH plays several important roles in the body. It serves as > > the "anchor" for maintaining the oxidation-reduction potential inside the > > cells, thus maintaining a chemical environment in which Intermediary > > Metabolism can take place properly. It acts to neutralize oxidizing free > > radicals, thus protecting other molecules in the cell from damage. It > > forms an important part of the Phase II detoxification system, which helps > > to make toxic substances soluble so they can be excreted in the urine. It > > is very important for protecting the cells of the immune system from the > > free radicals they generate themselves to combat infections. Glutathione > > is synthesized mainly by the liver, but also by other tissues. > > > > Most of the "triggering factors" for CFS/FM commonly reported by PWCs are > > known to draw upon reduced glutathione. These include infections, physical > > trauma, surgery, lack of sufficient sleep over a long period, excessive > > physical exertion, emotional stress, exposure to toxins or oxidants, > > excessive use of alcohol, and excessive use of drugs (including > > over-the-counter remedies such as acetaminophen). Reduced glutathione > thus > > serves as a "common denominator" that combines together the effects of > many > > different types of stressors. When the overall load of stressors becomes > > too great, the body's supply of reduced glutathione is reduced to the > point > > that its vital functions cannot all be covered. It's a case of too much > > straw for the camel's back. > > > > The supply side of the equation is also important. A diet deficient in > > antioxidants and deficient in protein sources of the amino acids that are > > precursors for making glutathione (especially cysteine and methionine, > > which can be converted to cysteine), particularly animal-based protein > > sources such as eggs and dairy products, is an important factor also, > > because it limits the body's ability to synthesize new glutathione. > > (Unfortunately, the same person who is burning her (or his) candle at both > > ends, who is involved in an emotionally stressful relationship or work > > situation, who is trying to compete in a marathon, and who is taking pills > > every day to keep going, may also decide to become a vegetarian! This > does > > not appear to be a good combination.) > > > > If the inventory of reduced glutathione becomes too low in the liver, it > > hoards the cysteine it needs to carry on its important functions and > > preserve life. The muscle cells then become deficient in reduced > > glutathione. This allows peroxynitrite, an oxidizing free radical, to > build > > up there. Peroxynitrite is made by reaction of superoxide radicals, which > > are constantly being produced in metabolism, with nitric oxide, which is > > present in many tissues. Peroxynitrite attacks the enzyme aconitase [5] > > and perhaps other enzymes as well in the Krebs cycle of the muscle cells, > > as discussed by Dr. Martin Pall in a recent paper [6], producing a partial > > blockade. This causes a drop in ATP production, which robs the calcium > > pumps of the energy needed to pump Ca ions back into the sarcoplasmic > > reticulum, and it also robs the myosin heads of the ATP needed to detach > > them from the actin fibers. This is a milder form of the processes that > > occur in rigor mortis. This leads to the observed fatigue, weakness, and > > contractions in the muscles. > > > > Meanwhile, in the Krebs cycle, citrate builds up, as observed by the > > University of Newcastle group, because citrate is just upstream of the > > partial blockade. Citrate is transported into the sarcoplasm, and it > > downregulates phosphofructokinase in the glycolysis chain, further > lowering > > the ATP production. > > > > This latter effect causes a glucose backlog in the blood, and the pancreas > > is forced to raise the insulin level to push it into the liver and fat > > cells, where it is converted to stored fat. This accounts for the weight > > gain in this subset of PWCs. The overshoot in the control system then > > produces hypoglycemia in many of these PWCs. They consume carbohydrates > > again, and the cycle is repeated. (This is why a low carbohydrate diet is > > helpful for many PWCs. It stops this cycle.) > > > > The resulting high average insulin level causes the fatty acids to be > > sequestered in the fat cells, and they are thus not available to be burned > > for fuel by the muscle cells. This accounts for the stubbornness of the > > weight gain in many PWCs. Since the muscle cells cannot use glucose > > efficiently because of the downregulation of glycolysis by citrate, and > > since they cannot get fatty acids because of sequestration by the high > > insulin, they burn amino acids for fuel, using what's left of the Krebs > > cycle, by anaplerosis. > > > > This causes the amino acid levels in the blood to drop (which has been > > observed and reported by several researchers). The shortage of amino acids > > in the blood then causes other problems: The lymphocytes are unable to get > > enough glutamine as well as cysteine and other amino acids, so > > cell-mediated immunity becomes dysfunctional. Since this is the type of > > immunity needed to counter viruses, intracellular bacteria, and yeasts, > > they begin to thrive. The result is infections that spread systemically > and > > do their damage on tissues, including the brain. This leads to the > observed > > cognitive problems. Another problem is that the cells of the small > > intestine are unable to get enough glutamine also, which is their main > > substrate. This leads to irritable bowel syndrome, dysbiosis and leaky gut > > syndrome. The latter produces the observed food allergies. There is also a > > shortage of tryptophan in the blood, and this leads to depletion of > > serotonin and melatonin, affecting mood and sleep. > > > > Another proposed etiology is the hypercoagulability theory of Dr. David > > Berg [7]. This etiology involves a genetic defect in one of several > > proteins involved in the coagulation of the blood. The action of the > > immune system in combatting a viral infection then erroneously causes an > > activation of the clotting system, depositing fibrin in the capillaries. > > This interferes with oxygen getting to cytochrome oxidase, and thus > > produces a partial blockade at the end of the intermediary metabolism > > chain. ATP production drops, and the same syndrome ensues. > > > > A third etiology is the excess phosphate reabsorption etiology of Dr. R. > > Paul St. Amand, discussed in his recent book [8]. In my opinion, this > > etiology is more likely for those whose onset is closer to "pure" > > fibromyalgia than the CFS. Also in my opinion (not in St. Amand's, at > > least not yet!) the excess phosphate ties up magnesium ions in the > > mitochondria as magnesium hydrogen phosphate, and this leads to > > downregulation of pyruvate dehydrogenase and/or isocitrate dehydrogenase, > > which are very magnesium dependent, thus putting partial blockades at one > > or both of these sites. Again, ATP production drops, and the same symptom > > set occurs. > > > > I suspect that there are probably several more etiologies, but I suggest > > that all of them somehow impact the intermediary metabolism, and that's > > what brings on CFS/FM. > > > > I have focussed here on the muscle cells, but other kinds of cells are > also > > affected, including cells in the nervous system. In the case of neurons, > > the major use of ATP is to drive the sodium-potassium ATPase ion pumps. > > When these are short of ATP, they are unable to maintain the intracellular > > ion concentrations at the proper values. This leads to a change in the > > osmotic potential inside the cells, because the pumps normally move three > > sodium ions out when they bring two potassium ions in. The results are a > > decreased concentration of potassium inside the cells and an increased > > concentration of ions in general inside, and the latter causes the cells > to > > absorb water and swell. This produces the observed edema, and may be the > > origin of the need to perform Chiari surgergy in some PWCs. Their brains > > may have have swollen too much for the available space allowed by the > bones > > of the head and neck. Another effect of the lack of ATP for the ion pumps > > is that the membrane potential drops, and this reduces the threshold for > > firing action potentials (nerve impulses). This may be one of the origins > > of the increased sensation of pain in FM. (The other appears to be spinal > > in location, and appears to be associated with lowered serotonin.) > > > > In keeping with the general principal in medicine that it is imperative to > > diagnose before treating, once the diagnosis of CFS or FM is made, it is > > still necessary to determine the particular etiology before prescribing > > treatment. I believe that this is particularly difficult because the > > etiologies are not all known yet. However, it is possible to assess the > > probability that a particular PWC had one of the proposed etiologies. For > > example, a person with the etiology of the depletion of reduced > glutathione > > is generally characterized by having ongoing infections with viruses or > > intracellular bacteria and high levels of heavy metals in hair or blood, > > and Dr. Cheney has found that such a person tends to have high urinary > > citrate and lipid peroxides, and low urinary alpha ketoglutarate. > > > > A screening test for the hypercoagulation etiology is the Westergren > > erythrocyte sedimentation rate test. If the sed rate is greater than 5 > > mm/hr, this etiology can be ruled out. If it is less than this, more > > specialized tests need to be performed, as described by Dr. Berg. > > > > The excess phosphate reabsorption etiology seems to be associated with > hard > > lumps or lesions in the muscles and a presentation that includes pain in > > the muscles, but not necessarily immune dysfunction. Dr. St. Amand > > palpates the lesion and maps them on a diagram. > > > > Once the etiology has been determined, treatment can be prescribed. It > may > > not be sufficient to treat only the root cause, especially in complicated > > cases or those of long standing, although this must be an important part > of > > the treatment. Where infections have been present for some time, for > > example, it may be necessary to attack them directly in addition to > > restoring the immune system to proper operation. Nutritional support, > > detoxification and other measures may be necessary. In my opinion it is > > not clear at this time whether a "cure" can be had in cases of long > > standing, because pathogens (such as viruses) or oxidizing free radicals > > may have done damage that is permanent, at least within the current state > > of the art in medicine. > > > > In the case of the depletion of reduced glutathione, orally supplemented > > nondenatured whey protein concentrates are reported by Dr. Cheney to be > > effective in restoring the glutathione inventory. > > > > In the case of hypercoagulation, Dr. Berg suggests the use of heparin as > > well as direct attacks on the pathogens. > > > > In the case of excess phosphate reabsorption, Dr. St. Amand recommends > > guaifenesin, together with avoidance of all forms of salicylate (which > > blocks guaifenesin), and a low carbohydrate diet for those who have either > > hypoglycemia or cravings for carbohydrates. > > > > In summary, the main point of the Metabolic Pathogenesis Hypothesis for > > chronic fatigue syndrome and fibromyalgia is that there are different > > etiologies, but all of them insert at least one chronic partial blockade > > somewhere within the Intermediary Metabolism. This explains the observed > > differences between people with these disorders, while at the same time > > sharing a more or less common set of symptoms. It is important to > > determine the particular etiology before prescribing specific treatment, > > but this is made difficult by the fact that all the etiologies are > probably > > not yet known. However, most of the cases may be accounted for by > > etiologies that have already been proposed. > > > > References > > > > 1. K. Fukuda, S.E. Straus, I. Hickie, et al., "The Chronic Fatigue > > Syndrome: A Comprehensive Approach to Its Definition and Study," Annals of > > Internal Medicine 121, 953-59 (1994). > > 2. F. Wolfe, H.A. Smythe, M.B. Yunus, et al., The American College of > > Rheumatology 1990 Criteria for the Classification of Fibromyalgia: Report > > of the Multicenter Criteria Committee," Arthritis and Rheumatism 33, > > 160-172 (1990). > > 3. P. Cheney, "Evidence of Glutathione Deficiency in Chronic Fatigue > > Syndrome," talk presented at llth International Symposium on Integrated > > Medicine, Vienna, Austria (1999), tape available as Order Code 07-199, > Tape > > 7, from Professional Audio Recording, P.O. Box 7455, LaVerne, CA 91750, > > phone 1-800-430-4PAR. > > 4. G. Bounous and J. Molson, "Competition for Glutathione Precursors > > between the Immune System and the Skeletal Muscle: Pathogenesis of > Chronic > > Fatigue Syndrome," Med. Hypotheses 53, 347-49 (1999). > > 5. P.Y. Cheung, D.H. Jong, and R. Schulz, "Thiols Protect the Inhibition > > of Myocardial Aconitase by Peroxynitrite," Arch. Biochem Biophys 350 (1), > > 104-8 (1998). > > 6. M.L. Pall, "Elevated, Sustained Peroxynitrite Levels as the Cause of > > Chronic Fatigue Syndrome," Med Hypotheses 54, 114-125 (2000). > > 7. D. Berg, L.H. Berg, J. Couveras, and H. Harrison, "Chronic Fatigue > > Syndrome &/or Fibromyalgia as a Variation of Antiphospholipid Antibody > > Syndrome (APS): An Explanatory Model and Approach to Laboratory > Diagnosis," > > Blood Coagulation and Fibrinolysis 10, 435-38 (1999). > > 8. R. Paul St. Amand and C. C. Marek, "What Your Doctor May Not Tell You > > about Fibromyalgia," Warner Books, New York (1999). > > > > > > Rich Van Konynenburg > > > > > > At 08:07 AM 10/01/2000 -0400, you wrote: > > > > > > > > > > > > > > > > > > > > >I note 6 chemicals including malathion cause "mitochondrial dysfunction" > > >which is the cell's method of generating energy. Is this a cause of > > >"chronic fatigue syndrome"? It might be worth investigating. > > > > > >Craig Stead > > >Putney, Vermont > > > > > > > > > > > >At 02:16 PM 9/30/00 -0400, you wrote: > > >>This serves as an example of how far off base the various "expert" > > >>panels have been over the years. > > >> > > >>Thay all persist in viewing sarin, pyridostigmine, several pesticides > > >>as able to do damage only by their "known" or "primary" action of > > >>cholinesrterase inhibition. > > >> > > >>Malathion is a "cholinesterase inhibitor" (like srin, PB, chlorpyrifos > > >>ad nausium). Yet, here is a toxicity assay for malathion that has > > >>nothing to do with this action. All the assumptions made by the IOM > > >>and others are based on the actions of these chemicals that may have > > >>no relevance. They are working at the textbook level, not the research > > >>level of thinking. PB also will kill cells in similar assays and > > >>probably not by the presumed action of PB (cholinesrterase inhibition). > > >> > > >> > > >>Moss > > >> > > >>************************************************************* > > >>Toxicology 2000 Sep 7;150(1-3):159-169 > > >> > > >> Cytotoxicity of the MEIC reference chemicals in rat hepatoma-derived > > >> Fa32 cells. > > >> > > >> Dierickx PJ > > >> > > >> Laboratorium Biochemische Toxikologie, Instituut voor Volksgezondheid, > > >>Afdeling Toxikologie, > > >> Wytsmanstraat 14, B-1050, Brussels, Belgium > > >> > > >> [Record supplied by publisher] > > >> > > >> The cytotoxicity of the MEIC reference chemicals was investigated in > > >>rat hepatoma-derived > > >> Fa32 cells. The total protein content was measured as an endpoint after > > >>exposure times of 30 min > > >> and 24 h, both in normal and glutathione-depleted cells. The neutral > > >>red uptake inhibition and the > > >> MTT conversion were also measured after 30 min. On average, the > > >>cytotoxicity was higher in > > >> glutathione-depleted cells when compared to normal cells, and was lower > > >>after 30 min than after > > >> 24 h. Evidence was obtained for lysosomal attack (of five chemicals) or > > >>mitochondrial > > >> dysfunction (of six chemicals) as the primary intoxication mechanism. > > >>Malathion and mercuric > > >> chloride belong to both series of chemicals. Good to excellent > > >>correlations were observed when > > >> the 50% inhibitory concentrations of the six different in vitro assays > > >>were compared. When the > > >> six in vitro assays in Fa32 cells were compared with the human > > >>toxicity, the correlation coefficient > > >> was almost always identical to that obtained previously in human > > >>hepatoma-derived Hep G2 > > >> cells. The latter was the best acute in vitro assay for the prediction > > >>of human toxicity within the > > >> MEIC study. Altogether the results integrate very well with the basal > > >>cytotoxicity concept > > >> (Ekwall, B., 1995. The basal cytotoxicity concept. In: Goldberg, A.M., > > >>Van Zutphen, L.F.M. > > >> (Eds.), The World Congress on Alternatives and Animal Use in the Life > > >>Sciences: Education, > > >> Research, Testing. Mary Ann Liebert Publishers, New York, pp. 721-725). > > >> > > >> PMID: 10996672 > > >> > > >> > > >>--- > > >>This message was posted to the GWVM mailing list. To unsubscribe > > >>from the GWVM list, send email to [EMAIL PROTECTED] with > > >>"unsubscribe gwvm" in the message BODY, not the Subject: line. > > >>--- > > >>The GWVM list is hosted by Verio, Inc. - http://www.verio.net/ > > >>Verio claims no responsibility for GWVM list contents and > > >>provides the GWVM list as a community service. > > >> > > > > > > > > > > > >--- > > >This message was posted to the GWVM mailing list. To unsubscribe > > >from the GWVM list, send email to [EMAIL PROTECTED] with > > >"unsubscribe gwvm" in the message BODY, not the Subject: line. > > >--- > > >The GWVM list is hosted by Verio, Inc. - http://www.verio.net/ > > >Verio claims no responsibility for GWVM list contents and > > >provides the GWVM list as a community service. > > > > > > > > > > > > --- > > This message was posted to the GWVM mailing list. To unsubscribe > > from the GWVM list, send email to [EMAIL PROTECTED] with > > "unsubscribe gwvm" in the message BODY, not the Subject: line. > > --- > > The GWVM list is hosted by Verio, Inc. - http://www.verio.net/ > > Verio claims no responsibility for GWVM list contents and > > provides the GWVM list as a community service. > > > > > -------------------------- eGroups Sponsor -------------------------~-~> > Get a NextCard Visa, in 30 seconds! > 1. Fill in the brief application > 2. 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