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A new hypothesis of chronic fatigue syndrome: Co-conditioning theory.

Discussion in 'Latest ME/CFS Research' started by shrewsbury, Mar 28, 2010.

  1. richvank

    richvank Senior Member

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    ***Hi, Mr. Kite.

    ***Thank you for the response. My comments are at the asterisks below.

    Still, in all these examples, glutathione depletion isn't the actual *cause.* It's merely a problem that then leads or contributes to the cause, whether the actual cause is the impaired aconitase enzymes, impaired methylation, or otherwise dysfunctional mitochondrial and cellular energy production, and so on.

    ***This may be partly an issue of semantics, but my view of pathogenesis is that it is like a row of dominoes, or more properly, a branching row of dominoes. The falling of each domino is an effect of the falling of the preceding domino, and is also the cause of the falling of the next one (or ones, if there is a branch point there). In other words, the pathogenesis is described by a cause and effect sequence, or more properly, a cause and effect "tree."

    ***So in this paradigm, glutathione depletion would be an effect of several possible causes (physical, chemical, biological, and/or psychological/emotional stressors, each of which independently can place demands on glutathione). Glutathione depletion would also be a cause of several effects, including a rise in oxidative stress, dysfunction of the detox system, a shift in the immune response away from Th1, and many more.

    Based on my own experience, it's also possible to have impaired GSH and not have full blown chronic fatigue syndrome, which then can come about following an immunological activation. Not to say that the CFIDS development is not tied to the pre-existing glutathione depletion, or that it doesn't have the stage set by the depletion (or the dysfunctional GSH systems), but that GSH depletion in and of itself is not always enough to cause CFS.

    ***I agree with you on this. In my hypothesis, CFS does not develop unless the glutathione depletion leads to a partial block in the methylation cycle, which involves a loss of protection of vitamin B12 in the cells. Whether this occurs seems to depend on the person's inherited genomic polymorphisms. There are many illnesses that produce low glutathione, but I suggest that they don't go on to produce a chronic partial methylation cycle block, which is the hallmark of CFS.

    In that case - CFS-like syndrome without immunological component - the "cause" of CFS appears to be more neurobiological and neurohormonal, involving a dysfunctional HPAA and corticosteroid receptor function, dysfunctional NMDA receptor complex, possibly dysfunctional neurotransmitter function (perhaps why some people improve with SSRI/SNRIs, wellbutrin, etc.), and related neuro functions, which themselves somehow cause the mitochondrial dysfunction. I suspect it's something very complex and yet undiscovered regarding NMDA function, ion channel and other 'downstream' system functioning having to do with NMDA, brain glutamatergic systems, etc., or maybe even some as yet entirely undiscovered neurobiological function.

    *** I agree that the phenomena you have discussed in this paragraph are features of CFS, but I suggest that they fit within the cause and effect tree that starts with glutathione depletion as a result of the action of a variety of stressors. I described where I think most of them fit in in my 2007 poster paper, which can be found at www.cfsresearch.org.

    I could also tell you some interesting stories about Co Q-10 that would definitely fit your theory (and some of Cheney's observations), including a CFS crash following fructose consumption (Cheney warns against fructose now, I recently found out) that led to increased fatigue and widespread muscular "fibro" pain (burning, aching, "lactic acidosis" feeling, etc.) that lasted for weeks, and then was alleviated 50-75% in one day merely by increasing Co Q-10 from 100mg. to 200mg., and eventually improving almost to baseline again over the following weeks by continuing the 200mg. dosage.

    Since then I had a fever that led to actual immunological CFS and can't tolerate more than probably 25mg Co-Q 10 per day -- and can't tolerate NADH at all, both of which lead to congestive heart failure symptoms (which itself was caused a by bad reaction to an SSRI!) -- so the tie-ins, often contradictory, both to Cheney's ideas and your own (and the mito-dysfunction, electron transport chain dysfunction, etc.) I think are obvious. It's not just a simple 1 ingredient problem, or answer, imho!

    ***Thanks for this information. In my hypothesis, the reason for Co Q10 depletion in CFS is that it is known that its synthesis requires methylation. So its depletion is a direct effect of the partial block in the methylation cycle. Supplementing Co Q10 helps some people, but others don't respond well to it. As an antioxidant, it is capable of prooxidant behavior if it is present in concentration that is too high relative to the concentrations of the other network antioxidants. That may explain what occurred in your experience.

    ***Fructose in large amounts is really not good for any of us, and some people are intolerant of even small amounts. Dr. Kenny de Meirleir tests his patients with a fructose loading test, followed by breath analysis. He finds that fructose is feeding unhelpful bacteria in many PWCs. Dr. Cheney has emphasized that fructose enters the glycolysis chain at a point beyond where it can support the pentose phosphate shunt. That means that it can't be used to produce NADPH, which is needed to recycle oxidized glutathione.

    ***I suggest that what happened in your case is that you were pushed into a more severe state of oxidative stress by the fructose, which blocked your glutathione recycle. The Co Q-10, being an antioxidant, was able to compensate for the oxidative stress and improve your situation.

    ***I suggest that later on, the problem has been that your supply of glutathione has been more severely depleted, so that just adding NADH (which can also be used for glutathione recycle) is not sufficient, because you don't have enough glutathione to recycle. The Co Q-10 is probably having a prooxidant effect at higher dosages now, because your network antioxidants (glutathione being the basis of the network) are too low.

    ***You might want to consider treating to lift the methylation cycle block, which can raise glutathione. As always, I want to emphasize that it is necessary to be working with a physician when one does this type of treatment.

    ***Best regards,

    ***Rich
  2. richvank

    richvank Senior Member

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    Hi, cfs since 1998.

    I don't know if you are aware of the work of Prof. Harold Foster. He has found that a supplement that contains selenium, NAC, and a small number of other amino acids is able to bring a person with full-blown AIDS back to being only HIV-positive. He has tested this in some of the African countries, and it works. I have tried to help him to get this implemented on a larger scale, but unfortunately the pharmaceutical approach to AIDS treatment has more clout behind it.

    The HIV virus has been shown by Taylor et al. to be one of the viruses (Coxsackie and Hepatitis-C are others) that have a built-in mechanism to combat the glutathione system in the host. They genomically code for a version of glutathione peroxidase that requires selenium. They make this enzyme, but do not use it to control oxidative stress. They use it to deplete selenium in their host, and this lowers the host's ability to make useful glutathione peroxidase. By depleting cysteine, they also lower the glutathione level in the host.

    Just building glutathione with NAC is somewhat helpful, but adding selenium and the other amino acids that have been depleted by the virus helps even more. Prof. Foster has written a book about this, called "What Really Causes AIDS?" I think an electronic version is available free from his website.

    Rich
  3. Cloud

    Cloud Guest

    Thanks Rich......this is very interesting how HCV has a built in mechanism to to knock down the glutathione. I vaguely remember reading about this years ago. So, the solution would be to of course to suppress the HCV, but also supplementing with NAC and Selenomethionine? Have you found it common that people with HCV have impaired methylation? Any good links on this?
  4. jeffrez

    jeffrez Senior Member

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    Hi Rich - what actually happened is that the crash occurred after "withdrawing" from the fructose, not while on it. It appears to be entirely metabolic, not fungal, bacteriological, etc. For some reason I developed a strong craving for cranberry juice, of all things, so I got some to try. Normally I drink only filtered water, exclusively. But I just had to have the cranberry juice.

    I diluted it 1/2 with water, and started with literally just a couple of small sips. When I was okay with that a few hours later, I drank about maybe 2-4 oz. of the dilution for a few more times throughout the day - maybe 10-12oz of actual juice in total. I definitely felt a little "sugary" as I don't ordinarily consume anything like that. Then I think the next day is when the crash happened, while rebounding from the fructose "high."

    What caused the CFS-like disorder originally was a similar thing where I had been on medrol steroids for a week or two for the allergic glutathione reaction, where I couldn't eat any food because of reactions. A mainstream doctor took me off the steroids improperly, failed to taper correctly, etc. and I crashed the next day with a massive hypoglycemic adrenal crisis episode, hands shaking, massively disoriented, etc. All I could think of on some primal pre-cognitive level was stuffing food in my mouth. Luckily I had some bread and stuff like that, which gradually recovered me from the attack, but I had a weird fatigue that never went away from then on, except for a few days once following neurofeedback.

    On top of that, I once after the CFS had a liver reaction to grape seed extract antioxidant, which apparently impairs some cytochrome enzymes. I had massive right quadrant pain and decided just to carrot juice fast for a day or two to take the burden off the liver. By the second day, however, I was so strangely fatigued in a weird way that I thought I might literally die. Something was definitely wrong with my energy metabolism. So I started eating some light food, my energy rebounded almost immediately, but along with it came really bad fatigue in the major large muscle groups (back of the legs, arms, chest muscles, etc.) and that burning lactic acidosis feeling, none of which has improved at all in a number of years since it happened.

    So with all these episodes, I understand now that the glucose or related sugar metabolism is somehow an integral part of the CFS. The improper glucocorticoid withdrawal, the GSE episode, and the juice episode all clearly point to some defect somewhere in cell energy metabolism, whether the electron transport chain or somewhere in the krebs cycle, or both. Impaired or damaged liver glycolysis and those kinds of reactions are probably also involved. Co Q-10 as you know is an intermediary between one or more of the ETC complexes, and I believe that was dsyfunctional somehow from the sugar metabolism derangements, which was restored again by application of the Co Q-10. In other words, even though I don't understand all the complex biochemical functions going on at that level, I think it was more a case of providing the energy co-factor that was depleted/impaired in some way rather than a purely anti-oxidant effect of the Co Q-10. Based on that result, I tried NADH, and even a small amount, like 1mg. really messed me up cognitively for a while, with bad ADD-like symptoms, brain fog, etc.

    So that is why I say - in my case, at least, although I would find it hard to believe that it wasn't a common mechanism in many cases, at least partially - the neuro-steroid system and receptors, HPAA dysfunction, the effects of those systems on the glucose/sugar and energy metabolism, are an integral part of the disorder independently of GSH, or perhaps with GSH dysfunction as a more "downstream" or symptomatic effect.

    I know this must be the case, because, as I mentioned before, after the initial CFS happened from the improper steroid withdrawal, a couple of years later the "chronic fatigue" was completely alleviated for about 4 days following a neurofeedback session. Did the neurofeedback electrodes suddenly inject glutathione into my body through where they were attached on my head? Obviously no. It seems, therefore, that the neurobiology -- the neurohormonal function, neurosteroid function, etc. -- is primarily what is driving the whole phenomenon, and that by altering that environment it is possible in some cases at least to remove that "block" by restoring normal brain function. The neurobiology appears to control it all, including the immune function. In fact, the alpha adrenergic receptors are intricately tied to glucose metabolism, as well as many brain enzymatic systems, glucocorticoid receptor systems, and so on. I think the NMDA receptors are probably involved, too.

    Anyway, that is my experience. If I get stem cells, half-jokingly I think I want them to be injected directly into my brain. But I think that is controlling most of the CFS phenomenon, including the supposed "blockages" in methylation cycles, krebs cycles, etc. Along with toxins, undoubtedly, but I doubt that is the whole story. The brain is "telling" these systems to be dysfunctional for some reason. Most likely because it has been put into that state either by some sort of emotional stressor (which obviously affects the HPAA, transmitter and neurohormonal systems), a viral implication or immune activation (which also signals the brain in whatever ways the immune system interplays), or some other trauma possibly in many cases leading to the shift in redox regulation and proposed resulting oxidative stress loops, peroxynitrite, etc. (which I think Dr. Pall theorizes could also signal through the NMDA complex). Otherwise it doesn't make sense why you couldn't just pump the person full of IV antioxidants, including IV GSH, which I have had (along with high doses of NAC), quench the radicals, and restore the redox balance. Something else is driving it and keeping it going.
  5. richvank

    richvank Senior Member

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    To Mr.Kite

    Hi, Mr.Kite.

    O.K., I see that your history is quite complicated. I think it could be sorted out, but it would require analysis of a detailed chronology and some metabolic testing, and would involve substantial expense.
    I think your plan to get the Vitamin Diagnostics methylation pathways panel run, which you expressed on another thread, is a good one. Checking out your methylation cycle is probably the most cost-effective way to go. I think it is likely from what you've reported that you will turn out to have a partial methylation cycle block.

    With regard to injecting stem cells into the brain, some of Dr. Cheney's patients are starting to get intrathecal stem cell treatments now, and that's about as close to the brain as you can get without poking right into it, so your idea is not far-fetched at all!

    Best regards,

    Rich
  6. kurt

    kurt Senior Member

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    How quickly did your CFS resolve after the neurofeedback session? Did that happen immediately, or take a few hours, or a day or two? Neurohormonal problems add stress and probably deplete glutathione. Neurofeedback might have temporarily relieved a stuck neurohormonal problem. If that happened then over a few hours you might have lowered oxidative stress levels substantially, and maybe even 'unblocked' your methylation cycle temporarily.
  7. jeffrez

    jeffrez Senior Member

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    It was immediate, the same day. Then it persisted a few days until the clinician had me train again, and then it "broke" again and never recovered again after that.
  8. Gerwyn

    Gerwyn Guest

    i am sorry i,m araid that i,ve heard that a number of times.Did it help with any other symptoms at all
  9. Cloud

    Cloud Guest

    I need to research TGF B1.....I didn't have that lab done. But my IL 1B, 6, & 8, as well as TNFA, GMCS, RnaseL and elastace were off the charts high.
  10. richvank

    richvank Senior Member

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    Hi, Cloud.

    With regard to treatment of hepatitis C, you might want to read the paper by Dr. Burt Berkson. It can be found here:

    http://www.tbyil.com/berkson.htm

    There have been some papers suggesting that methylation of some genes can be affected by the hepatitis C virus. As far as I know, there is not a general suppression of methylation capacity in hepatitis C, as there is in CFS, but the methylation, for example of tumor suppressor genes can be increased, causing hepatitis C to be associated with the development of liver cancer in some cases. If you go to PubMed and type "hepatitis C and methylation" into the search box, you will be able to read some abstracts of papers about this.

    Best regards,

    Rich
  11. PoetInSF

    PoetInSF Senior Member

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    That's right, it's all self-reported, at least till we have a objective diagnostic marker. Till then, anybody who claims CFS other than accepted criteria/ diagnostic guideline, such as "walking must produce PEM in CFS patients", are nuts.

    I don't know whom/what you are referring to. You report symptoms, but you still need to go through battery of tests of exclusions. That's how you got diagnosed after all, right?
  12. jeffrez

    jeffrez Senior Member

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    There is no "battery of tests" for someone who claims to be hearing voices, or who says they are depressed. They give them an anti-psychotic or SSRI, and that's it. They might run a basic metabolic panel, and that's usually the extent of it - unless the person becomes floridly psychotic or something like that, where they might run a brain scan or EEG or something looking for tumors or seizures. They simply take the person's word for it -- even though, by the doctors' own admission, the person is "psychotic" or depressed. They take the word of a psychotic person at face value.

    Strange how they don't take a non-psychotic patients' word for it in the same way when it's CFS and the patients say they are massively fatigued and can barely get out of bed for months at a time. And no, I do not have a CFS "diagnosis," since you raise that point. That's exactly what I'm saying. They blame the fatigue on everything else BUT the disease, whereas the exact opposite occurs with any other "psychiatric" complaint a person makes.

    In fact, in my own case, when the primary doctors all referred me to the psych-docs, the psychiatrists have been all too willing merely to say "depression," "anxiety," etc. without running *ANY* so-called "tests of exclusion," even though I have Hashimoto's disease and am massively hypothyroid, which can cause all kinds of secondary psychiatric symptoms, including depression and anxiety. So UNLIKE a person who claims to be hearing voices, the doctors do NOT observe the same standard when it comes to people who claim to be fatigued and have PEM.

    So it's a hypocritical double standard. In the one case, when it's supposedly a "psychiatric" disease, they will take the patients' word at face value: "I feel depressed." "Okay, you are depressed." "I hear voices." "Okay, you are psychotic." When it comes to CFS, though, they don't do that. "I am fatigued." "No, you are just depressed." That's a double standard, and it's also very poor reasoning and self-examination of those poor reasoning skills on the part of the mainstream medical establishment. They aren't being consistent in their diagnostic approach.
  13. PoetInSF

    PoetInSF Senior Member

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    If you have Hashimoto's, you can't possibly have the diagnosis of CFS (yet). You have to treat it first and see what happens regardless what you claim. Any doctor who does otherwise is malpracticing. It's not double standard, it's just a good medical practice.
  14. jeffrez

    jeffrez Senior Member

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    I had CFS way before I had hashimoto's. But I'm not going to waste any more time arguing with you. CFS patients are treated differently than other patients. It's the way it is.
  15. Dolphin

    Dolphin Senior Member

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    PACE Trial

    http://www.biomedcentral.com/1471-2377/7/6

    I think that makes sense.

    The thing is that what they've written is a bit misleading and they've misled you.

    They talk about symptoms being measured. However, if one looks closely, the symptoms being measured are "fatigue symptoms" - they use a fatigue scale. So they don't measure various other symptoms associated with CFS.

    With regard to disability, they only use actometers at the start of the trial. When they were initially applying for funds they were using them at the end to see if people improved or not. They decided to drop them.

    Now they are just using the SF-36 physical functioning where 40% of the questions ask about ability to walk. If people are going for a walk, but reducing other activities so aren't doing more steps in total on average, they can come up as being improved when they aren't really.

    The people who do the pacing leg probably won't push themselves in the 6-minute walking test. While the people in the exercise leg and CBT based on exercise leg will likely want to show what good people they are and push themselves. The 6-minute walk test isn't going to involve any blood tests or gas levels.

    Anyway, if you want to discuss this further, feel free to copy my message to another thread on the PACE Trial like: http://www.forums.aboutmecfs.org/sh...ooper-s-letter-to-MRC-Clinical-Trials-Manager and discuss it there - this thread has gone all over the place and I imagine most people have given up on it.
  16. HowToEscape?

    HowToEscape? Senior Member

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    This seems to be a cross conversation, using similar terms to mean different things.

    The disease being discussed here includes, at a mininum, several physiological components and is in no way exclusive of thyroid malfunction. Said malfunction must be remediated to the extent possible before the diagnosis can be applied, but many with this disease developed Hashimoto's concurrently. This is not suprising; we're discussing an immune system disorder.

    By contrast, the term "CFS" is often used to mean a quite different condition or conditions; in one usage it means "patient reported fatigue for a prolonged period in the absence of any measurable physical pathology". That sense excludes the disease being discussed here. A disorder which exists with normal blood pressure regulation, blood oxygen, immune sytem activity and responses to exercise is a different animal than what's being discussed here, no matter if it is given the same or a similar name.

    Part of the difficulty is that with limited reasearch there has not been a widely organized effort to define the disease or diseases which produce the set of symptoms we're discussing here, effects vary among different people who have either the same or similar diseases and an individual's symptoms vary over time. The conflicting uses of the same terms greatly exacerbate the problem.

    You could inquire at one of the few practices specializing in the disease group being discussed here - I'll call it M.E. - and get a feel for the physical markers which exist. I am aware ofno one, definitive and universally accepted test for M.E: it is not well understood and outside the few physicians having practices with many such patients it is hardly understood at all.
  17. jeffrez

    jeffrez Senior Member

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    Excellent post. What we're dealing with is the ignorance of the medical and scientific community, and then we're being chastised because we aren't conforming to their ignorance.

    If a person had leukemia or some other cancer, it would be ludicrous to say they didn't have cancer because they also had hashimoto's, or depression, or some other disease. But because of their ignorance in knowing what CFIDS is, they do say that when you have CFS and some other disorder. Sometimes (usually?) they say it even when you *don't* have the other disorder (e.g., depression, i.e., misdiagnosis). But saying you can't have CFS as long as you have anything else is actually part of their definition! That's how whacked out and wrong they are, saying you can't have CFS if you have anything else and all their "diagnosis of exclusion," b.s., which is just a cover for their own ignorance and of course is totally ridiculous.
  18. gracenote

    gracenote All shall be well . . .

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    For the purposes of research studies, though, I think excluding other conditions is necessary. Isn't the Fukuda basically a definition created for research purposes rather than for clinical diagnosis? Maybe someone can enlighten me on this.
  19. HowToEscape?

    HowToEscape? Senior Member

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    Thanks. It's very frustrating: I like to make good use of language, but now cannot assemble more than a few bits of information and express them in choppy fashion. What I said above can be said in fewer words to more forceful effect, but I had to settle for getting something written at all.

    O/T: I may have to do an elevator speech on "what is CFS" - including discarding the jello-phrase "CFS" and need to be factually correct. I've been diagnosed by a competent specialist (Dr. Enlander) but haven't had the expensive tests such as cytokines. I'm not aware of exactly what other tests are recognized by specialists or are common in the cohort, but have read that blood oxygen, some aspects of blood transport and mitochondria function anomalies are well correlated with this cohort.

    I do *not* want to just babble out "something I read on the internetz", if I say something is "known" that it needs to be known and accepted by people like Dr. Cheney, etc and to state that it "appears" then there should be clinical evidence and patient experience behind it. "I think so because I read it somewhere, and although I can't afford the test I think that is happening with me because, ah, well it's on the net" is not the right tool for this job.

    SO, is there a short list of physiological processes I can use to explain "what's this weird thing you have?" to someone who asks, although I haven't had the expensive tests done in research but not covered by insurance?
  20. jeffrez

    jeffrez Senior Member

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    Hi gracenote - I'm unaware of the origins of the Fukuda criteria, but I think it's generally pretty common practice to exclude people with so-called "comorbid" diseases from the study of most illnesses, not just CFS. Probably there are cases where researchers might want to study one or more disorders that commonly arise together, most often probably in psychiatry (anxiety + depression, OCD + schizophrenia, etc.), or maybe complications of AIDS and things like that, but as a rule I think researchers tend to want to isolate the problem under study as much as possible just as a basic practice or even tenet of good science. I think it's commonly said, however, that CFS is a "diagnosis of exclusion" clinically, and that's mainly what I was referrring to, at least.

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