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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. Gerwyn

    Gerwyn Guest

    all get studies are irrelevant get does not lead to any increase in overall activity levels merely substituting an increase in one area at the expense of decrease in another
  2. Gerwyn

    Gerwyn Guest

    walking off pem is a contradiction in terms if you have objectively measures pem.some people are given a diagnosis of CFS without having PEM-This kind of diagnosis is highly questionable
  3. starryeyes

    starryeyes Senior Member

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    That's hilarious and true at the same time fingers. Sometimes things are funny because they are the truth! Can we throw in a little "like" there? CFS - Continually Feeling like Shit.
  4. PoetInSF

    PoetInSF Senior Member

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    You seem obsessed with your own definition of CFS. I'll stick to mainstream research/clinical definition till you prove otherwise. I'm also waiting for your suggestion how to objectively measure PEM.
  5. richvank

    richvank Senior Member

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    Hi, Gerwyn.

    Thanks for the response. I welcome disagreement--that's what makes the scientific world go 'round! :)-)

    I agree that there are symptoms in CFS that are attributable to mito dysfunction, for sure, such as the physical fatigue. But I also think that there are other symptoms that are caused by glutathione depletion that do not involve the mitochondria. When I first realized that glutathione is low in CFS (and there is very good evidence for that now, especially if one looks at the plasma reduced glutathione level, not just the red blood cell total glutathione, which is easier to measure but does not reflect tissue cell glutathione levels as well), I tracked down the whole list of things that glutathione is normally known to do, and it was like a roll call of things that are not being done well in CFS. If you want to see them, I've discussed some of them in my 2004 and 2007 poster papers, which can be found at cfsresearch.org by clicking on CFS/M.E. and then on my name.

    As another piece of evidence, I would note that in our clinical study, in which we treated to lift the methylation cycle block, so that glutathione rose, the patients reported significant increases in their energy levels. I take that to mean that their mito function improved from this treatment, and that would be consistent with the methylation cycle block--glutathione depletion combination causing mito dysfunction.

    As another piece of evidence, I have seen the urine organic acids test results from quite a few PWCs over the past several years, and quite a few show a partial block in the Krebs cycle after citric acid. It is attributable to low activity of the enzyme aconitase, and that is one of the enzymes that is known to be susceptible to oxidative stress, because of its iron-sulfur complex. Decreased glutathione results in oxidative stress. So that is consistent with low glutathione causing a partial block in the Krebs cycle, which will manifest as mito dysfunction. So again, I think this fits together well with the notion that glutathione depletion causes the mito dysfunction in CFS.

    I agree that mitochondrial dysfunction is a major feature in ME/CFS, but what causes it? I don't think that either Dr. Myhill or Dr. McLaren Howard have come up with an explanation for that. The treatments given are partly substances that require methylation for their synthesis (such as Co Q-10 and carnitine), and I think that also points back to a problem with the methylation cycle, which is linked to the glutathione depletion by a vicious circle mechanism, which is what makes this disorder chronic, in my opinion. My point is that I think the pieces fit together well in this hypothesis, and I haven't heard of another comprehensive hypothesis that fits the evidence as well. But I'm certainly open to the possibility.

    Best regards,

    Rich
  6. Gerwyn

    Gerwyn Guest


    NO i,m obsessed with The correct diagnosis of ME so we can escape the psychiatists trap.PEM is crucial to that.it is measured objectively by measuring excercise tolerance in a person 24 -48 hours apart.You can stick to whatever diagnostic criterea that suits you but no PEM then the illness is not ME. The only diagnostic criterea that makes PEM mandatory are the Canadian Consensus Critera.XMRV has been discovered in patients that meet the Canadian criterea but has not been in patients who dont meet said critera. Other diagnostic criterea either exclude patients with ME or are unable to differentiate btween the fatigue caused by ME and chronic depression or both.
  7. Gerwyn

    Gerwyn Guest

    Hi Rich,

    I agree that glutathione depletion is a major player.I was convinced after our initial correspondence. I have somwhat the same question as you asked.What causes it?Post exertional malaise/excercise intolerance is a characteristic feature of ME/cfs.It is also a characteristic symptom of mitochondrial dysfunction. Elevated Nitric oxide(for long enough) would cause GLU depletion and direct mitochondrial damage.XMRV has been found inserted within the start sequence of a CREB gene.

    CREB/cre is involved in the activation of the IFNalphabeta gene by interferon following a viral infection.An upregulated IFN gene would lead to a level of NO which is able to overcome the negative feedback loop between iNOS and TGFbeta-1. This would give rise to the depletion of TGfbeta1 observed in ME and facilitating the T1/T2 shift in the immune system and the decrease of Il1.The CREB/CRE transcriptional regulatory system is also involved in the manufacture of crucial enzymes in the methylation cycle. Sorry this is rough I,ve been meaning to discuss this with you for some time.Gammaretroviruses can also act as transposons(mobile gene switches) which could (theoretically) account for the different symptom patterns that patients with ME can experience at different times during the course of their illness.I,m trying to put a schematic together for discussion but(as you know )my presentation skills leave a little to be desired!
    Nice to speak to you
  8. jeffrez

    jeffrez Senior Member

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    How do you "objectively measure" that someone is hearing voices, or hallucinating?

    You don't. You ask them, right?

    Why the bad faith for people with CFS when you are more than willing to take the word of a psychotic person about THEIR symptoms?
  9. jeffrez

    jeffrez Senior Member

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    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.

    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.

    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 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!
  10. cfs since 1998

    cfs since 1998 *****

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    Glutathione

    HIV causes glutathione depletion. In fact glutathione begins to drop within a matter of 1 to 2 weeks after initial infection. So if XMRV causes CFS I think it would explain glutathione depletion, assuming retroviruses in general can cause glutathione depletion. Of course glutathione is important for immune functioning and can also inhibit the virus, so raising GSH ought to help, although how much it helps is questionable. Trials of NAC in HIV haven't been too impressive as far as viral load or immune functioning are concerned, but it did normalize GSH levels which is probably not a bad idea in and of itself.
  11. cfs since 1998

    cfs since 1998 *****

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    By the way I do not believe this thread ought to be in the "Latest Research" subforum because it isn't research, it's published speculation.
  12. Gerwyn

    Gerwyn Guest

    i think we need somewhere where research published in seperate papers can be drawn together and commented on.Individual papers posted on a forum dont really do that and it is difficult to see an emerging picture developing.In the absence of a specific subforum it would seem reasonable to discuss research here with the aim of integrating seperate oten disperate biomedical perspectives.Presenting latest research may not help people without the scientific backgrounds to be able to understand and draw conclusions from the information available.that of course is just my opinion.
  13. Gerwyn

    Gerwyn Guest

    the point is how hiv causes glutathione depletion
  14. Dolphin

    Dolphin Senior Member

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    I'm somebody who is fussy on what is in the "latest research" section. But generally I think if it comes up in PubMed (or a similar database) under "Chronic Fatigue Syndrome", it should go here as otherwise it might be hard to find such papers.

    I certainly don't think that if it is in the "latest research" section it means it is being recommended.
  15. cfs since 1998

    cfs since 1998 *****

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    The thread was started for the Medical Hypotheses paper.

    It's not research, nor is that journal peer reviewed. I see your point about it being hard to find otherwise. Oh well, I said what I wanted to say and that's that. If the consensus is to leave it here that's fine.
  16. Hope123

    Hope123 Senior Member

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    Re: TGF-beta-1. I did a review of the few papers on this (less than 10) and a number actually showed increased levels of TGF-beta-1 in people diagnosed with CFS. There was 1 or 2 which showed no difference between CFS and healthy controls.

    I have several issues with the papers that have been out re: glutathione and methylation support. Call me simple but theories only go so far with me; I need clinical data. I have questions about the analysis and validity of the tests used but I will reserve those for when I have more energy.

    One question I particularly had was about the sponsorship of Rich's paper. It was funded "anonymously" and also by a group called the "Ratna Ling Working Group." I have not been able to find out who is in this group or what it is about. When reading a paper, one of the first things I do is look to see where the paper is from and who funded it as it may or may not impact how the study is conducted/ interpreted,etc. It is also common requirement in many journals and conferences to disclose funding resources and sponsors.

    (Indeed, pharma studies often have an overly favorable bent towards their drugs. The negative studies? Never published/ hidden away until people are harmed, pharma gets sued, and the news ends up in the New York Times.)

    (It's the same thing with the CAA CFS Biobank; while I like this idea, they should have disclosed that a sponsor was Glaxo Smith Kline. Dr. Lapp was clear in his announcement who were the sponsors.)
  17. richvank

    richvank Senior Member

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    Hi, Hope.

    I can understand your interest in finding out who sponsored our study. I look for the same thing when I read a paper.

    I have promised to keep the name of the anonymous donor in confidence at the donor's request, and I must respect that promise. I was given permission to acknowledge the Ratna Ling Working Group. I can tell you that there is no pharma involvement, no supplement company involvement, no one involved who stands to make money from the results of our study. I think the people were just motivated to try to figure out CFS, though of course, there is always some competition of ideas. The existence of this group is not a secret, but it has not been publicized very much, I think in deference to those who were not invited to join it. Basically, someone handpicked a small number of researchers and clinicians who specialize in chronic fatigue syndrome, and invited them to come together for a couple of seminars. A small number of cooperative research projects were developed and sponsored by a donor who requested to remain anonymous. Some of the members of the group asked that their participation not be revealed because they were in sensitive positions politically at their institutions or agencies, so I am not at liberty to give you the names of the participants. However, I don't see a problem with mentioning some who have spoken or written publicly about their participation: Paul Cheney, Ritchie Shoemaker and Jacob Teitelbaum. Dr. Nathan and I were also fortunate to be included in this group. As time went on, there were additional seminars for Lyme disease, autism, and autoimmune disease. I also participated in the Lyme disease working group. The hope was that we would be able to understand the connections between these disorders. I think we all still have a long way to go to do that.

    I think there has been a beneficial exchange of views between the people in this working group, and this exchange is ongoing, though the face-to-face meetings have stopped. I can't say that everyone in the group is in agreement on very much, but at least there is communication, and I think that's a good thing. There's nothing nefarious about this. I think it's just easier for people who may have fairly large egos (myself included!) as well as reputations to defend and a lot at stake, to meet together privately rather than publicly to air their views and possible disagreements. It's easier to risk looking like a fool if there aren't too many people around when you do it. In the long run, I think this working group effort will be beneficial for the CFS community as a whole. The study I participated in (which you can read about at www.cfsresearch.org) was made possible by the existence of this working group.

    I realize that things done in private meetings always cause people to wonder what is being hidden, but in this case, I don't think anything has been hidden. I have noticed that the other members of the group have not been bashful about speaking publicly about how they disagree with my thinking, for example. If you caught Dr. Cheney's talk in Virginia a while back, he was very clear about how he disagrees with me, and that's O.K. We need to be able to communicate and disagree if necessary. That will move things ahead faster than if people don't communicate at all. I've learned a lot from Dr. Cheney. Some of the members of the working group had never actually met and talked with each other, though most had been involved with CFS for many years, so I think that just bringing them together and having them sit down and eat meals together and exchange ideas was a good thing.

    I guess that's basically it. If you want to know more about my involvement, I can tell you about that, but I don't feel at liberty to "go public" about people who as far as I know have not done so themselves, or people who specifically asked to remain anonymous.

    I hope that helps.

    Rich
  18. Gerwyn

    Gerwyn Guest

    Cytokine dysregulation might be an important factor involved in the
    pathogenesis of CFS [29]. Tomoda and colleagues showed that production of
    TGF-beta1 protein was significantly depressed in patients with CFS and that
    serum levels of IL-10, IL-18, IL-4, TNF-alpha, IFN-gamma, and IL-6 were not
  19. richvank

    richvank Senior Member

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    Hi, Gerwyn.

    I think your ideas are very interesting, and I am going to have to do some studying to get my brain around them.

    I, too, have some concerns about TGF beta-1 in your argument, though. In our clinical study on women who had CFS and FM, we found high values of TGF beta-1, rather than low.

    I know that Dr. Ritchie Shoemaker also finds high values, as do some of the other clinicians. There's always the question of how representative each cohort of patients is of the entire CFS population, but there are a lot of high values of this parameter out there.

    Rich
  20. Gerwyn

    Gerwyn Guest

    I have only seen one study using ccc and they found underexpression of the TGF alpha gene. I,m really talking about the coregulation between tgf alpha gene and i Inos .I will dig up the relavent info along with CREB/cre regulatory systems involved.It will probably take me a couple of days I will post it and you can look at the refrences at your leisure(I could be completely wrong of course)

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