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A neuro-immune model of ME/CFS.

Discussion in 'Latest ME/CFS Research' started by asleep, Jun 22, 2012.

  1. Mula

    Mula Senior Member

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    Our collection use of terminology is failing. Fukuda, Ramsey, Oxford are only diagnostic criteria and the other studies are independent processes in isolation. Kindling is not a mechanistic model either and could never be tested later. Morris Maes have a complete mechanistic explanatory model. There is no doubt this is the only one.
    girlinthesnow likes this.
  2. Enid

    Enid Senior Member

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    No doubt yet.
  3. Mula

    Mula Senior Member

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    As you say rather succinctly, as further papers emerge it will be seen to flex or fold. It should at least generate may years of research.
  4. richvank

    richvank Senior Member

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    Hi, Mula.

    If you're willing to consider models not yet published in peer-reviewed journals, I invite you to view the video or check the slides by clicking on the blue print under the video at this site:

    http://iaomt.media.fnf.nu/2/skovde_2011_me_kroniskt_trotthetssyndrom/${weburl}

    The model described is comprehensive, mechanistic at the biochemical level, and explains the symptoms and biochemical abnormalities in ME/CFS. The seminar on this video goes into considerable detail and runs over three hours long in three parts.

    Best regards,

    Rich
    justy, Jenny and ukxmrv like this.
  5. JT1024

    JT1024 Senior Member

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    RE: Relapsing and Remitting....

    At this point in my life, to describe my condition as "relapsing and remitting" is a joke. However, I was not always like this. Given what I experienced many years ago, relapsing and remitting may not be the best choice of words. Waxing and waning isn't much better. My experience has been more of the frequency, distribution , and amplitude of my pain and fatigue .I can say I've had two days in the last 20 years without pain and fatigue. However, my pain, fatigue, and spasms have greatly increased in recent months.

    For several years, while I can not do anything like I could before, my life was more "normal" than it is now. Many had difficulty thinking I had anything wrong with me because I looked and "acted" normal when I was out among non-ME/CFS/FM people.

    Where I had been very athletic in the past and loved to swim, snorkle, scuba dive, ski, play tennis, bike, hike, sail, etc, I haven't been able to partake of any of these activities for years. My hands have long lost their ability to grasp anything securely so I am dangerous to others if I have a tennis racket or golf club in my hands. Given my balance and dizziness, hiking has been out of question. I miss my old life!

    Basic walking and stair climbing are a challenge. When co-workers actually see me struggling to get up stairs or walk, most are shocked. If I'm on even ground, I do much better and my restictions are less noticeable. After any prolonged sitting or after sleeping, I am at my worst.

    What I find most disturbing is that I've become too much of a recluse. Isolation and loss of hope is not good for any of us. I believe that any of us without any support and understanding from outside/beyond online forums is especially vulnerable.

    P.S. I'm very tired so I hope I don't have too many typos. If I've made an error, please let me know so i can correct it.
    leela and ukxmrv like this.
  6. Mula

    Mula Senior Member

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    Terminology issues again, but relapse and remission is waxing and waning.

    Rich you did say that you are working on what could eventually be a model, but that it was not not finished. I have edited the beginning of your comment to the start of that. How do you think you might explain PEM?

  7. justy

    justy Senior Member

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    Hi Mula, i do believe that remission and relapse are not the same terms as waxing and waning. I like others on this board had some years of very improved health, which i would call a 'remission' with a relapse at a later date into another phase of severe and chronic ill health. Within my latest 4 year relapse my symptoms do wax and wane, but on the whole i am now at a baseline of poor health.
    All the best, Justy.
  8. Mula

    Mula Senior Member

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    Wax and waning which I would argue to be the same as relapse and remission can still be present with a baseline. Could also say bad day good day.
  9. justy

    justy Senior Member

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    Hi Mula, i was trying to differentiate between good day bad day and the idea of a long sustained remission for months or years. This is what is meant by remission, not just the occasional good day.
  10. Mula

    Mula Senior Member

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    I would say relapsing remission is for a long and short temporal duration. PAR being another additional complexity.
  11. richvank

    richvank Senior Member

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    Hi, Mula.

    I think that PEM results from one of these two possibilities:

    (1) damage to the mitochondria that is caused by the increased oxidative stress that occurs when more demand is placed on the dysfunctional mitochondria than they are in condition to meet. It then takes time to repair this damage.
    Dr. Howard at Acumen Lab has observed damage to the mito membranes by electron microscopy. Prof. Garth Nicolson has had success in supporting these membranes with liposomal phospholipid supplementation.

    (2) it takes time to replace the ribose that is lost when ATP is driven too far down, i.e. to ADP, then to AMP, then to adenosine, then to inosine and lost from the cells. The cells have to rebuild the ATP from scratch, and synthesis of ribose is slow, because the cells are now depending heavily on glycolysis to make ATP, and the pentose phosphate shunt is downregulated to emphasize the main glycolysis pathway. This is basically the argument from Dr. Sinatra, which Dr. Myhill has adopted. This would be the basis for the observation that D-ribose supplementation can help.

    Perhaps both these mechanisms contribute.

    Best regards,

    Rich
  12. biophile

    biophile Places I'd rather be.

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    Ecoclimber,

    I think some of Asleep's arguments (on the other thread) are interesting, but I also think that Lipkin is one of the best people for the job and I'm glad to have him on board. Even Mikovits trusts Lipkin. However, some people became suspicious of him largely because he was appointed by people they do not trust, in a possible attempt to purposely debunk rather than investigate. I guess that may sound paranoid, it is not a view I really share and I'm not defending anyone in particular, but one I believe is totally understandable considering the history of NIH/CDC with ME/CFS. Patients have been ill a long time, largely due to government bungling, their livelihoods are depending on it and they will do what they think it right to secure answers, including casting serious suspicions on government sanctioned actions.

    Fair enough, if you are appealing to the authors' credentials rather than the validity of the content, but this can be just as misleading as inaccurate statements made by unqualified authors. I've learnt from reading too many biopsychosocial-orientated papers on CFS that nothing can be taken at face value and every citation is potential room for spin or even blatant errors. I wonder if a similar problem exists in the biomedical-orientated papers as well, but either way, I find it much more difficult to rely on peer review and qualifications. Peer review seems to be little more than a "paradigm gate" and glorified spell checker. Credentials never stopped the PACE Trial from being promoted as the highest grade of clinical evidence on par with well-conducted drug intervention studies (despite being unblinded) and qualified professionals erroneously claiming 30%+ recovery rates. "Endless rounds of peer review" didn't spot flaws or errors, meanwhile "unqualified" people did. However, one could argue that qualifications are more important for conducting and interpreting biological research, but even then, when recombinant contamination goes undetected in cell lines for over 10 years, people naturally wonder what else is going undetected.

    It is impractical to examine every single paper and citation for ourselves, so at some point we do have to place a degree of faith somewhere, and I can understand your reluctance to trust Morris' word based on your previous impressions of experiences with him.

    I have not examined the paper much yet but I've also seen criticism towards the paper for selecting and speculating about unreplicated research which favours the model. As if that isn't common in just about every review paper published on ME/CFS? It isn't a systematic review. Personally I would rather base a model on more evidence, but this is difficult because of the heterogeneity of ME/CFS, so at some point we have to chose what we think it correct and go from there.
    Sam Carter, justy and OverTheHills like this.
  13. jace

    jace Off the fence

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    This paper is not a 'last word' an end, final and complete. It's a step along the road, and suggests avenues for further research, and gives another way of thinking about the illness, not a totally unique one, that's for sure. What's the difference between Morris/Mae's cascades, and Jason's kindling, for instance? Perhaps they are talking about the same process.

    It did undergo rigorous peer review, more so than papers from those with millions of government money behind them, of that I am sure. It is what it is, time will tell how important it is to the general direction of research.

    The paper was written purely with voluntary effort - I started with Ger in November 2010, and Victoria took over from me when Ger broke my brain :confused: .

    Gerwyn has two BSc's, as I understand it, in Biology and Biochemistry, and he may by now have his PhD. I am sure, absolutely certain, that he would have had a doctorate years ago if he hadn't become ill with our dread disease. However, it is irrelevant what quals he has, we know more about the two authors of this paper than we do about many of the luminaries in the field. One thing's for sure, their motivation was not money!

    The politics has nothing to do with this paper. It stands or falls on its own merits. People are welcome to scrutinise the relevance of the references. I hope it will be a useful contribution to the debate.
    dannybex, Bob, justy and 3 others like this.
  14. JT1024

    JT1024 Senior Member

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    The quote below was posted by a guy who was cured of stage 4 renal carcinoma through treatments he learned about from an online patient forum.

    "there is an old saying in China- 久病成良医,
    which means prolonged illness makes the patient a good doctor."

    I think it is quite appropriate given the level of knowledge a number of patients have acquired since becoming ill. I can think of several who could interact on a professional level with some of the top researchers.

    Another quote I like is
    As iron sharpens iron, one man sharpens another". Proverbs 27:17.

    There are MD's and PhD's who are quite ignorant. There are also those without advanced degrees that can run circles around them. Credentials help in determining a person's baseline of knowledge but that doesn't ensure competency. I believe Gerwyn has degrees in law and psychology as well.

    Rather than focus on credentials, let's consider the paper as a starting point for discussion and hopefully future research and treatments.
    Snow Leopard likes this.
  15. Bob

    Bob

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    You seem to be talking about my own experiences, exactly, Alex!
    Except I've 'only' been pacing for about 5 years!
  16. ixchelkali

    ixchelkali Senior Member

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    Actually, Martin Pall does deal with those things you mention. The paper you referenced was about the NO/ONOO cycle in Multiple Chemical Sensitivities, not ME/CFS. However, if you read his book Explaining 'Unexplained Illnesses': Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, and Gulf War Syndrome,he discusses his model as it applies to each of these illnesses individually. In the chapter on CFS, he talks about post exertional malaise in some detail, because he sees it as the most characteristic symptom of CFS.

    If you didn't want to read all of Dr. Pall's book, which is extremely detailed and sometimes dense, Dr. David Bell has written a more approachable summary of Dr. Pall's model, in his book Cellular Hypoxia and Neuro-Immune Fatigue.

    I won't argue the relative merits of Dr. Pall's model vs. this new one, because I haven't read this latest one in detail yet, but I simply disagree that it's the only model.
  17. ixchelkali

    ixchelkali Senior Member

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    I have the impression that some people may not quite understand the purpose of modeling (or maybe their understanding is just different from mine :)). My understanding is that the purpose of a model is to provide a theoretical framework for the known facts. It isn't providing new evidence, it is synthesizing existing evidence. It answers "how" and "why" more than "what." It is, by its very nature, hypothetical.

    A good model explains all the known facts about the topic; it doesn't just cherry-pick the ones that fit the hypothesis. It should provide a tight, elegent explanation without gaps in logic. It should examine other possible explanations for the same group of known facts, and provide convincing arguments why this model explains those facts better than other models. A good model should be based on sound evidence, and cite the studies from which the evidence comes. And finally, a good model should be predictive and testable: it should say "If this model is correct, then when you do x study, y will be the result.

    A good model points the direction that future research should take. As that research provides new data, if the new data fits the model, the model stands. If not, the model is either scrapped or revamped to fit current knowlege.

    I got to watch this happen in my lifetime in the field of geology. We had all these facts, we had volcanoes, and earthquakes, and fault lines, and rocks on one continent that seemed to match rocks on another continent. We just didn't have a mechanism, a model that fit the pieces together. Then when the theory of plate tectonics was proposed, the pieces fell into place. Those who had proposed other models objected loudly at first, but mostly there was a kind of collective "aha!" among geologists as they could see how it explained more and more pieces of data. And then as new studies were done and new technologies were developed, they confirmed the predictions of the model.

    I haven't looked at this model in detail yet, so I have no opinion as to how good it is (and I'm too brain-fogged right now to do it). I do think that the answer to ME/CFS probably lies in this direction, though. Most of the other theories are too "blind men and the elephant"; they don't explain the whole thing. I don't know whether the whole neuro-immune, nitric oxide, ATP, mitochondrial thing is causal, or just the mechanism that produces the symptoms from another preceeding trigger. But I think we need to be looking at these positive-feedback loops and cascades.
    Sing and jace like this.
  18. Bob

    Bob

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    My understanding is that the paper proposes a hypothesis, based on a review of published literature. I haven't read the paper, but all the literature would referenced, such that anyone can look up the details for themselves, and come to their own conclusions. With the PACE Trial, we don't trust the authors, so we have studied the data tables to do our own analyses, and we have put in Freedom of Information Requests to try to get further data. Unless there was outright fraud going on with regards to recording the data, then we can analyse the data, and interpret the results, for ourselves. But with this paper by Gerwyn, none of the cited information is original, because all the information is already published, and so everyone can judge the quality and integrity of the study for themselves. The qualifications of the authors are irrelevant. As someone said earlier, this paper stands or falls based purely on its merits.
    Enid, biophile and OverTheHills like this.
  19. jace

    jace Off the fence

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    I know Ger has spent some most of his time since being ill studying. For all I know he may have been obtaining further knowledge and qualifications with the Open University, a rather fine institution, here in the UK.
  20. maryb

    maryb Senior Member

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    Doesn't a research paper stand on its own merit? surely that should be the focus for those who are interested, its not about the author's qualifications. What's with this persistence on needing to know more about people? I don't, and no I'm not under any 'spell'. And please don't put down the Open University, it has been a godsend for motivated people who work full-time and want to study, as well as sick and disabled people in the UK who otherwise would have been unable to study in a traditional university setting.
    Sing, justy, jace and 1 other person like this.

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