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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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    Pal lists observations not unique to MECFS and does not give a detailed explanation of how those levels are first elevated. Secondly Pal does not deal in any way with PEM, exercise intolerance, the remitting relapsing nature, autoimmunity, NK cells, CD69, TNF alpha. Pal's paper is not a model.

    The Morris Maes paper is the only published model for MECFS, and describes several new components that have never had a mechanistic explanation even in isolation. Work that does not explain the whole picture is not a model.
     
    jace, August59 and Enid like this.
  2. JT1024

    JT1024 Senior Member

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    Glad to see Gerwyn's work published (Copyright here: http://tinyurl.com/7smrfcf )

    George, glad to see your comments too! This is not easy stuff to understand.
     
    Sing likes this.
  3. richvank

    richvank Senior Member

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    Hi, Countrygirl.

    I was not able to find the full paper on the other forum. Will you please email it to me at richvank at aol dot com?
    Thank you.

    Best regards,

    Rich
     
  4. jeffrez

    jeffrez Senior Member

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    Pall's paper and other work make it clear that the conceptual framework he is working with is a common etiology for many disorders, many of which have no explanation, including CFS & MCS.

    And once again, Pall *does* explain how the levels become elevated. I just posted those reasons. It's really not much use discussing things with someone who says "there's no explanation for how the levels become elevated," when I have just quoted the author listing at least a dozen ways they become elevated! Further, Pall does deal with PEM. PEM comes from the ramping up of the peroxynitrite loop (which actually appears to be the source of the idea that the PEM results from the O&NS that's "borrowed" from Pall here). So I'm sorry, but your comments are inaccurate again.

    Would like to read the entire Gerwyn paper b4 commenting further, but I see no mention in the abstract of adrenal fatigue, cortisol irregularities or HPAA dysfunction, unless subsumed under the vague "autonomic disturbance" - which to me would seem rather to indicate OI and POTS. So by your very own standards, it's not a complete model.

    Iow, what you fail to see is that you are jumping to the conclusion that it is a "complete model" just because you want to believe it's a complete model. In reality, it's all speculation anyway, and there may be many other actual components or mechanisms at work that aren't accounted for in their "complete model." Your POV is biased and prejudicial. It's like when XMRV was all the rage, with no confirmatory evidence, and anyone who suggested that it wasn't yet proved and didn't seem likely was castigated for not jumping on the bandwagon. Nothing in this "model" is proved, either. It's merely a conglomeration of SOME observations in ME/CFS with a theoretical "explanatory" model constructed around those observations. That model is not taking into account things we don't know yet, and therefore is to that extent incomplete and merely theoretical.
     
    Jenny likes this.
  5. George

    George waitin' fer rabbits

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    Hey ya JT how you doin', you hot doggie you? (big grins)

    Hiya JeffRez
    It's good to see that brain of yours here and fired up. (big grins) I think you bring up a very good point here:

    This is my fault for not being clear earlier and I apologize. So let me clarify and hopefully this helps everyone.

    Hypothesis generation is an area of medicine that takes published research papers, sorts them into areas; removes papers or research that either dead ends or does not fit an overall model; generates a "theory" that can clarify the current body of knowledge and help to push the future of research into the illness or are into more productive directions.

    Hypothesis generation is not a "proof" and is not suppose to be biased but to provide a model for researchers to think about, argue with and hopefully explore in an effort to dis-prove the model, to im-prove the model or to actually try to prove the model.

    It is not meant to BE THE model or to provide any kind of proof. It's about organizing information and presenting in a way that's helpful.

    I hope that helps with the conversation here. (tail wags)
     
    ixchelkali, WillowJ, Hanna and 2 others like this.
  6. Countrygirl

    Countrygirl Senior Member

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    Hello Rich,

    I have just seen your post and have e-mailed the paper to you. If there is a glitch, let me know.

    Kind regards,

    C.G.
     
  7. jeffrez

    jeffrez Senior Member

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    Hi George, good to see you here!

    Absolutely good points that you make. As we can see, Pall's work was also hypothesis generation. ;-) In fact, without that work, Gerwyn et al. probably wouldn't have come up with *this* work in regard to ideas of oxidative and nitrosative stress. So it all (we hope) helps to move things forward.

    In the context of this discussion, I'm merely trying to clarify some of the incorrect and non-factual statements some have made that "there is no other explanatory model for ME/CFS," that other theories don't account for PEM, etc. Those statements are demonstrably false, and I think putting forth the idea that this paper represents the *only* explanatory model for ME/CFS actually hinders research into directions not covered by this paper. As you say, this paper appears to be really only a "clarification" of existing knowledge, filtered down to their own conceptual framework, and not something that is really breaking any new ground. Not to say we don't hope it can help lead to some answers.

    friendly woof! ;-)
     
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  8. Mula

    Mula Senior Member

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    Pal does not provide an initial mechanistic explanation for the few observations his paper interprets and he is not close to working out a model in which to fit only his work. The Morris Maes paper has achieved this.

    Where have you found PEM in this paper?
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1241647/pdf/ehp0111-001461.pdf

    The Morris Maes paper includes every reported abnormality you believe to not be present and all those reported in the literature, which allows for this to be the first and only complete model for MECFS and it is authentic work. I have read the paper. It is worth your time doing the same.

    A model need explain how all abnormalities interact to produce the know set of symptoms. No science ever moves beyond the theoretical. That may not sit comfortably for some, but it is the nature of all research.
     
    jace likes this.
  9. richvank

    richvank Senior Member

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    Got it. Thank you.

    Rich
     
  10. Sing

    Sing Senior Member

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    I appreciate this model and hope it will help organize researchers. Having recently listened to Dr. Anthony Komaroff's webinar, 9/16/10 for www.cfids.org, he summarizes all the validated research up to that point, which I am now seeing that this paper is pulling together to make a hypothetical model. Here is a link for the slides of this webinar http://www.cfids.org/webinar/slides-091610.pdf My iPad is not cooperating to bring you the audio link but you should be able to find it all together on the SolveCFS youtube site, as well as www.cfids.org in the Community section.
     
    George likes this.
  11. Sing

    Sing Senior Member

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    Here is the link for the recording and slides for the Komaroff review
     
    merylg likes this.
  12. jeffrez

    jeffrez Senior Member

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    First, it's Pall, not Pal as you keep writing it. Thought it was just a typo at first, but as you keep misspelling it I thought I'd correct that for you for clarity's sake.

    Second, Pall implicitly discusses PEM every time he mentions CFS. CFS is in large part defined by PEM, and the mechanism he believes is responsible for that, as I've noted repeatedly, is the NO/ONOO cycle.

    Lastly, I think you're missing the point that just b/c the M/M paper supposedly as you say contains "every reported abnormality" doesn't mean it's still complete, or that it's even accurate. It's quite possible - becoming very likely, in fact - that there are subgroups of ME/CFS, often with different predominant symptoms, different etiologies, causes, and possible treatments. Lumping everything in together as a monolithic disorder explained by a single "model" might in fact ultimately do more harm than good. At least for those who might have a subgroup of ME/CFS that's not explained by this model.
     
  13. Chris

    Chris Senior Member

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    Jeffrez, thank you for making that last point, though I would still like to read that paper. I have many of the central, "classic" ME symptoms--PENE, fatigue, OI, sleep problems, fog, autonomic dysfunction ( blood pressure disregulation,etc)--but there is another group I have not had--swollen lymph nodes, fevers, sore throat, joint or muscle pain, and a few others. I too vote for keeping definitions purposely a bit loose until things are cleared up.
    Chris
     
  14. Mula

    Mula Senior Member

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    Pall makes no connection to PEM in the article you had mistakenly believed to be a model.

    A model need explain how all abnormalities interact to produce the know set of symptoms. If one wished to construct a new model that contains the assumption of subgroups, this new model would have to include a mechanistically explanatory model of the subgroups, but this may not possible as the disease may not have subgroups. Arguably, you may only be wishing to define each individual as a subgroup.

    Models cannot be expected to accommodate research findings that have not at this time been produced, but with a model now available the strength of this can be tested in its ability to incorporate later research.

    The text does not put PAR as an different term for PENE, but as a different mechanistic process.
     
  15. George

    George waitin' fer rabbits

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    Very good points on the subgrouping. Based on the talk at June CFSAC the CDC is, for the first time, going outside of the CDC to define what is CFS. It was reported that the CDC was working with all 5 major ME/CFS groups to see if each doctor maybe working with a different subgroups and if CFS needs to be split up. For example; most of us have run into doctors that think Fibromyalgia and CFS are the same illness. However, per the Bateman/Light group Fibromyalgia, CFS and CFS with pain that does not have Fibro tender points, show 3 very distinct cytokine and chemokine signatures and are most likely different illness.

    The five groups as I understand it are
    Bateman/light - who seem to work with a lot of pain groups and per Dr. Bateman around 30% of her CFS patients are incorrectly diagnosed but are actually patients with Thyroid, Kidney, Diabetes, and Cancer rather than true CFS patients that have come to her after getting a CFS label elsewhere. The other 70% meet the CCC definition.​

    Dr. Kogolnik at Open Medicine is working with patients who have viral onset, PENE, and high IgG titers. (that may change based on what happens with the pilot study) He is looking for the group that respond to this treatment and how to define them from those who do not respond.​

    Dr. Montoya is looking a patients with high viral titers across the board and why some of the patients that he treats with antivirals get much much better while many see only mild improvements that plateau. What is the element that separates those groups?​

    Dr. Klimas is dividing out the fourth group and she is looking at high IL readings and TNF-a. She has a variety of protocols that she works with based on the individual patient but her baby or bias is immune dysfunction. Like Dr. Montoya she has about a 30% success rate (based on her talks only, not published) While other patients may respond mildly.Again the frustrating question these researchers are hitting is why only a small group are responding?​

    Dr. Karmoff is the fifth grouping. and you can take a look at the excellent link provided by Sing above for more information on his group and treatments. Dr. Karmoff was/is a huge backer of the EBV theory and recent work in Herpes virus mechanisms may vindicate him.HHV-1 and 2 cause mitochondrial damage reducing the energy that is available. ( I have the paper reference around here somewhere, I'll add the link when I find it, sorry big grins)​

    I have no clue how this will end up breaking down or how it will help with patient treatment. And it could as easily turn out that it's not subgroups at all but a lack of "complete" treatment for patients.

    A Hypothetical for instance might be sleep, which is mostly ignored by many of the above doctors, except to admonish the patient to practice sleep hygiene. (big grins) And really there isn't a lot that can be done pharmacological to help produce quality sleep at least currently.So good advice is all these docs have in their tool kit to work with. But that may change.

    There are dozens of papers that define the poor quality of sleep in ME/CFS patients. My favorite is one that Van Hoof et al which states:

    Bold is mine. Twitter version; we don't get to that deep sleep place where the body does it's healing and growing.

    If patients are not reaching Delta sleep where all healing and growing takes place, then there is a chance that no matter how many vitamins, antivirals or antibiotics we take, the body will not be able to complete the healing process. So we get incomplete results instead of a cure.

    Now there is recent evidence that TNF-a antibodies can disturb the sleep system (rather than the cycle) causing the patient to not reach the much needed Delta sleep state. Drugs like Ebrel, which is the drug that Mella and Fluge are trying on the non responders to Rituxian, work to calm the TNG-a antibodies in effect resetting the system and allowing the brain to reach Delta sleep. The hope is that it will allow the healing cycle to be complete and the non responders will then respond.

    I find their line of reasoning sound. I really look forward to the results. For the last century medicine has been about one problem, one drug and then move on to the next but it's changing. There is a better understanding that came about with AIDS that the systems are complex and interdependent and may need a more holistic approach.

    In regards to the Morris/Maes paper I can't really say if their attempt to bring everything under one umbrella is correct or not since any hypothesis needs time to be proven or dis-proven or adjusted. There is a swing among Research/Clinicians right now to go back to looking at subgrouping and that is the way the CDC is moving right now. We haven't had much success with subgrouping in the past but we have a lot more information to work with now. We also haven't had much luck with one size fit's all. (big grins)

    I'm leaning toward the Mella and Fluge approach of a tight definition, and a one two punch as a good hypothesis to try out!
     
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  16. Countrygirl

    Countrygirl Senior Member

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    I have just received you message Leela and hope the paper is with you by now..

    Is there anyone else who can't access the paper? Don't all besiege me at once though,:)

    Warm wishes,

    C.G.
     
  17. JT1024

    JT1024 Senior Member

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    Enid, anne_likes_red and George like this.
  18. justy

    justy Senior Member

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    Thanks JT - i look forward to reading it in full, when my brain feels a bit lighter. Speaking of brains, in the discussion on subsets (above) there seems to have been little talk of a subset with more obvious neurological problems, and i agree that the sleep aspect is missing too.
    all the best, Justy.
     
  19. Enid

    Enid Senior Member

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    I wonder if talk of subsets (predominance of specific symptoms) in a kind of "universal modelling" just yet. Also could they be related to the progress/particular damage sustained or ongoing so certainly to be considered/studied though. We went "the whole hog" - neurological - encephalitis - but that eases, others do not.
     
  20. jace

    jace Off the fence

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    Bob said
    Just to put the record straight, Ger had nothing to do with the 'setting up' of either of these forums (who? Ger? you are joking, aren't you?), he just moved to new homes when old homes became untenable for him. He no longer posts on forums, and maybe that's a good thing, because a lot of people take the wrong end of his stick.

    His left-brain damage has a lot to do with his difficulties in communicating. I love him, personally, as a unique human being who has wrapped his brain round the research, and taken the time to pull together a paper which may well help the understanding of our illness move forward.
     

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