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Metabolite-Detecting Gene Expression After Exercise in CFS, MS, and Controls

Discussion in 'Latest ME/CFS Research' started by CBS, Jan 3, 2012.

  1. richvank

    richvank Senior Member

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    Hi, all.

    For what it's worth, I agree with Snow and Alex that the Lights are observing downstream effects in the pathophysiology of ME/CFS. The changes in expression of these genes represent attempts by the body to respond to its more fundamental problem. They do not constitute the fundamental problem. At the Ontario conference, when this work was presented, I offered a comment about this from the floor mike during the discussion time. I suggested that the fundamental problem occurs at the biochemical level, and the gene expression changes are a response to that. This seems backwards to some people, because they know that the genes code for the proteins, which in turn carry out the biochemistry. But there is a lot of feedback between the biochemistry and the gene expression, and I think this occurs to an especially high degree in ME/CFS and autism because of the involvement of a problem the methylation cycle, which we have documented well, and the major effects that methylation is known to have on the expression of the genes. I don't know whether I was able to affect anyone's thinking, but I'm hopeful that the genome-wide methylation study underway at the CDC will shed some light on this issue.

    Best regards,

    Rich
  2. oceanblue

    oceanblue Senior Member

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    Interesting. Do you have any more info on that CDC study? It's news to me.

    As for cause or effect, you might be interested in Alan Light's reply to some questions from Cort
    So maybe Alan was listening to you...
  3. oceanblue

    oceanblue Senior Member

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    Comparison with previous studies by the same authors - no correlation with fatigue this time
    Some of the same ground has been covered by the same authors in their previous 2009 & 20011 studies, comparing CFS patients with controls (but no MS patients). Most of the genes previously identified as increasing expression post-exercise again increased expression in this study.

    However, while the earlier studies found good correlation between gene expression and self-rated fatigue and pain for most genes, this latest study only found a correlation between pain and the metabolite-receptor gene P2X4, with no gene expression correlating with CFS fatigue in response to exercise. It was the correlation between gene expression and symptoms in response to exercise that made the findings so interesting, so the lack of a correlation in this study is a concern (nb 6 of the 22 patients were the same as in the 2009 study).
  4. richvank

    richvank Senior Member

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    Hi, ocean.

    I don't have any details on the CDC genome methylation study. Virginia Falkenberg is the person who is doing it. She is alert to the possibility that the methylation deficit will have broad effects on gene expression, and will be looking for it. Time will tell if it will show up or not.

    Cort's interview with Alan Light took place before the Ottawa conference, but Alan emailed me something to the effect that we had some views in common, and that we should talk sometime. I have sent him some stuff. I have been trying to interact with the genetics researchers whenever I have been able to, because I think that the methylation deficit we have found in ME/CFS has to be important in their work.

    Best regards,

    Rich
  5. alex3619

    alex3619 Senior Member

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    Hi Rich, one of the things that should be considered is that increasing receptors might increase negative feedback on that path if the increased sensitivity sends a very large signal. This is similar to some of the comments that have been made but I think subtly different. I have been considering this in other contexts for many years now.

    A non-specific model would be like this. The body senses increased and damaging activity. It massively produces sensors that detect effects of these activities on energy related pathways. So the impact of, say adrenaline, is amplified by increased signal strength. This will be registered as hightened adrenaline, and adrenal and related pathways might then be subject to negative feedback, slowing them down.

    The important thing about this is that adrenaline is not likely to be the trigger, some kind of damage sensing is. This is consistent with increased oxidative or mitochondrial stress for example.

    Bye
    Alex

  6. Snow Leopard

    Snow Leopard Senior Member

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    The difficulty with predicting the biochemistry is due to the extreme level of cross reactivity. Lots of receptors and enzymes play multiple roles in various cellular pathways.

    Within normal bounds, a prolonged increased signal level leads to decreased receptor expression to maintain a normal equilibrium. The problem arises if enough pathways become deregulated, then the whole system may shift to a permanent abnormal equilibrium. The hypothesis presumably is that (partly by chance) a prolonged immune insult shifts the system into an abnormal equilibrium. Eg the system is 'stuck' in an dysregulated inflammatory state and is itself causing increased cellular stress and associated fatigue. It may involve dysregulation of the methylation cycle, but there are lots of possibilities, it is possible that there are different dysregulated cycles in different patients.
    oceanblue likes this.
  7. oceanblue

    oceanblue Senior Member

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    I think you're right about the difficulty of working out what could be responsible for the enhanced expression, as the complexity and interconnectedness of the systems involved could make many different explanations possible - so without more experimental evidence it's hard to know what's causing the problem.

    Re: an increased signal level normally leading to decreased receptor expression, the authors made that exact point about metabolit receptor expression in controls and MS patients:
    Rich: what's the evidence for the methylation deficit in CFS patients? I hadn't come across that before.
  8. richvank

    richvank Senior Member

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    Hi, Ocean.

    The rates of the methylation reactions in the body depend on the availability of SAMe, the main methyl donor, and on the ratio of SAMe to SAH, which is a product of the reactions. In our clinical study, we found that both were below normal before the people were treated. You can see this in the table in the poster paper that can be found here:

    http://www.mecfs-vic.org.au/sites/w...Article-2009VanKonynenburg-TrtMethylStudy.pdf

    In addition, a large number of additional ME/CFS patients have had the methylation pathways panel run by now. I can't tell you how many. It must be in the thousands by now. I frequently receive the reports from people who have run this panel, and I know that several physicians order it. Nearly always the results indicate a methylation deficit. Other testing usually shows deficits in substances that require methylation for their synthesis in the body. These include carnitine and coenzyme Q10, for examples. When the operation of the methylation cycle is improved by methylation treatments, as verified by repeating the panel, the people report symptom improvements.

    Best regards,

    Rich
  9. oceanblue

    oceanblue Senior Member

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    Thanks - has any of this been published?

    As an aside, I take N-acetyl-Cysteine as a supplement, which I believe is metabolised into glutathione. Could that be why it seems to help? I've tried dozens of supplements in the past but NAC is the one that does seem to make a difference (I think).
  10. richvank

    richvank Senior Member

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    Hi, ocean

    A shortened version of this paper was just published in the December 2011 issue of Townsend Letter. It's a magazine read primarily by alternative practitioners. It hasn't been published in a peer-reviewed journal. It's tough to do that without a placebo control group and an institutional review committee approval, which we did not have because of cost. This study was funded by an anonymous private donor, and we did what we could with the resources we had. I hope that a more "orthodox" study will be done by someone in a position to do so, which I am not. Funding is always a problem when there are no patented drugs involved.

    Yes, some people are helped by taking NAC, and that is likely because it gives a temporary lift to the glutathione, which is depleted in most cases of ME/CFS. I recommended treatments of this type from 1999 through 2004, before I learned about the methylation cycle partial block, which is upstream of glutathione synthesis and which prevents it from coming up on a more permanent basis. Since then, I have been recommending treatment of the methylation cycle block, and as you can see in paper I cited, this causes glutathione to come up automatically on a more permanent basis in most ME/CFS patients.

    Best regards,

    Rich
  11. Snow Leopard

    Snow Leopard Senior Member

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    I've always wondered how hard it is to get matching placebo pills and drops. I mean some of those in your protocol are quite distinctive.

    The alternative to a placebo group that could be acceptable, would be objective actigraph measurements and straightforward neuropsychiatric tests at periodic intervals and larger sample size (eg 50 receiving, 50 randomised not to receive, or to receive after 6 months as a crossover trial). Still not cheap though.
  12. Snow Leopard

    Snow Leopard Senior Member

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  13. Dolphin

    Dolphin Senior Member

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    Like oceanblue, I'm not sure the Lights have used the empiric criteria (Reeves et al., 2005).

    I think the only studies using empiric criteria are studies funded by the CDC, or studies using CDC datasets (e.g. from CAMDA), along with the odd study by Leonard Jason and his team examining the criteria.
  14. Dolphin

    Dolphin Senior Member

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    Yes, have always been suspicious of such theories.
  15. Dolphin

    Dolphin Senior Member

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    It's worth noting that the sample size is quite small here so there is also the possibility of false negatives (type two errors).
  16. Dolphin

    Dolphin Senior Member

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    1. I'm out of my depth biologically but I thought I'd throw this out there: with the illness, symptoms and biology might not be in tandem. So if one overdoes it, one might actually be on a bit of a high, symptom-wise, and not take the hit, symptom-wise, till later; and indeed, symptoms weren't peaking till 8-48 hours later. So perhaps with correlations between symptoms and receptors, one doesn't need to just compare simultaneously but also look at other time points.

      Unfortunately, a lot of data is also lost because one doesn't have continuous readings - just readings from a few time-points (not equally spread out) after the exercise. Also, there are more symptoms than just MF, PF and pain.
  17. Dolphin

    Dolphin Senior Member

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    In terms of matching people (whether controls or people with other illness groups), it might be good if researchers used pedometers/actometers/other motion sensing device for this (say over a week). Although I suppose the problem is that you would need to discard some of your controls so you would need to have extra ones, which might not be so easy to get.
    oceanblue likes this.
  18. mellster

    mellster Marco

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    This is interesting, Alex. I love spicy food so much and it cannot be spicy enough for me and it makes me feel good as well, but I have been wondering if it can have slightly adverse effects on the mitochondria as capsaicin is known to disrupt/kill the mitos of cancer cells (leading to apoptosis) which is great, but maybe it cannot always distinguish between good and bad cells and if you have suspected mitochondrial function/oxygenation issues maybe the benefits of eating chilis come with a small price in that area (wow what a long sentence)? Anyhow, it won't stop me from eating my beloved chilis. ;)
  19. Dolphin

    Dolphin Senior Member

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    I was pleased to see the Lights mention this study although it's not the one issue they mention with regard to metabolite-detecting receptors:

    It would probably be good if the Lights could measure postexercise levels of intramuscular pH in tandem with other research.
  20. oceanblue

    oceanblue Senior Member

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    True: the answer would be to do bigger studies but unfortunately the Lights have ruled that out. I simply don't understand why they rule out a statistical technique because of the problems of false positives, then go ahead and used it anyway - having also ruled it out from their previous paper. I think we'd be pretty critical if psychiatrists did this.

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