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Medscape Discusses Fluge and Mella FIndings of PDH Impairement

Discussion in 'Latest ME/CFS Research' started by Never Give Up, Jan 13, 2017.

  1. Tunguska

    Tunguska Senior Member

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    Not necessarily - I think no. People do that because of the comfy sedative effect, but if it tanks your blood sugar or messes with carbs significantly, it will actually predictably worsen sleep and/or the following day - personally did better taking it in the morning together with energy boosting substances.
     
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  2. ash0787

    ash0787 Senior Member

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    The value of doing exercise should, however, not be underestimated, and the level of activity tolerated will depend on the severity of the disease," Dr Fluge said.

    Did he really say this or is it a mistranslation ? did he perhaps say a word equivalent to 'exertion' in the native language ?

    Would he consider walking 50 metres once or twice per hour to be exercise ?

    Also snowleopard, if this isn't the central feature of the disease what is ? this seems to be the most visible thing they have found so far.
     
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  3. AndyPR

    AndyPR Senior Member

    Given that Fluge went on to say straight after
    He is obviously aware that some patients tolerated exercise would be very minimal, he's not making a call here for us all to head down to an aerobics class immediately.
     
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  4. ukxmrv

    ukxmrv Senior Member

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    It feels as though, he thinks that there actually is benefit from it for enough patients to make that comment and not enough danger from it to warn the other way. This is a huge red flag that something is maybe wrong in his understanding or the translation or the context.

    For me mentioning exercise as being "valuable" and not to be "underestimated"in relation to most patients with ME or CFS is a very bad thing.

    Even if we can explain it away as referring to a weird obscure tiny subgroup, this is so atypical of ME (as per Ramsay) that no physician should be talking about exercise in an interview in that way. It should be the opposite. A doctor who understands ME and CFS should be warning against the dangers of exercise and exertion. I don't have enough physical health to perform the needed exertion for daily living tasks like bathing and cooking right now.

    Exercise is not valuable to me or not to be underestimated. It's a specific and real danger.

    It may be a deficiency in his understanding of ME (after all he is an Oncologist) that in no way detracts from the wonderful research he is doing.
     
    Last edited: Jan 15, 2017
  5. AndyPR

    AndyPR Senior Member

    Yes, some may benefit from. Those who are able to exercise without crashing, as he says should be the aim.

    Therefore, sadly, you will probably be someone who won't benefit.

    If you exceed your limitations, yes, it is danger like it is to all of us with ME if we exceed our limitations.
     
  6. lansbergen

    lansbergen Senior Member

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    That is the key. Stay within your limitations.
     
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  7. perrier

    perrier Senior Member

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    When will they find something to help all the sufferers. I'm getting very despondent because researchers find so many things wrong with this condition, and not enough solutions. I know the wheels turn slowly,I understand,but life ( youth) is ebbing away for so many people.
     
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  8. ash0787

    ash0787 Senior Member

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    Depends what he means by exercise I suppose, based on my experience
    lifting up everyday objects = fine,
    hammering nails, power tool usage, occasional heavier object lift = fine,
    weightlifting = inadvisable,
    short moderate exercise which causes acute crash = ok but why do that,
    repeated exercise more aerobic than walking but which doesn't cause a crash = will probably cripple you
     
  9. Snow Leopard

    Snow Leopard Hibernating

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    We don't yet know the central/specific factor. All I can say is there will eventually be fanfare when it is discovered.
     
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  10. halcyon

    halcyon Senior Member

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    So your post in the immune modulator thread about pathogens, IL-10, and mTOR made me go take another look at the T cell exhaustion literature. Taking on board @nandixon's hypothesis about downregulated mTOR, this jumped out at me from this paper:
    So for those that don't know, PD-1 is a marker of T cell exhaustion found on chronically activated T cells that are continuously exposed to antigen, as in a chronic viral infection. Recent studies have shown that there are markers of T cell exhaustion found on ME patients T lymphocytes (including PD-1 and loss of the IL-7 receptor CD127). The Hornig/Lipkin cytokine study showed possible indirect evidence of it as well. So if there is an increase in PD-1/PD-L1 activity in ME, it seems like this could be another possible source of inhibition of mTOR and metabolic disturbance. PD-L1 comes in a soluble form as well so this could be one of the signals from the serum that Ron Davis is talking about. If I'm not wrong, every recent metabolic study in ME so far (including the Davis impedance assay), save for the blood based ones, has only used PBMCs. It seems like this wouldn't be a very good cell to look at given the additional complexity introduced by the way that PBMCs like lymphocytes regulate their metabolism differently based on their activation status and immune signals etc. It seems like muscle cells would be better to look at.

    IL-7 also plays an important role in lymphocyte metabolic control, so loss of that receptor on the cells that they are finding in a hypometabolic state might also be important, though this aspect is quite far above my head for now.

    The more I read about this the more I feel like the chronic immune activation/chronic viral hypothesis and hypometabolism hypothesis are really looking at two sides of the same coin.
     
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  11. eljefe19

    eljefe19

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    @halcyon Glad you were able to read that article, I was too fogged yesterday. It's interesting isn't it. I haven't known how to reconcile the fact that Oxymatrine/Astragalus inhibit mTOR but also apparently help a significant subgroup of PWME. None of my enterovirus titers were especially high except, weirdly, CVA. Therefore I don't know whether or not to try and treat a possibly nonexistent viral infection, especially if it's inhibiting mTOR further. Arbidol is interesting to me right now though.
     
  12. nandixon

    nandixon Senior Member

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    @halcyon I agree that could be the case. The substance(s) that Ron Davis is filtering out of the blood in his experiments might be PD-L1. I've thought off and on that it could be interesting to try pembrolizumab (Keytruda), an anti-PD-1 receptor monoclonal antibody, to see what blocking PD-L1 does in ME/CFS, but I didn't have such a nice theory as what you've presented. (In the study you cited it appears they're using an anti-PD-L1 (mouse) antibody instead, i.e., targeting the ligand rather than its receptor.)

    I'm familiar with Keytruda because I have a major hereditary mutation, a deletion actually, in the MSH2 mismatch-repair gene. This causes a cancer-predisposition disease called Lynch Syndrome (increases a person's lifetime risk of cancer to close to 90%). Keytruda is currently the most targeted treatment for the type of cancer that arises due to that mutation. It's already been FDA approved for some indications and is in clinical trials for others right now.

    If PD-1/PD-L1 is indeed a problem then I'd think it could work to add Keytruda directly to Dr Davis’ testing set-up to see if the measured impedance is corrected for when PBMCs are exposed to ME/CFS serum. Do you see any experimental problem with that?
     
    Last edited: Mar 8, 2017
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  13. eljefe19

    eljefe19

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  14. Tunguska

    Tunguska Senior Member

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    @halcyon Thank you for posting that article, it's incredibly good. I never followed how the FoxO can inhibit mTor and that shows one way. I love their conclusion:
     
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  15. halcyon

    halcyon Senior Member

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    Honestly I try not to worry too much about it. I've only had positive effects from these compounds so it feels a bit alarmist to me. You probably don't want to take rapamycin for a long time, but beyond that who knows. This is complex. Inhibiting or increasing activity of mTOR will have all sorts of positive or negative effects, depending on which immune cell type you're looking at and the situation etc.
     
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  16. halcyon

    halcyon Senior Member

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    No, seems like a good test to me. You could either add it to the patient cells to see if it reverses the effect, or add it to the healthy cells prior to exposure to sick serum to see if it protects them from any of the effects seems like.
     
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  17. M Paine

    M Paine Senior Member

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    If you're interested in Pembrolizumab, or other monoclonal antibodies which target the interaction between PD-L1 and the PD-1 receptor, then this podcast might interest you:

    Audiommunity 16 – Jimmy Carter’s Brain on Drugs
    http://www.microbe.tv/audiommunity/audiommunity-16/
     
  18. wastwater

    wastwater Senior Member

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    I’m likely missing foxc1 Axenfeld Rieger syndrome that acts on foxo1a
     

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