• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

Medscape Discusses Fluge and Mella FIndings of PDH Impairement

Messages
516
@Tunguska thanks for the advice! I just ordered allithiamine to take alongside the niacinamide. Do you think I should take niacinamide at night then?

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.
 

ash0787

Senior Member
Messages
308
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.
 
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 ?

Given that Fluge went on to say straight after
He added, "An ME/CFS patient's ability to handle exercise is very individual. Generally, I think the physicians should listen carefully to the patients, and find the optimal activity level through pacing, to avoid 'crashing' with the resulting major symptom increase that can last for weeks and months."
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.
 

ukxmrv

Senior Member
Messages
4,413
Location
London
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.

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:
It feels as though, he thinks that some may benefit from it and that is a huge red flag that something is maybe wrong in his understanding or the translation or the context.
Yes, some may benefit from. Those who are able to exercise without crashing, as he says should be the aim.

I don't have enough physical health to perform the needed exertion for daily living tasks like bathing and cooking right now.
Therefore, sadly, you will probably be someone who won't benefit.

Exercise is not valuable to me or not to be underestimated. It's a danger.
If you exceed your limitations, yes, it is danger like it is to all of us with ME if we exceed our limitations.
 

perrier

Senior Member
Messages
1,254
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.
 

ash0787

Senior Member
Messages
308
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
 

halcyon

Senior Member
Messages
2,482
Comment from the medscape article. Any thoughts from anyone?
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:
Therapeutic PD-L1 blockade requires mTOR activation
PD-1 is markedly up-regulated on exhausted CTLs and can inhibit proximal TCR signaling and distal AKT, mTOR, S6, and ERK phosphorylation (Francisco et al., 2009; Parry et al., 2005; Sheppard et al., 2004; Yokosuka et al., 2012). Moreover, blocking PD-1:pD-L1 interactions can restore TCR signaling (Fife et al., 2009; Zinselmeyer et al., 2013) and boost antiviral T cell responses and viral control during LCMV-Cl13 infection (Barber et al., 2006). First, we confirmed the ability of PD-1 to suppress mTORC1 activity (based on p-S6 staining) in virus-specific CTLs following TCR stimulation (Figure 3A). Next, to examine if PD-1 suppression of mTOR activity was relevant in antiviral CTLs in vivo, LCMV-Cl13 infected mice were treated with a blocking α-PD-L1 mAb, either with or without the mTORC inhibitor rapamycin. Anti-PD-L1 mAb treatment augmented the amounts of p-S6235/236, CD98, CD71 and glucose uptake in CTLs (Figures 3B-C) (Finlay et al., 2009). The increase in mTOR activity was accompanied by a marked increase in the frequency and number of IFN-γ- and granzyme B (GzmB)-producing virus-specific CTLs and decrease in viral load (Figures 3D-G). Importantly, rapamycin abrogated the beneficial effects of α-PD-L1 blockade on viral control and virus-specific T cell responses, including the aforementioned markers of anabolic metabolism (Figures 3B-F). Taken together, these data demonstrate that PD-1 suppression of the mTOR pathway contributes to CTL exhaustion in vivo and that recovery of mTOR activity is a part of the therapeutic effects of α-PD-L1 during chronic LCMV-Cl13 infection.
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.
 

eljefe19

Senior Member
Messages
483
@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.
 

nandixon

Senior Member
Messages
1,092
@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:
Messages
516
@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:
Additionally, our study has provided proof-of-concept that manipulation of FoxO1, and possibly other members of the PI3K, AKT, and mTOR pathway can regulate the expression and function of PD-1 in exhausted CTLs that could lead to therapeutic options for fighting chronic viral infection or cancer. However, our data would argue that fine-tuning of FoxO1 activities and/or temporal regulation thereof, as opposed to their complete blockade, may serve as more rationale therapeutic design.
 

halcyon

Senior Member
Messages
2,482
I haven't known how to reconcile the fact that Oxymatrine/Astragalus inhibit mTOR but also apparently help a significant subgroup of PWME.
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.
 

halcyon

Senior Member
Messages
2,482
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?
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.
 

M Paine

Senior Member
Messages
341
Location
Auckland, New Zealand
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
Taking the breaks off of the immune system can get it to attack cancer cells.

In this episode, Matt and Kevin discuss checkpoint blockade cancer immunotherapy (wow, that’s a mouthful). When cancer stamps down the breaks of the immune system, cutting the break line can allow T-cells to do their job

http://www.microbe.tv/audiommunity/audiommunity-16/