NIH Intramural study update

[bread.]

If healthy cells start behaving abnormally once plasma from patient blood is added and vice versa, then I can't see how this doesn't prove that the problem is elsewhere than in the mitochondria. It is IMO the most significant finding that Ron Davis' group has managed to produce so far because it directly points at the problem being in the blood, not in the mitochondria.

This model also aligns with my own experiences with so called temporary remissions. Once I get ill with a cold, all my ME/CFS symptoms resolve temporarily within 24 hours. Same thing with certain medications and supplements, although frustratingly, they always stop working at some point. Anyway, none of this would be possible if mitochondria were faulty. Davis has also observed this phenomenon, where the patient's cells start behaving more normally in the nanoneedle after the patient had been sick.

https://www.leafscience.org/mitocho...UHSzkrrZ6jB5Z0apD-dFzMllUaLaHnoSDe3Cea-yNkORg


Again, I will say this is no proof of anything, also this work of Davis is not published, there is no data, nothing.

 

[Pyrrhus]

Well, to get this thread back on topic, here's a new publication from the NIH "Post-infectious ME/CFS" Intramural Study:
https://forums.phoenixrising.me/threads/nih-me-cfs-pem-focus-group-study-results-published.81384/

After a couple of years running the study, the investigators decided to convene a series of focus groups to understand what patients mean by "Post-exertional malaise (PEM)". This publication is the result of those focus groups.

Characterization of Post–exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Background: Myalgic encephalomyelitis/chronic fatigue syndrome is characterized by persistent and disabling fatigue, exercise intolerance, cognitive difficulty, and musculoskeletal/joint pain. Post–exertional malaise is a worsening of these symptoms after a physical or mental exertion and is considered a central feature of the illness. Scant observations in the available literature provide qualitative assessments of post–exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. To enhance our understanding, a series of outpatient focus groups were convened.

Methods: Nine focus groups totaling 43 patients who reported being diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome were held between November 2016 and August 2019. Focus groups queried post–exertional malaise in daily life and participants' retrospective memory of post–exertional malaise that followed an exercise provocation with a cardiopulmonary exercise test. Data analysis followed the grounded theory method to systematically code and categorize the data to find meaningful patterns. A qualitative software package was used to move text into categories during data coding.

Results: A wide range of symptoms were attributed to exertion both in daily lives and following cardiopulmonary exercise testing. While three core symptoms emerged (exhaustion, cognitive difficulties, and neuromuscular complaints), participants' descriptions were notable for their unique individual variations. Of 18 participants who responded to questions centered around symptoms following a cardiopulmonary exercise test, 17 reported that symptoms started within 24 h and peaked in severity within 72 h following the cardiopulmonary exercise test. Patients described post–exertional malaise as interfering with their ability to lead a “normal” life.

Conclusion: The experience of post–exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome varies greatly between individuals and leads to a diminished quality of life. myalgic encephalomyelitis/chronic fatigue syndrome patients describe post–exertional malaise as all-encompassing with symptoms affecting every part of the body, difficult to predict or manage, and requiring complete bedrest to fully or partially recover. Given the extensive variability in patients, further research identifying subtypes of post–exertional malaise could lead to better targeted therapeutic options.

 

[Wishful]

"Given the extensive variability in patients, further research identifying subtypes of post–exertional malaise could lead to better targeted therapeutic options."

Maybe, but given the extensive variability in responses to treatments, I'm not sure whether this would be a good choice for research funding. I think a better approach would be to study the individuals that managed to find an effective treatment and figure out exactly why the treatment worked. I've proven that PEM can be effectively treated and even cured, but now it's too late to study why/how it worked for me. There must be some others who have found effective treatments that are still working reliably for them.

 

[Pyrrhus]

This NIH PEM study now has its own discussion thread here:

NIH: ME/CFS "PEM" Focus Group Study Results Published
https://forums.phoenixrising.me/threads/nih-me-cfs-pem-focus-group-study-results-published.81384/

 

[frozenborderline]

I'm not all that excited. I still believe that any decrease in ATP in muscles is a secondary effect of ME. To me, "the data is still statistically significant" sounds like it's a small difference, much less than would be expected if ATP production was the critical part of ME. A small but statistically significant difference is what I would expect from a secondary effect of ME.

I'm not a trained biologist (or statistician), so I could be wrong, but my feeling is that this isn't going to lead to a breakthrough.

Well, I agree all the metabolic stuff is secondary and downstream. But that doesnt mean we shouldn't be excited especially about replicable results... we start with secondary things and then follow the trail upstream...

 

[frozenborderline]

"Given the extensive variability in patients, further research identifying subtypes of post–exertional malaise could lead to better targeted therapeutic options."

Maybe, but given the extensive variability in responses to treatments, I'm not sure whether this would be a good choice for research funding. I think a better approach would be to study the individuals that managed to find an effective treatment and figure out exactly why the treatment worked. I've proven that PEM can be effectively treated and even cured, but now it's too late to study why/how it worked for me. There must be some others who have found effective treatments that are still working reliably for them.

While I acknowledge there are different treatments that work for different people, I'm not sure we should split as opposed to lump different groups ... I think that there is something underlying everyone who shares PEM and other core symptoms. Maybe different treatments work bc of different stages of the illness or bc they are treating something a bit downstream

 

[frozenborderline]

Why has the NIH study been so small and taken so long ? I was somewhat excited to see such a major study with deep phenotyping and thought since it's the NIH maybe it would also legitimize the disease and convince the NIH and other scientists to pay attention but the slowness and some details of the study scares me.

 

[Pyrrhus]

For a full discussion of the NIH research study, see:

Details on NIH study
https://forums.phoenixrising.me/threads/details-on-nih-study.43076/

 

[Rufous McKinney]

I've proven that PEM can be effectively treated and even cured, but now it's too late to study why/how it worked for me.

you could cease taking your cumin seeds, right?

 

[Rufous McKinney]

I'm really interested in some other form of testing us...

and while I recognize it may be difficult in severe folks stuck in bed, I often think about:

the DRIVING TEST..the DRIVING MACHINE. (on a machine, not really driving)

Our response time could be measured.

This could serve as a possible way to test folks and retest the same person.

applsci-11-02431-v2.pdf

The Japanese use executive function tests: having to decide things. I like this too.

 

[Rufous McKinney]

There are definitely substantial metabolic problems in me/cfs but it is not a primary mitochondrial disorder

its just that EVERY reaction in the body entails an ATP event. So ATP is definitely somehow involved. and the fragmenting....of mitochondria seems real...

 

[Wishful]

you could cease taking your cumin seeds, right?

Yup, I stopped taking cumin 2+ years ago. Still PEM-free. It solved my need for supplemental T2 too. Wonderful stuff ... for me.

its just that EVERY reaction in the body entails an ATP event. So ATP is definitely somehow involved.

Well, yes, but that's like saying that every reaction in the body involves hydrogen, but no one is claiming that hydrogen is the root cause of ME. I see no physical symptoms I can attribute to inadequate ATP production, so I'm convinced that my ME isn't due to mitochondrial dysfunction. It's possible that some neural cells aren't producing enough ATP, but I don't think that's the root cause. I'm still convinced that the root cause involves glial cells stuck in a positive feedback loop.

 

[Rufous McKinney]

there is alot of mitochondrial disruption from viral and bacterial illnesses.

For example, this is a very popular paper:

https://www.cell.com/trends/cell-biology/fulltext/S0962-8924(20)30018-0

Highlights

• Bacteria and viruses have evolved specific ways of targeting mitochondria to perturb mitochondrial function that can prove to be beneficial for these microbes.
• Many bacteria and viruses use specific virulence mechanisms to modulate mitochondrial dynamics, leading to either mitochondrial fusion or fission.
• Mitochondrial metabolism can also be impacted by bacterial and viral infections.
• While in some cases bacteria and viruses induce the mitochondrial cell death pathway, in others cell death is inhibited promoting intracellular bacterial and viral proliferation.
• Mitochondria regulate different innate immune signaling pathways induced upon bacterial or viral infections.

 

[frozenborderline]

. I see no physical symptoms I can attribute to inadequate ATP production, so I'm convinced that my ME isn't due to mitochondrial dysfunction. It's possible that some neural cells aren't producing enough ATP, but I don't think that's the root cause. I'm still convinced that the root cause involves glial cells stuck in a positive feedback loop.

Ehh, these two things are not necessarily totally different ecologies of ME, they could be related.

I believe glial activation and glutamate excess and lactate excess in brain (a sort of excitotoxic state) explains a lot of me/cfs symptoms and responses to meds, like people responding well to benzos and NMDA antagonists, and the brain on fire stuff

But theres definitely something wrong with metabolism globally in me/Cfs. I'm pretty sure its not the root cause as it is in inherited metabolic diseases, but there's still something up there. Probably downstream of something but still there

 

[halcyon]

I can not wrap my head around how anyone on this planet does not try to understand me/cfs as a mitochondrial disorder, it is just plain batshit crazy. Especially when it come to cases that fit Ramsay ME criteria. There is a lack of energy no „faulty tiredness“ in this disease

I don't think it's accurate to say that nobody is trying to understand it as a mitochondrial disorder. There has been a significant (in ME-relative terms) amount of research looking at muscle dysfunction over the past several years. The problem is that nobody has convincingly been able to link any specific intracellular mitochondrial/metabolic abnormality with objective findings of gross muscle dysfunction, to my knowledge.

The rough consensus (as best I can tell) around the time of Ramsay's death was actually that muscle function in ME is totally normal and that the problem is a central, neuromuscular one, based on research by Richard H. T. Edwards (Stokes et al., 1988; Gibson et al., 1993; Edwards et al., 1993). I'm not sure how to square this with today where I think the rough consensus is that there is actually peripheral intracellular dysfunction, however the nature/cause is unclear, and there are potentially still central, as well as autonomic circulatory, contributions to the muscle dysfunction (Jammes & Retornaz, 2020; Rutherford et al., 2016; Jäkel et al., 2021) .