Third Annual Community Symposium on the Molecular Basis of ME/CFS Sponsored by OMF - DISCUSSION

[nandixon]

I'm not familiar with Fisher's work - I'd be grateful for a link (not sure I'll understand it though). I agree that fission may be simply a consequence - but a biomarker for fission might be a diagnostic test (a plug for someone to fund more work by Bupresh Prusty)!

See this thread for Fisher's study:

https://forums.phoenixrising.me/thr...lized-lymphocytes-from-me-cfs-patients.77577/

Fisher seems confident that the results of the study of that thread are going to lead to a diagnostic test for ME/CFS and he is working on that right now. His results have some of the best p-values ever seen for an ME/CFS study.

 

[wigglethemouse]

They're so severely ill, in fact, that some may actually be suffering from catatonia rather than ME/CFS (although both these illnesses may be on the same spectrum for all we know).

This is a topic I'm also interested in. @mariovitali is interested in Glutamate findings in his machine learning work into ME. Glutamate is thought to be involved in Catatonia.

But catatonia is no longer considered to be just a condition associated with psychiatric diseases like schizophrenia. Rather now it's known to be associated with a wide range of medical illnesses. The Wikipedia article doesn't make that nearly clear enough. (I previously researched catatonia a fair bit because I was trying to figure out why Ativan was so helpful for some ME/CFS patients.)

So we don't know for sure whether the ultra-severe ME/CFS patients, i.e., those who may meet the catatonia criteria, are actually suffering from some number of other medical conditions which has also caused the development of catatonia in association with it (and ME/CFS may be one of those).

There are patient reports that the Stanford ME/CFS clinic sometimes prescribes low dose Abilify (threads here on PR). That is another drug used in Catatonia.

s4me is holding a Q&A for a video with Michael Van Elzakker. I left a question on this topic.
https://www.s4me.info/threads/quest...ith-dr-michael-vanelzakker.11496/#post-204728

 

[wigglethemouse]

See this thread for Fisher's study:

https://forums.phoenixrising.me/thr...lized-lymphocytes-from-me-cfs-patients.77577/

@FMMM1 This video is great to explain his work. In fact the video is better to understand how much depth he has gone into e.g. analysing 3000 metabolites/proteins in the cells to see the differences in raw material use
https://mecfsconference.org.au/videos/paulfisher/

 

[Cam Newton]

In Ron’s latest update video he says firmly that all ME/CFS patients have a damaging mutation in IDO2.

This is quite significant. It must mean that either the 1/70 that Rob presented at the Symposium has been investigated and reversed (maybe they don’t have ME/CFS), or that they have tested WAY more patients since, and Ron is simply approximating 1/150 to be zero.

Either way, it’s good news for the tryp/trap.

 

[Empi]

In Ron’s latest update video he says firmly that all ME/CFS patients have a damaging mutation in IDO2.

This is quite significant. It must mean that either the 1/70 that Rob presented at the Symposium has been investigated and reversed (maybe they don’t have ME/CFS), or that they have tested WAY more patients since, and Ron is simply approximating 1/150 to be zero.

Either way, it’s good news for the tryp/trap.

Dr. Davis addressed the finding of the patient without the damaging IDO2 mutation in a different video. He said they think that patient has a mutation to different gene involving a regulatory process of some kind.

 

[Cam Newton]

Dr. Davis addressed the finding of the patient without the damaging IDO2 mutation in a different video. He said they think that patient has a mutation to different gene involving a regulatory process of some kind.

Ah thanks, I saw that video pop up and ignored it assuming it was filmed before the symposium.

I just watched the relevant part. Ron seems much more confident in his latest video, I’m still assuming they have made progress on this 1 individual.

Anyway, thanks again for the heads up.

 

[FMMM1]

Ah thanks, I saw that video pop up and ignored it assuming it was filmed before the symposium.

I just watched the relevant part. Ron seems much more confident in his latest video, I’m still assuming they have made progress on this 1 individual.

Anyway, thanks again for the heads up.

Is this Ron's presentation at the Symposium or another video? If so could you post a link?

 

[Empi]

Is this Ron's presentation at the Symposium or another video? If so could you post a link?

Here you go:

 

[nandixon]

This is a topic I'm also interested in. @mariovitali is interested in Glutamate findings in his machine learning work into ME. Glutamate is thought to be involved in Catatonia.

There are patient reports that the Stanford ME/CFS clinic sometimes prescribes low dose Abilify (threads here on PR). That is another drug used in Catatonia.

The best possibility I could come up with for how Ativan (lorazepam) might be helping in ME/CFS is that it strongly binds to a receptor that is primarily located in the outer mitochondrial membrane called the translocator protein (TSPO), formerly called the peripheral benzodiazepine receptor (PBR). (This is in addition to it binding at the more commonly known GABA A receptor.)

Binding at TSPO could potentially tie in well with Fisher's findings of an impaired ATP synthase in ME/CFS (and Prusty's regarding mitochondrial fragmentation) because:

TSPO may modulate ATP synthase via a direct interaction between the ATP ‘synthasome’ (composed of ATP synthase, phosphate carrier, and ANT) and the PBR complex composed of TSPO, VDAC, and ANT.55,56

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351937/

I'm still not clear on whether Ativan was tested in the nanoneedle stress test or not.(?) For the possibility I've written above to be correct then I think Ativan should correct the impedance signal.

s4me is holding a Q&A for a video with Michael Van Elzakker. I left a question on this topic.
https://www.s4me.info/threads/quest...ith-dr-michael-vanelzakker.11496/#post-204728

Great!

 

[Rufous McKinney]

I'm still not clear on whether Ativan was tested in the nanoneedle stress test or not.(?) For the possibility I've written above to be correct then I think Ativan should correct the impedance signal.

Curious about this..... so this is a drug with pretty serious side effects....if it corrected this impedence signal, that may not suggest its appropriate to take on a sustained basis.... it seems like correcting the signal...is not the only issue...?

 

[nandixon]

@Rufous McKinney

Yes, it's possible that a drug could correct the signal but actually have no effect or even a bad effect on the patient.

The bad effect might happen either because of general side effects or because the manner in which it corrects the impedance signal (by normalizing mitochondrial membrane potential, for example) might potentially lead to a reduction in ATP synthesis (which could make matters worse based on the finding in Fisher's study that ATP synthase may already be impaired).

 

[FMMM1]

Here you go:

Thank you.

 

[Moof]

Curious about this..... so this is a drug with pretty serious side effects....if it corrected this impedence signal, that may not suggest its appropriate to take on a sustained basis.... it seems like correcting the signal...is not the only issue...?

Yes, it's possible that a drug could correct the signal but actually have no effect or even a bad effect on the patient.

The bad effect might happen either because of general side effects or because the manner in which it corrects the impedance signal (by normalizing mitochondrial membrane potential, for example) might potentially lead to a reduction in ATP synthesis (which could make matters worse based on the finding in Fisher's study that ATP synthase may already be impaired).

In a weird coincidence, I was prescribed Ativan in 1977 for ME. Not that anyone knew that it was ME at the time, it's just that our then-GP thought most conditions that affect women are psychosomatic – up to and including the multiple stomach ulcers that nearly killed my mum, and the cervical cancer that actually killed our neighbour – and Ativan was a snazzy new drug that tended to stop women complaining that they were ill, by sedating them. Bullseye!

Anyway, if it corrected any kind of signal in me, it wasn't noticeable. It just doubled my fatigue and cognitive dysfunction, wiped out several years of memories, and created an addiction (it took me ages to come off it by reducing the dose very gradually). My ME was much better once I'd stopped it.

 

[mariovitali]

@nandixon @wigglethemouse

FWIW, i ran an analysis specifically for TSPO using the latest data. The methodology i use suggests that the association between TSPO and ME is through inflammation and microglial activation (assuming microglial activation takes place in ME patients). I provide below a Network Analysis output of associated topics and also a list of highlly-related PUBMED abstracts hoping that this might help you @nandixon (note that Quinolinic acid appears below, which is a product of the Kynurenine pathway)

and here is Network Analysis :

Hope this helps.

 

[mariovitali]

@wigglethemouse

cc : @perrier

I decided to look more at catatonia. Very interesting commonalities with ME. With the Information Extraction system i use , i located the following paper as being higly relevant :

https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(19)30190-7/fulltext

The full text can be retrieved here :

https://sci-hub.tw/10.1016/s2215-0366(19)30190-7


From the text we read :

The acute-phase response is a core part of the innate immune system. The response is initiated by the activation of monocytes and macrophages by a stimulus, such as muscle breakdown, infection, physical injury, or psychological stress. In response to these stimuli, cells release proin ammatory cytokines such as interleukin1 (IL1), IL6, and tumor necrosis factor alpha (TNFα), which in turn act on receptors throughout the body to promote fever, anorexia, muscle catabolism, and activation of the hypothalamic pituitary-adrenal axis

I believe that rings a bell, right @wigglethemouse ? The work by Klimas et. al identifying TNF-α and IL-6 and HPA Axis :

https://www.s4me.info/threads/lever...-with-cfs-2019-morris-et-al.8878/#post-204804

I also attach here a machine learning run where IL-6 , TNF-α can be shown as part of the most higly predictors for a symptom / non-symptom state :

From the paper i linked some more interesting bits :

Data distinguishing different benzodiazepines are sparse, but some benzodiazepines, such as diazepam and lorazepam (both recognised treatments for catatonia) but not clonazepam, also bind to translocator protein (TSPO), a mitochondrial protein associated with phagocyte activity, immune cell migration, and cytokine function.54,55 In rats, diazepam reduces TSPO in the brain and decreases the number of CNS inflammatory cells, giving it a protective function against experimental autoimmune encephalomyelitis.55

 

[skandar]

I'm still not clear on whether Ativan was tested in the nanoneedle stress test or not.(?) For the possibility I've written above to be correct then I think Ativan should correct the impedance signal.

Agree. I believe I have listened to every talk, interview, and update that is available on-line of Ron Davis, and I have never heard him say they tested Ativan with the nanoneedle, but I keep wondering. I would be surprised if they have not done this. If so, I wonder if he fears that people will take too many benzodiazepines. On the other hand, Ron did show raw data of T cell respiration (Seahorse) in the presence of Ativan, which reversed the abnormal signal in cells from a pwme (one of the Australia talks 2019)

 

[nandixon]

@skandar, Your intuition may very well be correct. Yes, surely it would have been tested early on given Whitney's positive response to it. The Seahorse experiment is the only thing I've seen as well.

 

[borko2100]

Agree. I believe I have listened to every talk, interview, and update that is available on-line of Ron Davis, and I have never heard him say they tested Ativan with the nanoneedle, but I keep wondering. I would be surprised if they have not done this. If so, I wonder if he fears that people will take too many benzodiazepines. On the other hand, Ron did show raw data of T cell respiration (Seahorse) in the presence of Ativan, which reversed the abnormal signal in cells from a pwme (one of the Australia talks 2019)

Interesting. Considering a lot people here have taken benzos and not seen dramatic improvements, I am guessing there might be something special that Ativan does that other benzos dont.

 

[perrier]

Interesting. Considering a lot people here have taken benzos and not seen dramatic improvements, I am guessing there might be something special that Ativan does that other benzos dont.

Thanks for raising this. In fact, many CFS/ME doctors routinely prescribe Klonopin, for sleep and to tamp down the nervous system. Yet, it looks like Ativan is more beneficial. Both are highly addictive. Frightfully so. I know, as I see a family member trying to wean down from Klonopin (Clonazepam)

 

[Rufous McKinney]

Yes, surely it would have been tested early on given Whitney's positive response to it.

I"m in the throes of backing down my .5 mg Xanax I take to help me sleep. I'm at .25 mg. Things are ok, but the 4 am syndrome is starting up...awake, WIDE awake...lists....I had killed off the list, now the list is back.

Does anyone here know much about just TAKING GABA? I see it on supplement shelves. I've taken myself some of the stress mixes that have theonine, other herbs, some GABA...I did not find them NEARLY as helpful as: just give me that Xanax. Why is that?