Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients, Bertinat et al (2022)

I don't understand why it's so hard to figure out what exactly in the plasma is responsible for the various effects that have been reported, like this one. If it was up to me I would focus on this. It could finally answer the question of what this illness is while also giving us a basis for a diagnostic test.

 

There are probably many feedback loops where the body can try to restore function with a sluggish NO synthesis. However this may lead to further issues. So currently I see the problem as potentially inadequate regulation of lower than normal NO production, or slower NO production, and so on. However its intriguing that this might explain low blood volume, which has already been mentioned here. It might also explain much older findings but I am not currently able to investigate this. See the work by Vance Spence in the early 2000s.

This research not only needs to be replicated, they need in vivo replication as well as in vitro. Does this happen in live humans?

 

There are so many substances in blood and we keep finding new ones. If its a signalling molecule(/s) then it might require a major search effort, fractioning the blood via various methods to get more isolated samples with fewer substances so that other methods have a smaller range of substances to investigate. Alternatively if we can figure out the target of the signals we could work in reverse by using a purified sample to bind to whatever is in the blood.

Ron Davis' efforts on their something in the blood have suggested that its a large molecule or complex substance such as a vesicle. If this is true of this current research, which would need to be empirically verified, perhaps we could start by filtering the large substances out and concentrate the search there.

 

Yes, which is what I found disappointing about Ron Davis not following up on nanoneedle and is why I wonder how replicable that was.

With a replicable finding perhaps they could use gel electrophoresis of an active fraction initially separated by molecular weight, either centrifugation or molecular sieves, to isolate an active band and characterise that messenger and go from there.

 

They might have to test every single band to see if its the one. So the fastest way is to test subfractions, then fractionate the active one again and again, testing as they go. Alternatively, and not necessarily better, they can hypothesize a substance and test that. However even if its active it might not be the only active substance.

All of this requires a sufficient supply of plasma from PWME, with enough of a sample for each test. It might be necessary to use pooled blood plasma as well, in case there are patients who do not have the same biochemical issue. You wouldn't want to test with plasma from that patient.

 

But NO is a vasodilator. This study suggests ME/CFS plasma reduces NO production. So the results appear to be inconsistent with increased vasodilation in pwME – unless I’ve misunderstood (which is very possible).

This 2003 paper by Vance Spence and others, which highlights an apparent inconsistency between their findings and those reported in a paper on pyridostigmine, may be relevant:
https://www.meresearch.org.uk/wp-content/uploads/2012/12/Spence_PLEFA2004.pdf

 

I’m way out of my depth here but, if there is something in the plasma that is affecting the function of cells (endothelial and/or PBMC), is it possible, or even likely, that the quantity of this substance, and therefore the size of its effect on cell function, could increase in response to exertion? Have any of the “something in the blood studies” compared the effect of plasma from the same individuals before and after exertion? If not, is this something that might be useful to test?

If exertion increased the quantity of something(s) in the blood, which in turn affected the function of some types of cell, could that help to explain delayed PEM?

It would also be interesting to know if HELP apheresis had any effect on the effect of ME/CFS plasma on endothelial or other cells (if there is a reproducible effect).

 

This is what needs to be done imo.

 

That is my current take as well. However decreased synthesis in isolated cells do not take into account the systemic effects, including autonomic regulation. Figuring out ways to test actual patients, having identified issues of concern in isolated samples, is important to figure out what is actually happening.

 

there are other secondary messengers involved in vasodilation, off the top of my head, downregulation of one like NO might compensate for upregulation of another such as prostaglandin I2 (PGI2 aka prostacyclin or epoprostenol) to prevent excessive vasodilation. PGI2 inhibits platelet activation as well (as implicated in the clotting disorders which were linked to some vaccines recently) and that may be linked to homeostatic adjustment for sticky blood i.e. high ESR in PWME, perhaps to reduce risk of clots or anaphylaxis

source - Physiology, Vasodilation
https://www.ncbi.nlm.nih.gov/books/NBK557562/

it sounds like a very complex regulatory network and potentially subject to short term fluctuations

something as simple as walking up some stairs to get to a blood draw could change what is in some PWME samples compared to other PWME samples

so imho both subtypes and variability might both prove obstacles to replicability

I remember in my undiagnosed phase, sitting next to a radiator in a GRE exam and having to scrub my test because I could not keep my eyes open and only completed about half the test when previously I had been able to do all of a test in the given time in practice sessions at home and that felt like it involved vasodilation, so there is temperature as well to consider

 

@boolybooly

Most pwME have low ESR. Mine was 2.

 

Yes, may not be vasoconstriction, might be failure to compensate for increased demand, such as in exercise. However I think its likely it may induce lower blood volume, via very slight vasoconstriction.

 

Yes you are right, which is what I meant only I got it the wrong way round! Have struck it through with shame and embarassment!!

 

I was part of the study. There was no way to influence the results so the technician explained what they were doing and my results to me.

I had acetylcholine dripped onto my arm which dilated the blood vessels, then they used a doppler machine to measure how quickly the vessels went back to normal.

He said that I was typical of the patients in the study because it took much longer than normal for it to happen. The only positive test I ever had for my ME

 

l-Arginine increases NO
I just trialled a small amount and not sure if it was something I’d try again
I tried it as it’s mentioned in relation to CADASIL and wonder if a partial cadasil may exist and could it be more common

 

Arginine is considered by some to be a viral replication promoter especially with herpes viruses.

It is found in abundance in chicken and turkey and eating these can trigger a virus episode of recurring virus or prodrome nerve pain for me, which has happened many times.

There is a folktale recommended fix which is taking lysine which is believed to somehow compete with arginine and reduce its effect which I find only moderately helpful.

But whenever I get the pain of a viral recurrence starting I take lysine and if I make chicken or turkey broth these days I throw in a spoonful of lysine for luck.

For these reasons arginine is not something I would take as a supplement. FYI

 

Many patients have tried arginine and other agents over the years, I don't recall ever hearing of major results. One thing we do not know is if arginine works properly in ME. We also do not know how the suppression works.

As @boolybooly said, it can cause issues. I think this is because some viruses require a lot of arginine to replicate, and lysine can be used instead but the virus is less viable. I used to know this stuff 20 years ago, now not so much.

 

In my theories for delayed PEM (which I admit have no basis in actual knowledge), one explanation is that the delay results from processes that take time to ramp up.

For instance, I often have 'immune' type symptoms. This doesn't mean the immune system is actually involved, of course; but if it were, maybe PEM involves one of the immune processes that needs a bit of time to recruit, relocate, or manufacture a cell type or molecule in order to cause noticeable symptoms?

 

I think it also involves our stress hormones (thyroid etc). It feels like a maladaptive stress response, so instead of gearing-up for the day, it takes a crash, which could be why I feel worse in the mornings.