My grand theory of etiology part II

[Rufous McKinney]

3. Glymphatic system and connection with cci, and csf flow and pressure, and detoxification and cleaning of brain.

I'm really into this aspect....it feels like what I deal with alot.

Detox is very broken here. And every time I try ANYTHING, the level of More sick is shocking and I largely can't willingly handle it.

 

[frozenborderline]

Er, why is that desirable?

"Kynurenic Acid is a possible metabolite of tryptophan, and it comes directly from kynurenine, an intermediate in tryptophan metabolism. Metabolism of kynurenine is dependent upon reduced, phosphorylated vitamin B3 as NADPH and upon kynureninase which is very sensitive to vitamin B6 function as pyridoxal 5-phosphate.

High Levels: Usually, elevated kynurenic acid means that vitamin B6 is functionally deficient. This impacts the body’s ability to form nicotinic acid (vitamin B3) and picolinic acid, both of which are eventual metabolites of kynurenine and tryptophan. Severe vitamin B3 deficiency results in pellagra. Vitamin B6 deficiency symptoms are consistent with elevated kynurenic acid: fatigue, irritability, gastrointestinal distress,
neuritis and neuropathy."

This may be about mistaking cause and effect. There may be some disorders that cause elevated kynurenine but I think that a) this doesnt mean kynurenine causes these disorders, it could simply be an indicator, causality the other way and b )overly low kynurenic acid and kynurenine is the issue in ME/CFS according to the metabolic trap theory.

Additionally, kynurenic acid is an NMDA antagonist, which is a class of substances that tend to be neuroprotective, but there is a 0plethora of studies that it specifically is neuroprotective. Also, there are a plethora of studies showing high glutamate in the brain of me/cfs pati4nts , and from inference , I am as close as I can be to knowing I have high glutamate in my brain, without doing a brain biopsy or spectroscopy. I react extremely positively to anything that lowers glutamate like NMDA antagonists, lithium (low dose at least), gaba agonists, and anything like that. They cause remitting of many of my symptoms.

Anyway, kynurenic acid is tested in humans and considered safe orally I believe , but we have to do more research before I take it. announcing I will take it means at some time. Not right this second. We haven't even found a source.

But, it seems very very probable that our bodies have different issues. My theory of etiology is not solely based on my body but is based on a subset of people with similar symptoms and comorbidities. I do use my labs and myself as a prototype for it , but it's not solely about myself. However it's not going 5o cover everyone. For 3example, I have high glutamate in my brain, and you dont, or you have said that's not a problem if my memory is correct. And I have low blood volume, but 20% of patients with me/cfs dont according to dr bell (rest in peace) , if my memory doesnt fail me.

 

[frozenborderline]

I'm really into this aspect....it feels like what I deal with alot.

Detox is very broken here. And every time I try ANYTHING, the level of More sick is shocking and I largely can't willingly handle it.

I honestly think it may be the most important part , but it's also the least well understood. By me, or anyone

 

[Learner1]

If I had some conveniently available, I'd take it just to see what the effect was, since I do believe that my ME involves my kynurenine pathway. If it made my symptoms better or worse, at least that would reveal a link in my ME. Even no effect might be useful information, though I'd double-check to see whether KA crosses the BBB or if there's some other reason why taking it orally doesn't get it to brain cells.

I'd also probably try 1-methyltryptophan and L-4-Chlorokynurenine, just to see what happens. Hopefully rather than or .

Have you had your B6 level tested? Or trypttophan or niacin?

 

[sometexan84]

@frozenborderline This is SO interesting!!!

What else can you tell us??!!?

 

[frozenborderline]

Have you had your B6 level tested? Or trypttophan or niacin?

The claims about metabolic trap and levels of kynurenine pr tryptophan in the omf hypothesis are based on neurons , and what is present inside the cell, I dont think blood levels apply but I could be wrong.

 

[frozenborderline]

@frozenborderline This is SO interesting!!!

What else can you tell us??!!?

I could show you etiology part I. Since I never really finished part II.

https://walkerstorz.com/me-cfs-etiology/

Here it is

 

[sometexan84]

I could show you etiology part I. Since I never really finished part II.

https://walkerstorz.com/me-cfs-etiology/

Here it is

Now I just feel bad

I react extremely positively to anything that lowers glutamate

Ok, so, I urge you to look into Enterovirus in ME/CFS, and check out the studies on interactions between Enterovirus and glutamine/glutamate.

I know you like research, so I recommend reading the articles that talk about the negative effects Enterovirus has on Glutamate, but ALSO, the cell tropism of Enterovirus, and the effects that glutamate and glutamine have on those cells.

I also highly recommend trying to remove yourself from the IDO metabolic trap theory... and instead, just focus on your own research... you are in a far better position to study ME/CFS, than Ron Davis. Use that! And don't let NON-sick researchers dictate where you go w/ your research.

Either trust what THEY say.. OR do your own thing. There's no in between. Because one will impact the other.

 

[frozenborderline]

Now I just feel bad

Bad about what ?

 

[frozenborderline]

I also highly recommend trying to remove yourself from the IDO metabolic trap theory... and instead, just focus on your own research... you are in a far better position to study ME/CFS, than Ron Davis. Use that! And don't let NON-sick researchers dictate where you go w/ your research.

I only include a link to the ido trap bc even after being skeptical of it for some time, I'm interested in the general area of bistable systems. Additionally I think that the fact that the main metabolite hypothesized to be low was something that is a glycine site NMDA antagonist, and lowers glutamate , makes the hypothesis all the more plausible. It still need to be tested. But the point is , it's an interesting possible connection that would explain a lot. We really barely know anything in ME/CFS but I've noticed some things that point very obviously to high brain glutamate, although of course there are already studies showing high brain glutamate. But the thongs I've noticed clinically that point that direction... the whole wired -tired feeling. Having that feeling with cognitive PEM but having it extinguished by meds that affect and lower glutamate, meds from NMDA antagonists like ketamine or magnesium to gabapentinoids to gaba agonists like benzodiazepines. And then having that feeling worsened by even low doses of classic stimulants and having an absurdly low threshold for that. As well as weird rebound stuff the next day with gabaergics

Either trust what THEY say.. OR do your own thing. There's no in between. Because one will impact the other.

there is an in between. I am pretty much in favor of patients having a role in research but we need professionals too, and people with the energy of healthy people. I dont have a black and white attitude. The omf I've been very very critical of, but I can still point to a concept or work they've done I like . Even moreso with other researchers.

 

[Wishful]

Have you had your B6 level tested? Or trypttophan or niacin?

I did have a KYN/TRP level done. The result was the opposite of what I expected, but I expect it's meaningless because as frozenborderline pointed out, serum levels probably don't have much correlation to the levels in brain cells. Non-standard tests are inconvenient here in Canada, so I wouldn't bother with testing unless it was clear that the results would have real meaning. Instead I try supplements. B6 shows no significant effect. B3 had a serious negative effect, though I haven't tested it recently.

If I had a serum test done for vitamins or proline (which I'm unusually sensitive to), what would an abnormally high or low reading mean? Who could make a valid interpretation of it? I could imagine some situations where an abnormal reading could lead to a treatment, but I think that's the rare exception rather than the general case.

 

[frozenborderline]

If I had a serum test done for vitamins or proline (which I'm unusually sensitive to), what would an abnormally high or low reading mean? Who could make a valid interpretation of it? I could imagine some situations where an abnormal reading could lead to a treatment, but I think that's the rare exception rather than the general case.

a lot of the tests on the market for metabolic stuff and things like proline I dont think is standardized enough to behelpful, plus the part about serum levels not necessarilyreflecting cellular and paracrine stuff,.

Vitamins , depending on the vitamin, are often a bit more standardized for blood levels. But there can still be issues 2with the tests. However I mostly trust stuff like b12 tests, vitamin d tests, and so on.

did have a KYN/TRP level done. The result was the opposite of what I expected, but I expect it's meaningless because as frozenborderline pointed out, serum levels probably don't have much correlation to the levels in brain cells. Non-standard tests are inconvenient here in Canada, so I wouldn't bother with testing unless it was clear that the results would have real meaning. Instead I try supplements. B6 shows no significant effect. B3 had a serious negative effect, though I haven't tested it recently.

Yeah, serum tests of this could be interesting but besides naturopaths who have vested interest in selling tests I haven't heard of any tests for medical use that manage to get useful readings on stuff like that, and of course even if the serum test was standardized, I dont think it would reflect what's in the cells. By "stuff like that" I mean metabolic stuff akin to what's studying with metabolomics in the lab with 3000 dollar machines. I do not think theres useful personalized Medicine interpretations of this.

Honestly the only questions to ask here before experimenting with kynurenic acid are "is it safe in general, based on the literature. Or would it be expected to be safe based on how much is absorbed and how it functions endogenously ? "
And then "is this a reliable source of kynurenic acid"..

Also id recommend KA rather than kynurenine as its thr active form , just in case kynurenine doesnt convert for some reason.

 

[frozenborderline]

So I want to hire someone to work on some research things for me. But have some 2questions. I want to pay for actual time working and not get fucked over as I'm disabled and dont have much money. Are there3 apps for hiring freelancers where you can monitor how much work they're doing , or when they're working , like on their computer (consensually).

Or te other option is to just pay half up front and half on completion

 

[frozenborderline]

Purinergic signalling is going to be worked in here at some point. As well as hereditary alpha tryptasemia

Btw How does one find a doctor willing to work as a partner and listen to ones own theories

Has anyone found that at all???

 

[frozenborderline]

https://www.nature.com/articles/ng.3696

 

[frozenborderline]

Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number

• Jonathan J Lyons,
• Xiaomin Yu,
• …
• Joshua D Milner

Show authors
Nature Genetics volume 48, pages1564–1569 (2016)Cite this article

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Abstract
Elevated basal serum tryptase levels are present in 4–6% of the general population, but the cause and relevance of such increases are unknown1,2. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase–encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.

 

[frozenborderline]

https://www.nature.com/articles/s41581-020-00357-4

 

[frozenborderline]

Stuff about purinergic signalling :

https://www.ncbi.nlm.nih.gov/pubmed/25695577/

Lidocaine is a p2x7 antagonist, which is very interesting. The controversial cfs doc jay Goldstein used intravenous lidocaine in ME/CFS patients as one of his most used treatments.

“No one can justify life by linking happy moments into a rosary.”

https://openletteropenmedicinefoundation.com
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frozenborderline
Senior Member
“The transmitter ATP, usually coreleased with NE, is extremely nocicep- tive and has been implicated in the pathophysiology of reflex sympathetic dystrophy, also known as complex regional pain syndrome. It is released from microvascular endothelial cells during migraine headache and angina. ATP release is associated with distension of the tubular viscera (Burnstock G, 2001). There are two classes of purine receptors, P1 (adenosine) and P2X (mostly for ATP). The P2X2 and P2X3 receptors can be coexpressed to pro- duce a channel with a slowly desensitizing response. P2X3 receptors are not affected by pH, but recombinant P2X2 receptors are strongly pH sensitive. The combination of the two is still pH sensitive but to a lesser extent (Stoop R et al., 1997). Acid pH augments the excitatory actions of ATP on dissociated mammalian sensory neurons. Because prescribing suramin, a general an- tagonist of all PX receptors, is not feasible, and receptor-specific antago- nists are not yet available, consideration should be given to mild alkalini- zation of patients with painful neurosomatic disorders. The response is prompt, and the alkalinizing agent may be titrated by tolerance and effec- tiveness.” From Goldstein’s “tuning the brain”. So he is suggesting either other hypothetical purinergic antagonists which could be safer than suramin or altering ph to affect purinergic receptors

 

[frozenborderline]

https://pubmed.ncbi.nlm.nih.gov/20043284/
The fact that mmp-9 , which is known to be a problem in my case and is central to the connective tissue damage in etiology theory part I, can regulate nmda recptors, which are important to part II of the etiology theory, shows that these parts can be connected and we have only barely b started digging

 

[frozenborderline]

"Matrix metalloproteinase-9 reversibly affects the time course of NMDA-induced currents in cultured rat hippocampal neurons
Tomasz Gorkiewicz 1, Katarzyna Szczuraszek, Paulina Wyrembek, Piotr Michaluk, Leszek Kaczmarek, Jerzy W Mozrzymas
Affiliations expand

• PMID: 20043284
• DOI: 10.1002/hipo.20736

Full text linksCite

AbstractPubMedPMID
Abstract
Matrix Metalloproteinase 9 (MMP-9) has been demonstrated to play a crucial role in maintenance of NMDA receptor-dependent LTP and in lateral mobility of these receptors. However, the effect of MMP-9 on NMDA receptor (NMDAR) functional properties is unknown. For this purpose we have investigated the impact of recombinant MMP-9 on the whole-cell NMDAR-mediated current responses in cultured hippocampal neurons. Treatment with MMP-9 induced a reversible acceleration of desensitization and deactivation kinetics but had no effect on current amplitude. Interestingly, phorbol ester, a PKC activator known to enhance NMDAR lateral mobility, induced kinetic changes of currents similar to those produced by MMP-9. In conclusion, our results show that MMP-9 reversibly modulates the NMDAR kinetics and raise a possibility that this modulation could be related to the lateral mobility of these receptors."