My grand theory of etiology part II

[frozenborderline]

I've posted my unifying theory of etiology before. But part II is not quite done yet, however it has a lot of the parts there, just not all there, and not assembled properly or in order, so I've decided to kick off working on assembling it by posting about it here.


None of the parts by their own are that novel but I think all together they are.

To be really brief : the main four things are
3 internal factors:
1. NMDA upregulation, and excitotoxicity which connects in novel way to the metabolic trap bc kynurenic acid is low in metabolic trap and is glycine site specific (the best kind, according to my personal guinea pig and also the evidence) NMDA antagonist . Unfortunately I can't obtain KA atm but I have tried xenon and plan to try phenylalanine, and I can say so far the class of meds lives up to potential.
Connects easily to both mechanical injury and biotoxins for quite obvious reasons.

2. The "imbalance" between innate and adaptive immune system with the result of "mcas" alongside various types of immune deficiencies. Maybe should've been number one bc its key to the development of me/cfs in the first place. But point is. As maitland and I'm sure others with credentials and even expertise have noted, the immune system isnt just either over or under activated. It can be both. Bc the innate inmunebsystem , which includes but not ltd to mast cells. Can overcompensate for the adaptive immune system, which can be low in immunoglobulins of various kinds, key to making antibodies, which are part of w more targeted immune response (less friendly fire ). This gels with my experience but I'm sure others have noticed same thing in their labs. I just need to pull more sources ,I do have some of maitland saying this, and there's some literature on CVID which suggests it lead to excess inflammation but I need more sources. This problematizes MCAs, which I've always though was wielded as oversimplified if important concept that should be seen as part of greater whole.

3. Glymphatic system and connection with cci, and csf flow and pressure, and detoxification and cleaning of brain. This could be upstream of immune problems. Also key to disturbed sleep, and related to structural issues and feedback loops. It connects mainstream (sort of ) structural theories of cfs with esoteric ideas about toxins from environment and detox impairments, that people like Daniel cagua koo and Lisa petrison have.



Then there's the 1. Main EXTERNAL factor.

Only it's not a single simple thing. The external factor is whatever the main outdoor toxin effect is. which is probably some combination of pollution or chemical and biotoxin but we dont yet know specifics. Probably impossible to study well without tons if money.


Also maybe related to earlier etiological theory by glutamate excess stuff and maybe can refresh the very important things about the processes that damage collagen or elastin or any connective tissue component. Mmp-9 and tgf beta and tryptase and more more more more.


@Hip maybe you'll like this, even the highly simplified and devoid of sources form

 

[frozenborderline]

@sb4 you too

 

[frozenborderline]

@rpapen77

 

[Irat]

I've posted my unifying theory of etiology before. But part II is not quite done yet, however it has a lot of the parts there, just not all there, and not assembled properly or in order, so I've decided to kick off working on assembling it by posting about it here.


None of the parts by their own are that novel but I think all together they are.

To be really brief : the main four things are
3 internal factors:
1. NMDA upregulation, and excitotoxicity which connects in novel way to the metabolic trap bc kynurenic acid is low in metabolic trap and is glycine site specific (the best kind, according to my personal guinea pig and also the evidence) NMDA antagonist . Unfortunately I can't obtain KA atm but I have tried xenon and plan to try phenylalanine, and I can say so far the class of meds lives up to potential.
Connects easily to both mechanical injury and biotoxins for quite obvious reasons.

2. The "imbalance" between innate and adaptive immune system with the result of "mcas" alongside various types of immune deficiencies. Maybe should've been number one bc its key to the development of me/cfs in the first place. But point is. As maitland and I'm sure others with credentials and even expertise have noted, the immune system isnt just either over or under activated. It can be both. Bc the innate inmunebsystem , which includes but not ltd to mast cells. Can overcompensate for the adaptive immune system, which can be low in immunoglobulins of various kinds, key to making antibodies, which are part of w more targeted immune response (less friendly fire ). This gels with my experience but I'm sure others have noticed same thing in their labs. I just need to pull more sources ,I do have some of maitland saying this, and there's some literature on CVID which suggests it lead to excess inflammation but I need more sources. This problematizes MCAs, which I've always though was wielded as oversimplified if important concept that should be seen as part of greater whole.

3. Glymphatic system and connection with cci, and csf flow and pressure, and detoxification and cleaning of brain. This could be upstream of immune problems. Also key to disturbed sleep, and related to structural issues and feedback loops. It connects mainstream (sort of ) structural theories of cfs with esoteric ideas about toxins from environment and detox impairments, that people like Daniel cagua koo and Lisa petrison have.



Then there's the 1. Main EXTERNAL factor.

Only it's not a single simple thing. The external factor is whatever the main outdoor toxin effect is. which is probably some combination of pollution or chemical and biotoxin but we dont yet know specifics. Probably impossible to study well without tons if money.


Also maybe related to earlier etiological theory by glutamate excess stuff and maybe can refresh the very important things about the processes that damage collagen or elastin or any connective tissue component. Mmp-9 and tgf beta and tryptase and more more more more.


@Hip maybe you'll like this, even the highly simplified and devoid of sources form

I m fully with you on the NMDA receptors upregulation and excess glutamate.this scenario is not only the case in post viral ME,but also in drug injured ppl with an SSRI or antibiotic,or after a chemical injury.However whatever you try to lower the glutamate for example by blocking the NMDA receptors can make things worse by further upregulation.

 

[Learner1]

While this may help explain your situation, I'm not convinced it applies to all of us.

1. NMDA upregulation, and excitotoxicity which connects in novel way to the metabolic trap bc kynurenic acid is low in metabolic trap and is glycine site specific (the best kind, according to my personal guinea pig and also the evidence) NMDA antagonist . Unfortunately I can't obtain KA atm but I have tried xenon and plan to try phenylalanine, and I can say so far the class of meds lives up to potential.
Connects easily to both mechanical injury and biotoxins for quite obvious reasons.

KA is not low in everyone.

2. The "imbalance" between innate and adaptive immune system with the result of "mcas" alongside various types of immune deficiencies. Maybe should've been number one bc its key to the development of me/cfs in the first place. But point is. As maitland and I'm sure others with credentials and even expertise have noted, the immune system isnt just either over or under activated. It can be both. Bc the innate inmunebsystem , which includes but not ltd to mast cells. Can overcompensate for the adaptive immune system, which can be low in immunoglobulins of various kinds, key to making antibodies, which are part of w more targeted immune response (less friendly fire ). This gels with my experience but I'm sure others have noticed same thing in their labs. I just need to pull more sources ,I do have some of maitland saying this, and there's some literature on CVID which suggests it lead to excess inflammation but I need more sources. This problematizes MCAs, which I've always though was wielded as oversimplified if important concept that should be seen as part of greater whole.

Though I find much of this is true for me, I've seen labs from many other patients, and this is not true for them. Some people are not immunodeficient, and others don't seem to have autoimmunity, and some don't have MCAS, though some do.

CVID in itself does not lead to inflammation. My inflammation markers are low much of the time, and occasionally rise, but there's usually a reason.

MCAS can be reduced by working on triggers and mast cell mediators.

3. Glymphatic system and connection with cci, and csf flow and pressure, and detoxification and cleaning of brain. This could be upstream of immune problems. Also key to disturbed sleep, and related to structural issues and feedback loops. It connects mainstream (sort of ) structural theories of cfs with esoteric ideas about toxins from environment and detox impairments, that people like Daniel cagua koo and Lisa petrison have.

This is a very interesting area. I would like to learn more about this. Do you have any references to any research on these topics?

1. Main EXTERNAL factor.

Only it's not a single simple thing. The external factor is whatever the main outdoor toxin effect is. which is probably some combination of pollution or chemical and biotoxin but we dont yet know specifics.

Are you thinking that this is one of the chemtrails things? A RoundUp consequence?

Seriously, various people here have been exposed to various toxins, whether they are mold, heavy metals, gadolinium, or chemotherapy drugs. I don't think it's one thing for all of us.

 

[Rufous McKinney]

This is a very interesting area. I would like to learn more about this. Do you have any references to any research on these topics?

I tend to park on this topic/aspect as very huge in my case.

 

[frozenborderline]

While this may help explain your situation, I'm not convinced it applies to all of us.

would you really say that there is any single , shared explanation for all of the cases of me/cfs ? I dont claim to explain all cases. The phrase a unifying etiology just refers to trying to put together the facts for a shared group of patients ... I am looking at it as more of a lumper than a splitter, but even so, I would not ever presume I could explain every single me/cfs case. A good theory could maybe explain between a third and 75% of me/cfs cases.

KA is not low in everyone

I've never had mine measured. I do think that it's not measurable as the intracellular amount, especially in brain cells, is more representative of true picture than blood levels. However I'm not saying that proves that KA is high. This isnt a hill I'd die on. I used to be skeptical of robert phair theory, until I saw the NMDA antagonism angle. Glycine site specific NMDA antagonists are so, so powerful in their healing effects, and qualitatively different from other types of NMDA antagonists. That I started to become interested in them as a possible me/cfs cure. Then I learned that Kynurenic acid, the metabolite that would be low if the metabolic trap theory is correct. Is one of the glycine site NMDA antagonists and a potent neuroprotective medication. This connects the idea of bistability and a "metabolic trap " to the problems of glutamate excess and NMDA upregulation in me/cfs. I was already convinced NMDA and glutamate were central to me/cfs pathology, but the metabolic trap could help explain why me/cfs patients would have more glutamatergic excess after what to other people would be minor brain injuries or toxic exposures... I'm not saying its necessarily correct. But it's quite an interesting link and made me reconsider @HTester theory

CVID in itself does not lead to inflammation. My inflammation markers are low much of the time, and occasionally rise, but there's usually a reas

I'm really taking the words of others. Including anne maitland, at face value here. Maitland claims that there is an important relationship btwn immune deficiencies in adaptive immune system and an overexcited innate immune system including mast cell activation. I've also seen this said about IgA deficiencies by others, and I've seen some inter3sting remissions , partial or full, in mcas and autoimmunity , from ivig.

Seriously, various people here have been exposed to various toxins, whether they are mold, heavy metals, gadolinium, or chemotherapy drugs. I don't think it's one thing for all of us.

I don't know whether its all.one thing for all of us. One can both be a "lumper" and a "splitter" without contradictions if dialectical enough... for example I can see how the mechanical basis story and others like it show the brainstem is a possible locus of pathology even if I dont think everyone has mechanical compression of it. The point of looking for a common underlying pathology isnt that there's only a single cause but I think that it's about looking for patterns, which will help even if there's variation case by case. Brainstem inflammation can certainly cause similar symptoms to mechanical brainstem compression, and cyanobacteria or mold toxins can cause similar symptoms to heavy metals or pollution or viruses...

 

[frozenborderline]

This is a very interesting area. I would like to learn more about this. Do you have any references to any research on these topics

Yeah it took me a minute to dig up, but this: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681798/
It's certainly only a single study and there isnt enough research in this area but a lot of this is very intuitive to me bc:

1) we know that csf flow and the recently discovered and somewhat unknown glymphatic pathways are connected
2) we know those pathways have to do with waste, both metabolic waste products like proteins that influence neurodegeneration, and , at least according to the study I linked. Conventional toxins, heavy metals, mold, etc.
3) we already know about 5he csf flow connections to cci and chiari. What we dont know is exactly how that relates to the glymphatic system which is related to but not exactly the same as, the csf flow system.
4) proper restorative sleep is cleansing, with the csf flow 4rhythms and glymphatic system taking all of the waste out of the brain. We know that many people with cci note unrefreshing sleep. That doesn't stand out from "normal" cfs. But on the other hand, I'm talking about like really extreme sleep disturbances and problems compared to the norm. And things that get fixed after surgery or restoration of proper place of craniocervical junctions.

 

[frozenborderline]

Here are quotes from the aforementioned article:

Interstitial fluids flow out of the parenchyma along perivascular pathways. Since the brain has no lymphatic vessels or glands and it is not connected to the lymphatic system, it instead uses the perivascular spaces to move nutrients in and wastes out. Because of this, the author has also long maintained that the perivascular spaces serve as the lymphatic system of the brain and that sluggish CSF flow may play a role in pathology of neurodegenerative diseases and the increase in the presence of breakdown byproducts, viruses, bacteria, and heavy metals such as aluminum and iron [20, 21, 28, 91, 98, 102, 128, 234]. More recently it was discovered that in addition to providing pathways for the removal of wastes, the glial support cells that form the perivascular spaces also act as macrophages, which led to the term glymphatic system. Researchers now suspect that protein aggregation diseases, such as Alzheimer's and Parkinson's and the accumulation of beta amyloids and alpha synuclein, respectively, may be due to sluggish CSF flow [235–239]

These are pretty definitive sounding and impressive but I haven't combed through the references yet, it could be bs. It's a lot of work to vet each article. And it seems like csf flow and glymphatic system and even cci, is all stuff that's still being debated about and we dont know the dynamics of. I've seen some very heated debate on s4me about this very thing.


Michael vanelzakker and Paul Cheney (RIP) have pointed to more prominent or enlarged perivascular spaces as a feature of ME/CFS. But that's not why unpicked this section of the study. I picked it for the other stuff.

 

[Learner1]

would you really say that there is any single , shared explanation for all of the cases of me/cfs ? I dont claim to explain all cases. The phrase a unifying etiology just refers to trying to put together the facts for a shared group of patients ... I am looking at it as more of a lumper than a splitter, but even so, I would not ever presume I could explain every single me/cfs case. A good theory could maybe explain between a third and 75% of me/cfs cases.

No, I wouldn't. I think there are maybe about 25 different problems, and different patients have different groupings within that 25. I may have seven of them, you may have four, another patient may have 15. This makes finding one single cause, one single theory problematic, and even grouping people into subsets is difficult because of the mix and match nature of the various problems. We need a toolbox of tools to deal with all of this.

Then I learned that Kynurenic acid, the metabolite that would be low if the metabolic trap theory is correct. Is one of the glycine site NMDA antagonists and a potent neuroprotective medication. This connects the idea of bistability and a "metabolic trap " to the problems of glutamate excess and NMDA upregulation in me/cfs. I was already convinced NMDA and glutamate were central to me/cfs pathology, but the metabolic trap could help explain why me/cfs patients would have more glutamatergic excess after what to other people would be minor brain injuries or toxic exposures... I'm not saying its necessarily correct.

It may be correct and very important for some patients, but a number of us don't have glutamatergic access

I'm really taking the words of others. Including anne maitland, at face value here. Maitland claims that there is an important relationship btwn immune deficiencies in adaptive immune system and an overexcited innate immune system including mast cell activation. I've also seen this said about IgA deficiencies by others, and I've seen some inter3sting remissions , partial or full, in mcas and autoimmunity , from ivig.

I have immunodeficiency, autoimmunity, MCAS, and have been on IVIG. I have not gotten a remission from IVIG, though Rituximab greatly reduced my autoimmunity. But, it is possible to have all of this without a great deal of inflammation if one works at reducing the inflammation component and the things triggering the autoimmunity. And reducing the impact of infections in those that are immunodeficient.

The point of looking for a common underlying pathology isnt that there's only a single cause but I think that it's about looking for patterns, which will help even if there's variation case by case.

There are definitely patterns, not in a single cause. There are a variety of genetic and environmental factors that combine together to produce symptoms of ME/CFS.

Yeah it took me a minute to dig up, but this: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681798/
It's certainly only a single study and there isnt enough research in this area but a lot of this is very intuitive to me bc:

1) we know that csf flow and the recently discovered and somewhat unknown glymphatic pathways are connected
2) we know those pathways have to do with waste, both metabolic waste products like proteins that influence neurodegeneration, and , at least according to the study I linked. Conventional toxins, heavy metals, mold, etc.
3) we already know about 5he csf flow connections to cci and chiari. What we dont know is exactly how that relates to the glymphatic system which is related to but not exactly the same as, the csf flow system.
4) proper restorative sleep is cleansing, with the csf flow 4rhythms and glymphatic system taking all of the waste out of the brain.

I think this is a very interesting area to be looking into. Again, I don't think it's a factor for everyone, but it is definitely a piece of the disease and many patients.

I was in a significant car accident just prior to my developing ME/CFS, resulting in a whiplash injury and torn rotator cuff. I had cranial sacral therapy, which I would think is b******* if I read about it, which affects the flow of the fluid up and down the spine, and laying there, with this woman working on me, I felt marked releases at times, which reduced pain and improved my overall symptoms. So, I think there's something to all this.

 

[Rufous McKinney]

And it seems like csf flow and glymphatic system and even cci, is all stuff that's still being debated about and we dont know the dynamics of. I've seen some very heated debate on s4me about this very thing.

My body is far more sick on the right side and the collagen is far more broken down on the right side.

My neck is unravelling on the right side.

Pressure and fluid weight accumulate at the base of the skull and neck, and lymphatic system primarily on the right side.

body parts which include structural elements possessing more collagen, are degraded. On the right side.

More "illness" in the right half of my body expressed thru the lymphatic system, has degraded collagen.

I've lost so much padding on the bottoms of my feet I can't hardly walk barefoot on the kitchen floor.

 

[Rufous McKinney]

I had cranial sacral therapy, which I would think is b*******

My very smart and rational friend receives alot of help with her issues from cranial sacral therapy, as does her daughter.

 

[frozenborderline]

@HTester

@Janet Dafoe

 

[frozenborderline]

I have already worked on my own theory of ME/CFS etiology. It is pretty good but is due for an update. I like collaborative work and I'd someone brings new ideas that I find fitting or plausible ill incorporate them and give credit. But the main thing is I am too severe to type much or do anything other than record instructions with a voice recorded.

I have most of the theory of etiology in my head.

I know most people with cfs probably cant help but there's a spectrum of severity here , and I'm pretty far to the severe end so I figured there might be a few people to be able to do it. I also figure there maybe a few friends of ppl with cfs here and /or people who are caregivers or loved ones of pwME who are healthy themselves. I can also offer barter maybe and I can pay a small amount (I live on ssi so I don't have a ton to offer but for out of work ppl this may sweeten the deal ?). I also think that helping me finish this theory would contribute a lot to the furthering of me/cfs research, even more so if we can put it in a real medical hypotheses formal journal.

So yeah

Additionally I could use a bit of help with some web design and SEO related to promoting these theories and organizing them into charts that are interesting and visually comprehensible and minimalistic. But the main thing is finishing the theory itself .

Anyway , this is all a long shot but its important to me and I had t o
try

Reminder. I can offer some money. But not a lot. But if your desperate for even a bit lmk

 

[frozenborderline]

Any thoughts ?

 

[frozenborderline]

I'm wondering about how my newfound diagnosis of Hereditary alpha tryptasemia will fit iinto this paradigm. It doesnt rule out mastocytosis or mcas , but it is a genetic disorder that actually simplifies things in terms of explaining connective tissue problems and their connection to mast cell issues and GI and autonomic issues, it unifies all that into a single disorder rather than having 5hem be all separate and treated as separate. Yes, the gene can be asymptomatic even if u have it but given my constamt typtase and histamine and ige levels and my major symptoms it seems pretty obvious this is the real thing , once I got my genetic test results.

 

[frozenborderline]

also I still am absolutely going to take kynurenic acid if I get my hands on it... which is the stuff that connects the IDO trap to the glutamate problems.

 

[frozenborderline]

My new mcas immunologist was going to help with a lot of this and has been abdicating responsibility

 

[Learner1]

also I still am absolutely going to take kynurenic acid if I get my hands on it... which is the stuff that connects the IDO trap to the glutamate problems.

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."

 

[Wishful]

Er, why is that desirable?

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 .