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The true nature of an autoimmune disease, Leisk and Nocon 2021

Discussion in 'BioMedical ME/CFS Research' started by Jaybee00, Mar 14, 2021.

  1. Jaybee00

    Jaybee00 Senior Member (Voting Rights)

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    https://www.researchgate.net/profil...oimmune-disease.pdf?origin=publication_detail

    Preprint—not peer reviewed.


    Abstract
    Here we propose a hypothetical model seeking to map the pathogenesis of a herpesviridae-positive serology subtype of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME) as a simultaneous α-ketoglutarate dehydrogenase (α-KGDH) and pyruvate dehydrogenase (PDH) deficiency, with degraded beta-adrenergic signalling cascade and impaired hepatic gluconeogenesis, phasic hyperlactatemia and hyperammonemia - as caused by herpesviridae-mediated antibodies and latent cell burden.
    For example, “M37GO37” targets dihydrolipoamide succinyltransferase from the α-ketoglutarate dehydrogenase complex (α-KGDC), creating an acute deficiency of α-KGDH, impairing Citric Acid Cycle (CAC) metabolites from succinyl-CoA / Complex V through malate, accumulating α-ketoglutarate (α-KG), reducing adenosine triphosphate (ATP), NAD+ and respiration.
    “M18GP8”, “M82GP8”, “M37GPl1” antibodies to pyruvate dehydrogenase complex (PDC), plus hypoxia, low physical activity and/or antibodies creating beta-adrenergic dysregulation can each cause a decrease in PDH, Cori Cycle efficiency and insulin resistance.
    When combined with succinate and argininosuccinate (ASA) deficiency, plus elevated α-KG, nitrogen disposal shunts to nitrogen retention via metabolism to L-glutamate and L-glutamine, triggering glutaminolysis.
    Sleeping, fasting and respiration decrease lactate and nitrogen retention via metabolic shunting, partially rescuing succinate availability for CAC, urea cycle metabolism via GABA.
    -1-

    Each of these α-KGDH, PDH and beta-adrenergic cascade deficiencies are able to cause both of the others, adding additional complexity to diagnosis and treatment. These phases can be accompanied by debilitating symptoms associated with hyperammonemia, GABA deficiency, glutamate-induced excitotoxicity, uremia, hyperlactatemia, adrenergic and cortisol dysregulation, with accompanying hair, skin, GI, collagen, immune, sphingolipid, endocrine, sleep and neurological disorders.
    This further suggests investigating the herpesvirus family as causal for numerous disorders.
     
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  2. borko2100

    borko2100 Established Member (Voting Rights)

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    If herpesviruses are at the root of ME/CFS, then how come we are currently amidst a long-covid (which is almost certainly CFS) epidemic caused by a coronavirus?

    I am not dismissing this theory though. Maybe it is possible that a herpesvirus is not the trigger itself, but rather reactivates in response to another triggering virus (eg. covid). I recall another researcher making a similar hypothesis about another virus family, whereby an infection allows a harmless latent virus to enter the brain / CNS and become pathogenic.
     
  3. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I don't think this is worth spending time on but it seemed odd to me that it is supposed to come from 'Aline Nocon's Lab when Dr Nocon works in regulatory affairs at Kinghorn Cancer Centre. This looks much more like daydreaming than a scientific review.
     
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  4. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    How exactly are these anti-PDC antibodies getting into the mitochondria?

    The manuscript reads as if they plucked together a few ideas and are trying really hard to make them all fit together, with scattered fragments of biochemistry mechanisms.

    The pathway diagrams are interesting, but they haven't provided any information as to how these were derived.

    The discussion about diagnostics is lacking in evidence. For example, there is suggestion that the various herpes virus tests often aren't any good, but this begs the question why? If EBV is not found in circulation, then tell us where to look instead!
    Likewise, the discussion of treatments is hypothetical, but should explicitly be phrased in a way that proposes testable experiments.
    For that matter, I think all hypothesis papers should explicitly propose specific experiments (methodology) - after all, the whole reason why you'd publish a hypothesis paper, rather than do the experiments yourself is because you lack funding/access to a suitable lab.
     
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  5. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    There has been a longstanding debate about how easy it is for antibodies to get into intracellular compartments, with Alarçon-Segovia being a key figure. I think the evidence is good that IgG gets into cells. There are receptors that can cycle IgG into cells and there is a molecule called TRIM21 which I think is part of the Ro complex to which there are antibodies in Sjogren's, that seems to act like a sort of intracellular C1q for intreating with IgG. Antibodies can almost certainly get at nuclear proteins and ribosomal proteins inside cells. Translocation into mitochondria might also occur - I don't see why not.

    On the other hand I don't think this home-made review by someone who claims to have a lab but does not even seem to appear on the staff list of the relevant organisation makes any sense at all!
     
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  6. joshua leisk

    joshua leisk Established Member (Voting Rights)

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    Hi All,

    Author here. Happy to help!

    > If herpesviruses are at the root of ME/CFS, then how come we are currently amidst a long-covid (which is almost certainly CFS) epidemic caused by a coronavirus?

    Hypoxia from COVID-19 triggers reactivation of EBV.

    > I don't think this is worth spending time on but it seemed odd to me that it is supposed to come from 'Aline Nocon's Lab when Dr Nocon works in regulatory affairs at Kinghorn Cancer Centre. This looks much more like daydreaming than a scientific review.

    "Aline Nocon's Lab" is just the default name that ResearchGate applies to a group. We have no physical lab - this research is theoretical work, only, based on the 273 citations.
    Here's a little more info on Aline's background.

    https://au.linkedin.com/public-profile/in/dr-aline-nocon-phd-52559263

    I'm more of an anomaly. I'm a fully recovered CFS/ME sufferer with a strong background in IT and and interest in bioinformatics. I "retired" at 38 and got bored. I like puzzles, pathways and systems. This was a puzzle that had bothered me for a few decades, so I thought it was worth helping people solve.

    > The discussion about diagnostics is lacking in evidence. For example, there is suggestion that the various herpes virus tests often aren't any good, but this begs the question why? If EBV is not found in circulation, then tell us where to look instead!

    For CFS/ME - the liver. My opinion is that it's a combination of the antibodies from the lytic phase, PLUS the primary issue of latent viral hepatitis - the metabolic burden of the latent cell activities, hard-wired by KGA, GLS1, etc., for protein-synthesis tasks, glutaminolysis and lactate production interfere by the behaviour of the neighbouring hepatic cells. eg Lactate cycle metabolism. Arresting the lytic phase does not solve CFS/ME, but it will reduce the antibodies. Check EBNA IgG counts for systemic latent infection and infer localised hepatic infection by performing the 'succinate challenge' I mentioned in the paper. For other disorders and diseases, it's largely tissue specific.

    > Likewise, the discussion of treatments is hypothetical, but should explicitly be phrased in a way that proposes testable experiments.
    For that matter, I think all hypothesis papers should explicitly propose specific experiments (methodology) - after all, the whole reason why you'd publish a hypothesis paper, rather than do the experiments yourself is because you lack funding/access to a suitable lab.

    As the test is also very simple and merely involves a handful of over-the-counter dietary supplements and some pathology markers, the paper was written in a way to deter everyone on the internet just jumping in trying it ahead of any clinical trials, however some limited case report data will follow.

    We would happily perform the experiments ourselves, but as you say - we're a pair of researchers without a lab facility. We would love to run a clinical trial based on some robust preliminary test results, however we are reliant on others for properly testing this hypothesis. We are currently engaging with some existing parties to make that happen, although are open to assistance from any other parties.

    We're happy to work with others. In case we have misinterpreted any cited papers, we're open to any discussion and correction.
     
  7. Trish

    Trish Moderator Staff Member

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    Hi @joshua leisk, welcome to the forum. Thank you for explaining the background to your hypothesis.
     
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  8. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I am afraid I do not understand what the finding of some antibodies to mitochondria in liver disease has to do with ME/CFS where there is no evidence for any such antibodies. People have been trying to piece together stories involving EBV and involving autoimmunity for ME/CFS for decades and there is precious little to suggest it is worth ploughing the same furrow further. Suggesting treatments on the basis of speculation like this seems to me unhelpful and potentially damaging for desperate patients looking for answers.
     
  9. joshua leisk

    joshua leisk Established Member (Voting Rights)

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    Hi John, I understand where you're coming from.

    I think you might be focusing on the wrong aspects of the paper. What I demonstrated was a model where any 1 of many situations causes the same "loop" and state.

    I also demonstrated how that would happen from a non-HHV source, eg. C.diff.

    Reversing this loop can be demonstrated easily, using a handful of common over-the-counter supplements. I intend to publish some case reports on this in the near future.
     
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  10. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Do you have any competing financial interest in supplements?
     
  11. joshua leisk

    joshua leisk Established Member (Voting Rights)

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    No, but we have filed a patent based on the method.
     
  12. mariovitali

    mariovitali Senior Member (Voting Rights)

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    Hi @joshua leisk Thank you for your posts and welcome to the forum.

    I read through your paper. It is way above my knowledge but it appears to have a lot of interesting concepts -based on my personal research- being identified, namely Glutamate, Liver function, Complex V, Cholinergic signaling, PDHC and DHT.

    Before asking some questions here is my quick story :

    -Patient of ME/CFS for many years now fully functional using supplements only. I got ME/CFS gradually after i stopped finasteride which is a 5-alpha reductase inhibitor.

    -I used a -now- patented methodology using Machine Learning and Network Analysis methods with the goal to identify important components of ME/CFS but also other syndromes such as Post-Acccutane syndrome, Post-finasteride syndrome, Post-treatment Lyme disease syndromne and Gulf war syndrome (among others).

    -Of interest is your mention on the Liver. The methodology i used identified that any Liver Injury can set the stage for ME/CFS (as opposed only to viruses) . Please see tweet below :





    My questions :

    1) Does your model apply to cases of ME/CFS where a hepatotoxic agent such as fluoroquinolones (or any other hepatotoxic medication) may have been the trigger ?

    2) The intervention you described using supplements will be a "one-fits-all" intervention or we should be looking at a personalized treatment?

    3) Could your model be applicable to Post-accutane syndrome (13-cis retinoic acid) and Post-finasteride (5-alpha reductase inhibitor) syndrome?



    Thank you in advance
     
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  13. joshua leisk

    joshua leisk Established Member (Voting Rights)

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    The background on this discovery is that in the course of my normal consulting, I had a cluster of 5 diet coaching clients over roughly one month presenting for a number of different goals, yet similar issues - with a common complaint of daytime fatigue.

    Most had joint pains and involuntary muscle contractions. The male and female clients had endocrine, sleeping and neurological disorders, such as acute anxiety. The males and females exhibited signs of alopecia. All had extensive pathology data, spanning more than 10 years and a history of symptoms longer than 15 years. Only one client had ever been officially labeled as a "CFS/ME" patient.

    I compiled and analyzed their pathology data and saw a common pattern of urea cycle abnormalities, cortisol / adrenal cortex dysregulation and mild leukopenia - specifically, borderline subclinical lymphocytes. ANA, CK, cRP, ESR, thyroid markers all unremarkable. Some minor liver enzyme elevations in some clients, which appeared to match their body composition and life choices. I thought the overall pattern was interesting, so I kept investigating.

    Most clients had acute eating disorders. Ear/nose/throat infections were common. Environmental allergies were common. There was a history of GI issues and all had a specific pattern of food intolerances. Eggs and lecithin were consistently mentioned. I found that even more interesting.

    I assessed their dietary habit using one of my favourite nutrition tracking tools, "Cronometer". The observed protein intake was very low - typically less than 40 grams per day, which did not match the unusual serum urea also being observed - BUN was typically high range, or in one client, very low range. This was interesting, because it suggested that either glutaminolysis was being used, and / or the urea cycle was impaired at different times.

    3 of the clients had reported some benefits from ketogenic diets. 1 of them was currently employing a ketogenic diet. The others had not attempted this. This 1 client chose to discontinue their ketogenic diet and had an acute worsening of symptoms. This was interesting because it demonstrated a pattern of mitochondrial impairments.

    All clients had a habitual lifestyle that obsessively revolved around dietary supplements. This was also interesting and it allowed me to ask them what supplements they took regularly and why.

    Importantly, I also asked them what they didn't take and why - "what had they experienced negative reactions to?"

    A common list of "problem" supplements for all clients was acetyl-l-carnitine, EGCG, choline, arginine, citrulline. Some of them reported that acetyl-l-carnitine caused acute edema and myopathy. I found that very interesting, also - suggesting influences to fatty acid oxidation / PDH, GDH, acetylcholine receptors, respectively.

    All of the clients had exercise intolerance to even the mildest exertion levels, with suboptimal lactate threshold and oxygenation, even beyond my expectations for a sedentary lifestyle.

    3 of the clients had prescriptions for salbutamol inhalers.

    From this combined data, I saw more patterns forming. I analyzed other data they had captured, including HTMA tests, which excluded heavy metals, etc as a source of hypoxia.

    At this point, I decided to take a personal interest in these cases and chose to work closely with 2 of these clients on a daily basis, exploring published literature and talking with them for typically 5-8 hours a day over many months, observing and analysing high levels of detail about their diet, daily activities, symptoms, influences / triggers / responses, while assembling connections between individual data points. This was a performed without any financial consideration. Being "retired" made this level of dedication and focus possible.

    Dietary intervention of adding 2 eggs and some soy lecithin to every meal and 2 more before bed improved or resolved involuntary muscle spasms, with some not-unexpected discomforts. This was partially replaced by choline bitartate.

    Pathology for Plasma Amino Acids found some common abnomalities with elevated glutamine, glutamic acid, low 1-methyl-histidine.

    Exploring the literature and looking at the published CFS/ME metabolomics data, I saw many parallels between client data and published data. I explored this further, creating new connections along the way.

    Serology markers showed high titre active EBV in both cases. There were differences in testing method availability, due to geographical location.

    At this point, I considered that we had maybe progressed beyond "smoke", to "fire".

    [QUESTION - "Perhaps the impact from lytic EBV infection or CMV was the source of the symptoms?"]

    The location of pain and the relationship to the salbutamol dosage suggested strongly that beta-oxidation pathways were involved and the lactic acid cycle was impaired at hepatic gluconeogenesis. It didn't explain the cause of the high lactate, which I considered to be related to the impairments surrounding energy production.

    Via close observation of client myopathy vs activity, I could see that unusual amounts of lactate were being generated, in addition to impairments in hepatic conversion back to glucose.

    Combined with the noted urea cycle abnormalities and hypoxia, this was pointing strongly to a deficit in succinate and fumarate. The general lack of energy was suggesting an insufficient amount of ATP was being generated. This pointed to Complex V.

    Gradually, over these months, I collected enough information from observations and literature searches to collectively create a hypothetical map.

    There was a strong suggestion that spironolactone has efficacy for arresting EBV, CMV lytic phase.

    Both clients had some tangible improvements to many symptoms, but were still showing all of the hallmark CFS/ME pattern of impairments I had personally experienced all those years ago.

    [ANSWER - "The lytic phase is only partially responsible for CFS/ME. (n=2)"]

    [QUESTION - "Wonderful, so what does this mean?"]

    Looking at the pathway map I had created, three "hot-spots" were a-KGDH, PDH and selective beta-oxidation pathway insensitivity.

    NutraEval reports are incredibly useful for identifying these abnormalities, however these need to be interpreted based on the level of activity prior to sampling, in much the same way that metabolomic studies need to be controlled against time of day and prior activity levels to provide any meaningful data.

    Further to this, my research into the behaviour of HHV-infected cells revealed a metabolic preference for glutaminolysis (Krishna G et al), just like many cancer cells (Song Z et al.) and an ability to replicate via transcytosis (Hutt-Fletcher L et al.). This suggested a number of things, not the least of which was that these infected cells would be susceptible to the same metabolic influences as those cancer cells (Saunier E et al.). I considered that just like in certain types of cancer cells, the location and behaviour of the latent cells would have influence on the neighbouring cells. Where these are hepatic cells, this would unduly influence the hepatic function, in particular with regards to lactate metabolism / gluconeogenesis. In other tissues, many other disorders would be expected, where collagen synthesis and other tasks downstream of prolyl hydroxylase activities are degraded, leading to various states of inflammation and cortisol dysregulation.

    As such, in my capacity as a diet and health coach, I educated Client 1 and Client 2 on the benefits of specific over-the-counter dietary supplements which are known for addressing these pathways, with advice to verify with their physician if contraindicated in their illnesses.

    In the general population, like most dietary supplements in general, these specific dietary supplements would have little to no noticeable effects or benefits beyond those provided by a normal, balanced diet. They chose to purchase these from their local health food store or supplement vendor and self-administer them. They further chose to provide me with reports on their experiences with this self-experimentation.

    Unlike the typical 'non-response' expected in the general population, the effects from these specific supplements were reported as both rapid and acute in both clients. Their energy levels returned to normal and they regained normal daily functionality and lifestyles. Due to their natural curiosity and a long history of experimentation with supplements, they also tried different combinations and dose schedules of these supplements and reported the effects. I analysed their reports and noticed a pattern, where failure to address any one of these "hot-spots" I had educated them on led to a consistently repeatable pattern of initial impairments and a resumption of full CFS/ME symptomology.

    Using the combination of dietary supplments, viral EBNA IgG has been demonstrated to have decreased by 25% over 2 months, suggesting reduced systemic burden.

    [ANSWER - "We are long past 'smoke', well past 'fire' and currently 'discussing the merits of different coloured fire extinguishers.'"]

    [QUESTION - "This needs robust testing - how do I share this information with people who are in a better position to make use of it and without creating problems associated with communicating this around a demographic of patients who are desperate for early answers?"]

    At this point, although having read perhaps 900 papers, I thought it would probably be best if I studied the literature further, wrote a review and shared it with the community. This presented some new difficulties, as although demonstrated by my recent manuscript, through personal interests my understanding of metabolism, rheumatology, cellular biology, immunology, endocrinology and biological pathways could be considered with some equivalencies to a PhD level education, due to my life choices and preference for self-education, usually by intense reading, I lack the credentials required to present these findings to a wider audience, in the format they would normally be inclined to appreciate and give due consideration.

    I prefer to learn things in my own way and explore topics in an organic way, where my brain absorbs them efficently. I find structured education traditionally 'grinds my gears' by causing frustrations and inefficiencies, therefore I limit any formal education and certifications to the barest minimum required to permit me to work in any specific field. This is also likely why I left school at 14 and "retired" at 38. Overall, I have lived an unusual life.

    A self-taught "diet and health coach" traditionally does not write medical journal articles on complex metabolic disorders and virology. This is a significant anomaly, although my life to-date has been one long anomaly. Importantly, I also lacked a full understanding of the nuances and expectations of academia, with regards to publishing material for peer-review.

    [ANSWER - "Fortunately, through fate and/or luck, my life-partner and co-author happens to be a brilliant scientist, holding a PhD in Neuroimmunology, with a Masters in Biochemistry. Keeping in line with my usual preference for organic learning, she helped me understand the normal requirements for publishing a paper, assisted and answered questions about lab methodology, where I found criticisms of papers I was reading, edited and helped proof the manuscript, along with many other key aspects of the journey towards where we are today. I'm always thankful for having her in my life." ]

    In the process of continuing to map the pathophysiology, draw the diagrams and write the paper, my research connected the dots with a broader array of disorders and diseases. I realised that my research had significantly greater implications for many diseases and disorders. During the many weeks that was required to author the paper, I was was also contacted by some other clients and friends who had a number of different diseases / disorders - including bipolar disorder, schizophrenia, ehlers danlos syndrome, lupus and rheumatoid arthritis, which were already strongly hinted at having a common origin, by the growing manuscript and diagrams.

    Consequently, I found the same signature of metabolic alterations and serology markers in those clients and they show an acute response to the same dietary supplement advice, although there are variations and further optimisations possible where hepatic impairment cannot be demonstrated or where lytic phase cannot be detected in serology. For each of these disease model sub-types, I have drafted early specifications that can be used for testing in clinical trial research around these disorders. In CFS/ME or hepatic infection, there are currently known limitations, preventing a perfect solution. There are two small mitochondrial "leaks" to resolve regarding a-KG accumulation and ROS. They're manageable and still provide a treatment which allows normal daily life, however this can be further improved.

    This is where we need help in continuing this journey.

    [QUESTION - "Can you please assist?"]
     
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  14. joshua leisk

    joshua leisk Established Member (Voting Rights)

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    Thanks for the warm welcome, Mario!

    1) I haven't specifically tried applying known reported "flox" symptomology (this area is not widely represented in literature), however 2 of my clients had also reported being 'floxed'. They each had EBV lytic infections.

    2) It's about 90% common, with some individual variations based on use case and activity levels.

    3) Likely, yes. It is mentioned in the paper that 5-ARi use adds complication to this disease model by influencing endocrine dominance towards the adrenal cortex, by way of a rebound effect.
     
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  15. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    I had that impression too. Much of the ideas remind me of certain discussions on PhoenixRising and there is the curious mention of CD36 without explanation too (something I discussed).
     
  16. mariovitali

    mariovitali Senior Member (Voting Rights)

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    @joshua leisk

    Thank you for your latest posts and answers.


    Regarding the comment made by @Snow Leopard on CD36. I recently was able to implement an Information retrieval system that scores published research when given a set of terms.


    Querying the system for CD36 returns the following :


    thrombospondin.csv=0.38404042
    lcfa.csv=0.3839724
    ppargamma.csv=0.38379708
    abca1.csv=0.38369322
    fatty_acid_oxidation.csv=0.38362488
    cholesterol_efflux.csv=0.38356775
    peroxisome.csv=0.3835373
    pparalpha.csv=0.3835187
    abcg1.csv=0.3835178
    carnitine_palm.csv=0.38337752
    palmitic_acid.csv=0.38328147
    lxr.csv=0.38323513
    cd14.csv=0.38320637
    ampk.csv=0.3831823
    lipotoxicity.csv=0.38316205


    Thrombospondin has been identified as a research subject to the ME community :

    https://www.omf.ngo/study-of-thrombospondin-1/


    - lcfa = long chain fatty acids

    - ppargamma is the PPAR-γ receptor.

    - lxr is the Liver X Receptor


    I see many concepts related to cholesterol metabolism and fatty acids. Observe also the entries on palmitic acid. A good question / hypothesis here would be if palmitic acid has some effect (either negative or positive) to ME patients. Palmitic acid is used in many foods as a cheap addition of fat.

    I hope this is of help to your research.
     
    Last edited: Mar 17, 2021
  17. Trish

    Trish Moderator Staff Member

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    I don't have the knowledge foundation to follow the biochemical details of this hypothesis, however I am struck by the description of just 2 people, who may or may not have ME/CFS and seem to be on a wide range of medications and supplements already, being used as the basis for a hypothesis involving over the counter supplements.

    As i am sure everyone here is aware, there is a plethora of similar claims all over the internet, and complicated nutritional protocols, all of which are based on a few anecdotes, some involve patented mixtures, and some are the basis for potentially lucrative incomes gleaned from desperate sick people willing to try anything.

    Given all that, I think it would be reasonable to expect more evidence than a couple of unverifiable anecdotes for this to be taken seriously.
     
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  18. joshua leisk

    joshua leisk Established Member (Voting Rights)

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    Like.. a clinical trial?
     
  19. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    No, some consistent clinical observation on large numbers and some meaningful connection between the elements of the theory before exposing people to unnecessary interventions that may cost them money and raise false hopes.
     
  20. joshua leisk

    joshua leisk Established Member (Voting Rights)

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    I can understand your skepticism, given the amount of research everyone has already placed into this. However, the cost of testing this per patient, is roughly $5 worth of treatment protocol and $x amount of pathology. I'm not seeing the cause for concern.
     
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