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

@joshua leisk,

I realise that my comments may sound unduly critical. I don't doubt that you would like to help PWME but the field is so overburdened with bad science from people who should know better it is hard not to get exasperated.

I think a general point may be worth making.

When I talk about pseudoscience I am including about 90% of papers in this sort of biomedical field now appearing in journals. Whereas a volume of Annals of Rheumatic Diseases from 1966 might contain ten papers, six of which are still regarded as foundational to the field, the average journal volume from 2020 will contain nothing that will be of any consequence in five years time. We are awash with garbage, and you can tell it is garbage easily enough. Most papers serve to bring in salaries, not to advance science.

I think that is likely to be a major problem if you are wanting to take an information technology approach because you will get garbage in garbage out. Even within fields like immunology the main problem is that researchers do not have a wide enough experience of the practical realities of the things they study in the lab so they are making false connections.

As an example, you quote the production of some monoclonal antibodies by a Japanese team from PBC patients. Looking at the abstract of citation 3 they say that they produced these using EBV transformation of patient B cells. In this situation the EBV has nothing whatever to do with the pathology. It is just a lab trick for making B cells clone in vitro. The antibodies involved have no relation to EBV. These days the antibodies would be pulled out using PCR from RNA without going anywhere near herpesvirus.

The other things that a single monoclonal antibody from a patient tells us very little because will be just one of millions of clones any of which may cross react with anything else. This sort of experiment was popular in the early 1990s because monoclonal antibodies were a new probe, but by 2000 it became clear that it told us little or nothing. We have gone back to measuring functional effects of polyclonal populations in patients. And PWME, so far, have not shown any clinically significant autoantibody populations.

The recent studies on mitochondria in ME are worth keeping an eye on but it should be remembered that on past experience we can expect a 95+% likelihood that they will not hold up. If a group sets out to study mitochondria it has to find something that looks like a result in order to get another grant in. Forty years ago you could afford to get a negative result and publish. The pressures from competition now are too harsh for that. Also, the observations on tranformed lymphocytes are very hard to interpret. There are maybe three likely explanations fora difference in ME patients. There might be a genetic difference but that would not make sense because it should be operating from birth. There might be an effect on lymphocytes from acquired signals like cytokine production but that should have washed out during the cell culture process. There might be a sampling artefact so that lymphoblasts are being cloned from a different original subset. That is plausible but it would mean that the results do not tell us anything.
 
Last edited:
@joshua leisk,

I realise that my comments may sound unduly critical. I don't doubt that you would like to help PWME but the field is so overburdened with bad science from people who should know better it is hard not to get exasperated.

I think a general point may be worth making.

When I talk about pseudoscience I am including about 90% of papers in this sort of biomedical field now appearing in journals. Whereas a volume of Annals of Rheumatic Diseases from 1966 might contain ten papers, six of which are still regarded as foundational to the field, the average journal volume from 2020 will contain nothing that will be of any consequence in five years time. We are awash with garbage, and you can tell it is garbage easily enough. Most papers serve to bring in salaries, not to advance science.

I think that is likely to be a major problem you are wanting to take an information technology approach because you will get garbage in garbage out. Even within fields like immunology the main problems that researchers not have a wide enough experience of the practical realities of the things they study in the lab so they are making false connections.

As an example, you quote the production of some monoclonal antibodies by a Japanese team from PBC patients. Looking at the abstract of citation 3 they say that they produced these using EBV transformation of patient B cells. In this situation the EBV has nothing whatever to do with the pathology. It is just a lab trick for making B cells clone in vitro. The antibodies involved have no relation to EBV. These days the antibodies would be pulled out using PCR from RNA without going anywhere near herpesvirus.

The other things that a single monoclonal antibody from a patient tells us very little because will be just one of millions of clones any of which may cross react with anything else. This sort of experiment was popular in the early 1990s because monoclonal antibodies were a new probe, but by 2000 it became clear that it told us little or nothing. We have gone back to measuring functional effects of polyclonal populations in patients. And PWME, so far, have not shown any clinically significant autoantibody populations.

The recent studies on mitochondria in ME are worth keeping an eye on but it should be remembered that on past experience we can expect a 95+% likelihood that they will not hold up. If a group sets out to study mitochondria it has to find something that looks like a result in order to get another grant in. Forty years ago you could afford to get a negative result and publish. The pressures from competition now are too harsh for that. Also, the observations on tranformed lymphocytes are very hard to interpret. There are maybe three likely explanations fora difference in ME patients. There might be a genetic difference but that would not make sense because it should be operating from birth. There might be an effect on lymphocytes from acquired signals like cytokine production but that should have washed out during the cell culture process. There might be a sampling artefact so that lymphoblasts are being cloned from different original subset. That is plausible but it would mean that the results do not tells anything.

Thank you, Jon - truly. This is the type of conversation I came here to participate in. Appreciate your comment.

To clarify, in those early paragraphs, I'm aware of the research-use of EBV to transform b-cells for this purpose. Rightly, or wrongly, I was trying to tie Fukushima's work to EBV, or another HHV, via Kojima et al. 1999. (doi:10.1007/s005350050324). I circled back to this later by saying:

At this time, it’s not at all clear which pathogens express the antigens associated with each antibody. Early indications would suggest that EBV, MHV-68, CMV, HHV-6, HHV-7 would have the highest probability of being causal in CFS/ME, however this area has not been adequately explored and it’s likely other common pathogens may have successfully evolved through the use of similar vectors[157].
..
Research into creating a comprehensive map of antigens / antibody targets for each pathogen is sorely needed.

Now, I don't think we really know which virus is creating specific antigens at this time, only that they exist. EBV is an easy one to finger because of the 90+ known antigens which it expresses. There's a long list of targets. The other HHV family members aren't much better, from my understanding.
Nilsson et al. 2020 (doi:10.3389/fmed.2020.00108) compiled a nice list derived from other papers, listing some antigens commonly found in CFS/ME.

fmed-07-00108-t001.jpg


So these were used in the paper as an example of potential inputs to creating this looped state.

Whether or not the antibodies to PDC or α-ketoglutarate dehydrogenase complex exist in CFS/ME patients becomes less relevant, only that their existence would trigger this loop.
I then went on to demonstrate a number of other ways / entry points to trigger this loop state.. excess ROS (particularly H2O2, HNE) triggering α-KGDH depletion, NAD+ depletion via IDO biosynthesis impairments (Khasi, Davis - doi:10.3390/diagnostics9030082), same again for mitochondrial membrane damage from eg. salicylates, hypoxia or other induced PDH deficiencies(Fluge et al.) and GDH excess (or insufficiency) triggering a-KG elevation and then α-KGDH depletion. Tretter (doi:10.1098/rstb.2005.1764) had a lot to say about the duality of a-KGDH - how sensitive it is and how much it controls TCA efficiency.

Now, in the n=2 I showed later, a lytic EBV or CMV phase wasn't the cause of CFS/ME in those two cases - zeros on PCR tests, post-aldactone. They'd already temporarily 'patched' these 3 hotspots I mentioned, so they had normal daily lives again, however it was dose dependent, even without a lytic phase.

This seems to leave just the latent cell behaviour... and location.

So taking the known behaviour of both CMV (Chambers - 10.1128/JVI.02123-09) and EBV (Krisna - doi:10.3390/v12080811), where over-expression of KGA, GLS1, GLUD1 & GLUD2 causes the cells to prefer glutaminolysis, we'd see the same behaviour as various cancer cells. This of course means lactate, ammonia and hypoxia and has been shown to influence neighbouring cells. Some organs.. and one in particular.. have some key roles around lactate metabolism and energy production, etc.

Happily, their current therapeutic interventions are also reducing their viral burden.

EBNA IgG from 297 > 229 U/mL. VCA unknown as both exceed the report ranges.
For these 2 people, it'll be interesting to follow up later this year and see how this progresses.
Importantly, if the titres being reduced correlate with any changes in untreated symptoms.

In the meantime, we'll continue to run some limited case studies and I should have an answer next week about the pilot.

I'd happily take input for the pilot design, if anyone has suggestions of what they'd want to see incorporated into the pilot study.
 
Last edited by a moderator:
Now, I don't think we really know which virus is creating specific antigens at this time, only that they exist.

I don't understand what you are trying to mean here. Each virus encodes a series of its own proteins which are the antigens for the host antibody response to virus. (I don't understand what you meanly long list of targets.) As far as we know that has nothing to do with autoantibodies except conceivably in Guillain Barré syndrome although I am increasingly doubtful about the meaning of Willison's work even in that case.

There is an old idea from the 1960s that antibodies to viral or bacterial proteins cross-react with host proteins in autoimmune disease but there was never any evidence for this at the time and pretty much none since. The idea should have been buried and forgotten long ago.

The antibodies described by Nilsson are found at much the same levels in normal people so they mean nothing. Tables like that are totally misleading.

I am finding it quite hard to see how you are making any sort of connection here to ME/CFS. It almost sounds as if you are confusing viral antigens with host antigens but I find that hard to believe.

Theories based on what I think you are invoking, which is called molecular mimicry, have been around for fifty years and consistently have been found to go nowhere. The fact that people still raise these ideas seems to indicate that a lot of people in immunology are not able to distinguish a theory that works from one that goes nowhere but sounds superficially as if it should work (molecular mimicry doesn't actually make sense as a model on close inspection even if at first it does). Sadly, that was the conclusion I came to over the years. A handful of my colleagues understood what they were talking about but the majority just seemed to follow fashion.

The remainder I do not follow at all. Loops are an essential part of a systems analysis but I find it hard to believe they occur in basic metabolism. This sounds like the 'metabolic trap' idea that I suspect has no basis. The rest sounds like free floating systems theory detached from any relevance to a real illness. Systems analysis is essential to understanding long term biological dysregulation but each step needs to be firmly grounded otherwise you rapidly float off into fairyland.

Building theories like this is extremely hard for any one person to do. I know from experience working on the role of B cells in autoimmunity. I had a group of about six people at any one time and theories were built by hours of dialogue, with each person with their particular expertise contributing. Much the greatest amount time was devoted to working out why one person's suggestion couldn't work based on another's expertise.

To put it another way, I don't think any of the building blocks you have chosen will act a well-fired brick. They are still blocks of soft mud. A viable theory needs every one to be solid. Medical research is for real. It has to get things right, just as Boeing has to make sure its planes don't crash. In ME we have seen vast numbers of people exposed potentially harmful treatments because medical academics have not bothered to get things right - whether BPS or virus theories - it is the same.
We need people to check ideas make sense.
 
The remainder I do not follow at all. Loops are an essential part of a systems analysis but I find it hard to believe they occur in basic metabolism. This sounds like the 'metabolic trap' idea that I suspect has no basis. The rest sounds like free floating systems theory detached from any relevance to a real illness. Systems analysis is essential to understanding long term biological dysregulation but each step needs to be firmly grounded otherwise you rapidly float off into fairyland.

Building theories like this is extremely hard for any one person to do. I know from experience working on the role of B cells in autoimmunity. I had a group of about six people at any one time and theories were built by hours of dialogue, with each person with their particular expertise contributing. Much the greatest amount time was devoted to working out why one person's suggestion couldn't work based on another's expertise.

To put it another way, I don't think any of the building blocks you have chosen will act a well-fired brick. They are still blocks of soft mud. A viable theory needs every one to be solid. Medical research is for real. It has to get things right, just as Boeing has to make sure its planes don't crash. In ME we have seen vast numbers of people exposed potentially harmful treatments because medical academics have not bothered to get things right - whether BPS or virus theories - it is the same.
We need people to check ideas make sense.

It’s very much like the “metabolic trap” and explains a lot of Fluge’s work.

Essentially, both of those papers bolt directly into this disease model without any alteration and directly extend it.

For the purposes of being responsible to the wider community, we intentionally did not spell out the treatment / model testing protocol in the paper, however we will happily share it privately with any researcher who wants to explore it further and assess any potential risk factors.
 
I'd happily take input for the pilot design, if anyone has suggestions of what they'd want to see incorporated into the pilot study.
A 2 day CPET before the study and after, say, a year of treatment to test whether the person fits the expected pattern for someone with ME/CFS before treatment and whether they still fit it after treatment.

Wearable medical grade activity monitor worn all the time for at least 2 months prior to starting the study and throughout the study with outcome measure predefined as, for example, total steps for the 2 months before and for 1 month after 6 months and 12 months treatment.

Symptom diaries monitoring frequency and severity levels of symptoms.

Questionnaires such as SF-36 before, and at 3 month intervals to gauge subjective changes in function.

Preferably also some degree of blinding, with or without crossover so the prescribers and patients don't know whether they are on the treatment or dummy pills for the first or second 6 months of the study.

That may sound like overkill for a small pilot study, but we have seen others doing pilots of nutriceuticals that only lasted a few weeks and where patients knew they were on the active treatment and outcome measures were subjective. Such studies, are, in my opinion, a misleading waste of time, since the power of hope and placebo effect can lead to an upturn in subjective measures and activity levels that can be sustained for a few weeks or months, but may not last beyond that initial hopeful period.
 
A 2 day CPET before the study and after, say, a year of treatment to test whether the person fits the expected pattern for someone with ME/CFS before treatment and whether they still fit it after treatment.

Wearable medical grade activity monitor worn all the time for at least 2 months prior to starting the study and throughout the study with outcome measure predefined as, for example, total steps for the 2 months before and for 1 month after 6 months and 12 months treatment.

Symptom diaries monitoring frequency and severity levels of symptoms.

Questionnaires such as SF-36 before, and at 3 month intervals to gauge subjective changes in function.

Preferably also some degree of blinding, with or without crossover so the prescribers and patients don't know whether they are on the treatment or dummy pills for the first or second 6 months of the study.

That may sound like overkill for a small pilot study, but we have seen others doing pilots of nutriceuticals that only lasted a few weeks and where patients knew they were on the active treatment and outcome measures were subjective. Such studies, are, in my opinion, a misleading waste of time, since the power of hope and placebo effect can lead to an upturn in subjective measures and activity levels that can be sustained for a few weeks or months, but may not last beyond that initial hopeful period.

Sounds sensible and efficient.

With the case reports, we’re currently just using consumer grade wearable fitness trackers. eg.
CFCC6718-B7F1-48E0-9BD3-56428321E141.png
 
Last edited by a moderator:
A few more things that come to mind:

Independent expert review of rationale and proposed treatment protocol prior to starting to assess whether it is ethical and scientifically and medically appropriate to put patients through up to 12 months of treatment that has the potential to be harmful or ineffective.

Preregistration of trial with clearly defined outcome measures.

Success based on intention to treat, not just those who stayed the course.

Ethical approval

Medical indemnity insurance

Confounding effects of other concurrent treatments

Confounding effects of comorbid conditions

Recording of harms and adverse events

Provision for an independent person to unblind and review data at 3 months to see if it's worth continuing the trial.

Having someone medically and nutritionally qualified as lead researcher

How patients will be recruited

What you are asking patients to do and not do over the course of the trial.

Likely dropout rate

Funding including costs of lab testing, patients' expenses, medical oversight etc.

Who is going to diagnose the patients and based on what criteria
 
I have been reflecting on this thread and the various contributions to it. Here, for what it's worth, is my conclusion. @joshua leisk it is, of course, entirely up to you whether you take any notice of my thoughts and the input from others here.

1. What we have seen so far is an article that is posted on a preprint site where anyone can post an article about a medical subject. The article has a somewhat overblown title 'The true nature of ..'. To me that's a red flag already. No scientist would give a serious scientific research paper such a title.

2. As far as I am aware, the article is not being peer reviewed by any medical or scientific journal. So the first step is to seek peer review. Luckily S4ME has some people capable of doing such peer reviews, and 2 of them, Jonathan Edwards and Snow Leopard, have given their verdict. That verdict is, from my reading of their comments, that there are many flaws and problems with the hypothesis presented in the article. In their estimation the article would not reach the standards required for publication. That they spent their time voluntarily to review the article is a valuable gift. And one to be taken seriously if the authors want to progress their ideas.

3. We have been told that case studies are under way, and results are looking promising. But there seems to be some confusion about what conditions the clients presented with. It appears from timelines that these cases are current and have only been treated for a few weeks or months. And there are only a handful of cases. It therefore seems to me to be far too early to be planning clinical trials, even a pilot study.

4. @joshua leisk, finding your clients say their health is improving on your treatment is heady stuff - it's a great feeling that you are helping people. But there are downsides to the desire to 'help people'. We can get things wrong, people can get sicker, there may be a flaw in the model, the treatment may work for a while, but taking nutritional supplements that help one set of symptoms may cause imbalances in other parts of the body, or stop working once the excitement of all the attention wears off.
Interpreting people's medical test results and designing treatments for them is skilled work, not to be taken lightly. Unqualified people doing so is a big red flag to me.

5. My conclusion is that, far from ploughing on excitedly, it's time to step back. Sort out the fundamentals. Get experts to review your treatments, and advise on possible pitfalls. Give the current clients a couple of years to see whether the effects last before you persuade others to spend their money on tests and supplements that may not be right for them.

6. And while you wait to see whether the effects last on the few who are trying the treatment, spend the time deciding which direction your wish to help people and your keenness on learning/research is best directed. Do you really want to be a scientist creating hypotheses? If so, there really are no short cuts - medical/nutritional scientists need a firm foundation of the basics (ie undergraduate level biochemistry, physiology, nutrition, etc.), followed by postgraduate learning how to do research. If you don't want to do the slog to get the basics, then really the door is closed to your progress as a medical scientist. Reading research papers without the fundamentals leaves anyone ill equipped to make sense of what they are reading. So you end up making the sort of errors Snow Leopard and Jonathan Edwards have pointed out.

There are other ways you can help people. You can continue with the things you are qualified to do, you can raise money for research on nutritional treatments for ME/CFS to be carried out by properly qualified experts.

Sometimes we get stuck into something and devote a lot of time and effort to learning about it and get excited that we can use our new knowledge to help people. I did that - I spent 4 year full time training as a alt med practitioner 40 years ago (I already had a science degree). See this thread.

The more I learned of medical sciences as part of that course, the more fascinating I found it all, and the more I realised how little I knew and how ill equipped I was to do anything more than listen to lonely people, give them a nice comforting massage and persuade them to make some healthy changes to their diets. A little knowledge is, as the saying goes, a dangerous thing. We mess about with other people's health at our, and, more importantly, their peril.
 
Last edited:
A 2 day CPET before the study and after, say, a year of treatment to test whether the person fits the expected pattern for someone with ME/CFS before treatment and whether they still fit it after treatment.

Wearable medical grade activity monitor worn all the time for at least 2 months prior to starting the study and throughout the study with outcome measure predefined as, for example, total steps for the 2 months before and for 1 month after 6 months and 12 months treatment.

Symptom diaries monitoring frequency and severity levels of symptoms.

Questionnaires such as SF-36 before, and at 3 month intervals to gauge subjective changes in function.

Preferably also some degree of blinding, with or without crossover so the prescribers and patients don't know whether they are on the treatment or dummy pills for the first or second 6 months of the study.

That may sound like overkill for a small pilot study, but we have seen others doing pilots of nutriceuticals that only lasted a few weeks and where patients knew they were on the active treatment and outcome measures were subjective. Such studies, are, in my opinion, a misleading waste of time, since the power of hope and placebo effect can lead to an upturn in subjective measures and activity levels that can be sustained for a few weeks or months, but may not last beyond that initial hopeful period.

The activity monitor shouldn’t be a Fitbit or similar casual use device. I used one and it did sort of work, but not well enough for a scientific study. It’s also not waterproof, at least not washing machine proof. Oops.
 
Hi Trish,

The paper was submitted for peer review on the same day as the preprint.

4A57A338-CF74-4BAC-9CA1-B39B86469F49.jpeg

It was apparently too long for that publication, so has been resubmitted.

I’ve considered your other points and decided to respectfully disagree, but appreciate you taking the time to make them.

The approach I’ve taken my entire life served me well. I see no reason to change my methods at this time.

I’m happy for guidance on specific technical details if/when I make an error or am aware of a knowledge gap. I have no plans to change the direction of this journey at all.

As it stands, I have a number of clients, including some who have been previously bedridden, for over a decade, now mobile and living normal lives.

I can understand people’s skepticism, but time and data will demonstrate otherwise.

Thanks,

Joshua
 
The activity monitor shouldn’t be a Fitbit or similar casual use device. I used one and it did sort of work, but not well enough for a scientific study. It’s also not waterproof, at least not washing machine proof. Oops.

Cheers,

I’m quite surprised to hear this..

All the the recent generations are waterproof and we’ve previously tested them to within 5% error margin over a month with DEXA scans, combined with food logging. I was surprised, as the DEXA machine has a tolerance of about 4%.

Was there a particular issue you had that would preclude their use in a study? I’m genuinely curious.
 
I agree about not using a fitbit for a clinical trial. I have worn one (replaced twice with newer models) for a few years now. They are good enough to give me a general idea of my activity level, but because they are worn on the wrist, they record all sorts of activities that use the arm for quite small movements as steps, yet they completely fail to record some steps when I'm moving slowly around the house without swinging my arms.
 
I'm not qualified, or competent, to follow/understand many of the posts on this thread, but the following caused some concern.
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.
Really? You talked to 2 pwME for 5-8 hours a day, for many months?

I stopped reading at this point.

For someone who says they had ME/CFS, posting on an ME forum, your posts are incredibly long.

Your description of what you consider typical symptoms does not match my experience, in a couple of cases it is diametrically opposed.
 
I'm not qualified, or competent, to follow/understand many of the posts on this thread, but the following caused some concern.
Really? You talked to 2 pwME for 5-8 hours a day, for many months?

I stopped reading at this point.

For someone who says they had ME/CFS, posting on an ME forum, your posts are incredibly long.

Your description of what you consider typical symptoms does not match my experience, in a couple of cases it is diametrically opposed.

Indeed. In fact, I continue to talk with those people and many more. My day is basically talking with people who have ME and helping / listening / understanding.
 
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.

(Shared with full consent / expressed permissions.)

Client 1 -
EBV EBNA IgG++
EBV VCA IgG+++ (exceeded reporting thresholds)
EBV VCA IgM-
EBV EA was not provided
CMV IgG-
CMV IgM-
HSV-1++
HHV-6+
aPL-
AChR-MUSK-

Client 2 -
EBV EBNA was not provided
EBV VCA IgG++
EBV VCA IgM+
EBV EA was not provided
CMV IgG ++
CMV IgM -
aPL-
AChR-MUSK-

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?"]

I reached out to those 2 clients' physicians and requested assistance. Under their care, off-label spironolactone (aldactone) was initiated at 25mg/day (Campo et al.) and client 1 increased to 2 x 25mg/day after 1 month. Client 2 also chose to self-administer nigella sativa for their CMV infection.

Over 3 months of close interactions, I observed many patterns in triggers / responses and durations, including associations between both clients' reported salbutamol usage vs timing of and cessation of upper-right abdominal pain, with increased energy levels.

The abdominal pain followed periods where they had been feeling better, with improved energy levels and decided to make use of them. Due to concomitant hypoxic symptoms, they self-administered salbutamol and this demonstrated a pattern of resolving their abdominal pain and also a reduction of the duration and intensity of post-exercise malaise. It also increased their energy levels. I found this very interesting.

The location of the 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.

Client 1 obtained a high result for EBV PCR roughly 1 month after starting spironolactone and flow cytometry, from the same sample showed low CD4. At 2 months, returned negative on PCR tests. WBC / flow cytometry all amazingly unremarkable.

Client 2 obtained negative results on both EBV and PCR test at roughly 6 weeks.

This was a strong suggestion that spironolactone has efficacy for arresting EBV, CMV lytic phase. Only expected side-effect being increased urination, requiring increased hydration and electrolytes.

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?"]

Just skimming through the list of observations from your clients, few of those fit myself. I don't have alopecia, no leukopenia, my leukocytes are elevated but just within reference range. No elevated liver enyzymes or any other abnormality that could be found on routine blood tests. I tested positive against some chronic bacterial infections, but didn't have any improvement following antibiotics. I also briefly trialed valacyclovir, which made me rapidly worse, but at the dosage I took, it likely had nothing to do with its antiviral effects, but maybe due to secondary metabolic effects. I almost never get ill with acute infections despite coming in contact with sick people (this started after I developed ME/CFS symptoms). When I do get sick once every five years, my ME/CFS symptoms improve.

I have never had any eating disorder. I have some seasonal allergies, no food intolerances, eggs are not a problem at all. I have restricted my diet since getting ME/CFS as I noticed lots of carb intake made me feel worse, but it doesn't seem to be related to a specific type of food. I have trialed the ketogenic diet, felt better at first, but after a few days of ketosis became overriden with fatigue and flu-like symptoms. I have trialed lots of supplements, but I wouldn't describe it as a lifestyle or obsession, rather I think it works as form of morale boost for me to trial new things. I find even the supplements that work initially stop working within matter of days or weeks, which suggests they are not really addressing a deficiency, but rather pushing my body and metabolism temporary into some direction where symptoms become less severe. NO booster supplements containing arginine and citrulline produced the same, temporary benefit lasting a couple of days. Over the years I have also noticed a decreased tolerance for any drugs or supplements, which has forced me to entirely stop most supplements.

Comparing my background to your clients, it seems to me there's a big risk you are observing features that are not specific to ME/CFS and that might not have anything to do with the core pathology of ME/CFS. Again that's just based on my own N=1 sample, but your sample size isn't that much bigger.

P.S. Since your paper mentions PDH, have you looked into Victoria Bohne's treatment (link to patent)? This was discussed on ME/CFS forums a couple of years ago, there might be some overalp with your research. Bohne has compounded a mixture of oxalic acid foods that supposedly addresses the PDH deficiency. Similar to your protocol, it's a mix of natural ingredients that needs to be taken several times daily. Bohne claims she has kept herself and some patients healthy with this protocol, but it has all gone very silent and I'm not exactly sure what the latest status is.
 
Last edited:
@joshua leisk


I did a bit of searching on your regimen. So, spironolactone has anti-androgenic properties :


https://en.wikipedia.org/wiki/Spironolactone


Here is where it gets more interesting. Machine Learning identified Apigenin as a proposed target for amelioration of ME symptoms :



Screen Shot 2021-03-21 at 08.46.46.png

Apigenin may be important in clearing EBV :


Results: Apigenin inhibited expression of the EBV lytic proteins, Zta, Rta, EAD and DNase in epithelial and B cells. It also reduced the number of EBV-reactivating cells detectable by immunofluorescence analysis. In addition, apigenin has been found to reduce dramatically the production of EBV virions. Luciferase reporter analysis was performed to determine the mechanism by which apigenin inhibits EBV reactivation: apigenin suppressed the activity of the immediate-early (IE) gene Zta and Rta promoters, suggesting it can block initiation of the EBV lytic cycle.


But, apigenin may have anti-androgenic activity (?):

https://pubmed.ncbi.nlm.nih.gov/12032841/

https://pubmed.ncbi.nlm.nih.gov/28947342/


I wonder whether after taking finasteride and stopping it, i got an EBV reactivation. @Jonathan Edwards does this (EBV clearance from apigenin) seems plausible?

@joshua leisk have you had ME male patients? Has spironolactone affected their androgen levels?
 
Last edited:
@joshua leisk


I did a bit of searching on your regimen. So, spironolactone has anti-androgenic properties :


https://en.wikipedia.org/wiki/Spironolactone


Here is where it gets more interesting. Machine Learning identified Apigenin as a proposed target for amelioration of ME symptoms :



View attachment 13626

Apigenin may be important in clearing EBV :





But, apigenin may have anti-androgenic activity (?):

https://pubmed.ncbi.nlm.nih.gov/12032841/

https://pubmed.ncbi.nlm.nih.gov/28947342/


I wonder whether after taking finasteride and stopping it, i got an EBV reactivation. @Jonathan Edwards does this (EBV clearance from apigenin) seems plausible?

@joshua leisk have you had ME male patients? Has spironolactone affected their androgen levels?
That’s very interesting! Arresting lytic phase helps with some of the daily annoyances.

So far no issues at 25mg or 2x25mg/day dosing, over 5+ months. The studies have 30% of males showing symptoms from anti-androgenic behaviour at 100mg, single dose per day. This is even less of an issue with ME, as many people have elevated DHT via adrenal cortex dominance / impaired gonadal synthesis route.

The underlying aldosterone issues most people have with ME also get addressed at the same time as the Complex V issues. (doi: 10.1681/ASN.2010050481)
 
Last edited:
the paper said:
A mild aromatase (CYP19) inhibitor to rebalance the oestradiol to DHT ratio could be considered in unusual cases - as HASD CFS/ME patients would be expected to already exhibit high DHT and low oestradiol, owing to chronic cortisol elevation[ 115].
Joshua, you seem to be suggesting people with HASD CFS/ME have chronically elevated cortisol levels. The reference you give doesn't relate to the elevated cortisol part of the sentence. What makes you think people with ME/CFS have elevated cortisol? Looking at cortisol in ME/CFS studies broadly, there's little evidence for abnormal levels, especially high levels.

You also seem to be suggesting low oestrogen levels as a result of high cortisol levels. What evidence is there for that?

the paper said:
This discovery prompted an encouraging pilot study of patients with positive serology for EBV (n=21), by Campo et al, 2020[ 18], with 5 out of 16 participants who tolerated 25mg/day of spironolactone and multivitamins showing full remission of CFS/ME and the remaining participants showed a reduction of CFS/ME symptoms at the time of the report.
I've made a thread to discuss this study:
Spironolactone as a treatment for CFS in patients with positive Epstein Barr virus serology, 2020, Campo and Taylor
 
Back
Top Bottom