Mitochondrial and Energy Metabolism Dysfunction in ME/CFS — Myhill, Booth and McLaren-Howard Papers

sb4

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@debored13 Yeah I have been taking 30drops /3g Pyrucet for a couple weeks now and I can eat high carb breakfast + 1tbsp C8 oil and then even some carbs at noon with only small amount of heart palps. I still feel a bit more on edge or something after carbs so I suspect that it is only reducing symptoms in that respect.

I do have some EA coming although I will admit I am slightly hesitant to try it in higher doses like I originally planned due to those LD50 calculations. Perhaps it burdens the liver or keeps GSH at zero too long. We will see.
 
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I would expect our reactions to a product that increases glucose oxidation to be pretty different given I react pretty decently to carbs and they give you heart palps. I now do about sixty drops a day. Sometimes it does help semi-dramatically and I do think it would be good for anybody that thinks their main problem is inflammation and metabolism absent an ongoing unaddressed toxin or pathogen cause
 

sb4

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@debored13 I forgot to mention above that I have been getting very sleepy tired morning to early afternoon after taking my dose. It could be something to do with coming of testosterone however it could also be Pyrucet. Do you notice anything similar? I just had to have a small nap now which is fairly unusual for me.
 
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@debored13 I forgot to mention above that I have been getting very sleepy tired morning to early afternoon after taking my dose. It could be something to do with coming of testosterone however it could also be Pyrucet. Do you notice anything similar? I just had to have a small nap now which is fairly unusual for me.
my symptoms flare according to so many different variables I really couldn’t tell you anything but my in-the-moment reaction
 
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I would just like to add that Pretorius amino acid complex was recommended to me by Prof Neil McGregor. It does not contain tryptophan or arginine.

Not affiliated at all.

(I am extremely sensitive to arginine even though I am low in it - 1/6 of a dose left with with a day of air hunger and severe POTS symptoms. )
 

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Learner1

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I looked it up. It does contain arginine. This is what each capsule contains:

L-Glycine 140.0mg
L-Proline 81.2mg
L-Hydroxyproline 77.9mg
L-Glutamic Acid 65.4mg
L-Alaine 58.3mg
L-Arginine 51.1mg
L-Aspartic Acid 39.3mg
L-Serine 23.6mg
L-Lysine 22.9mg
L-Leucine 21.6mg
L-Phenylalanine 15.7mg
L-Valine 14.4mg
L-Threonine 13.7mg
L-Isoleucine 9.8mg
L-Hydroxylysine 6.5mg
L-Histidine 5.2mg
L-Methionine 4.6mg
L-Tyrosine 3.3mg

By comparison, and based on my labs, which seem to support what Fluge and Mella's amino acid study found, this is what I'm taking - I wrote my daily dose next to the dose in tge Proteus supplement:

Typical composition per capsule:

L-Glycine 140.0mg. 4.5g
L-Proline 81.2mg. 2g
L-Hydroxyproline 77.9mg 0g
L-Glutamic Acid 65.4mg. 3g
L-Alanine 58.3mg. 2g
L-Arginine 51.1mg. 0g
L-Aspartic Acid 39.3mg. 1.5g asparagine
L-Serine 23.6mg. 0g
L-Lysine 22.9mg. 3g
L-Leucine 21.6mg. 6g
L-Phenylalanine 15.7mg. 0g
L-Valine 14.4mg. 0g
L-Threonine 13.7mg. 2g
L-Isoleucine 9.8mg. 6g
L-Hydroxylysine 6.5mg. 0g
L-Histidine 5.2mg. 0g
L-Methionine 4.6mg. 3.5g
L-Tyrosine140.0mg 3.5g


Plus, I also need these, which are not in tbe Proteus product:

1.5g citrulline
2.5g ornithine
2g N-acetyl-cysteine

The amounts are laughable compared to my needs, which are on top of eating meat at lunch and dinner and protein at breakfast.

I have done much better with PEM after getting my glutathione producing amino acids up (glycine, glutamine, NAC), and my isoleucine and leucine up. Tyrosine and asparagine have been critical as well.
 
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Thanks for pointing that out. The bottle I have hay a different list of ingredients and doesn't say arginine. I am not sure why,maybe they changed the formula?

Holy cow, I clearly need to boost my amino I take. Sorry if you have already said this but are you getting this professionally compounded or making it yourself?
 

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ZeroGravitas

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Hey @Hip - seeing as you seem to be somewhat of an expert on the Myhill, Booth, McLaren-Howard papers :thumbsup:, what is your take on the newly published study that reports failure to replicate their findings? (If/when you have the chance to take a good look, of course.:)): https://www.nature.com/articles/s41598-019-47966-z

There's a thread on the new paper here on S4ME (but none on PhoenixRising I've seen as yet): https://www.s4me.info/threads/asses...tory-test-aug-2019-morton-newton-et-al.10703/

Of course the Myhill group does not seem impressed so far. From the very early correspondence (yesterday) via moderators in the official Facebook group for patients:
[Drs Myhill and McLaren will be working on a more detailed response next week and we will post that when it is ready] DR MYHILL QUOTE 1--This test was never ''marketed'' as a diagnostic test for CFS/ME! It is simply a measure of mitochondrial function 2--Before any study was done, paired samples should have been taken to see if the Oxford test matched the Acumen test – this was offered by Professor Norman Booth, Dr John McLaren Howard and myself but was refused by the group doing the study. They [may] have compared apples with oranges UNQUOTE
 
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Marylib

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I have just been catching up on all this. Thanks to everyone for being so detailed in what they have found to be helpful. When I first got sick - maybe 25 years ago (you could call it a gradual post-viral onset of FM, with a more sudden post-viral onset of M.E. 15 years ago) I went to a doc who measured the amino acids in the blood, and he said it was the lowest levels he had every found except in a corpse. Years have passed since then. I am thinking that the only way I benefit from enhanced nutrition is IV nutrition from a naturopath. This totally bypasses my digestive system. And the wonderful "alive -again-and-restorative-sleep- again" feeling only lasts until the urine carries the nutrients out. I am reluctant to spend money on amino's taken orally because of this observation about my own case. Any thoughts? I think I may be better off with immune modulators like isoprinosine, Thanks for considering my question and comments.
 

Marylib

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Hey @Hip - seeing as you seem to be somewhat of an expert on the Myhill, Booth, McLaren-Howard papers :thumbsup:, what is your take on the newly published study that reports failure to replicate their findings? (If/when you have the chance to take a good look, of course.:)): https://www.nature.com/articles/s41598-019-47966-z

There's a thread on the new paper here on S4ME (but none on PhoenixRising I've seen as yet): https://www.s4me.info/threads/asses...tory-test-aug-2019-morton-newton-et-al.10703/

Of course the Myhill group does not seem impressed so far. From the very early correspondence (yesterday) via moderators in the official Facebook group for patients:
@Hip, do you think that the people who wrote the recent paper misrepresented Dr Myhill in terms of the fact that she never intended it to be a biomarker? As far as general nutrition goes, her recommendations have always seemed very practical to me.
 

Learner1

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As far as general nutrition goes, her recommendations have always seemed very practical to me.
I get derailed nutrient trsting done every 9 months, and have found the findings of Myhill, Fluge and Mella, Naviaux, Maureen Hanson, and other ME/CFS researchers to all be helpful.

The key is to find what your body needs and to carefully work your way out of a malnourished state.
I went to a doc who measured the amino acids in the blood, and he said it was the lowest levels he had every found except in a corpse. Years have passed since then. I am thinking that the only way I benefit from enhanced nutrition is IV nutrition from a naturopath. This totally bypasses my digestive system. And the wonderful "alive -again-and-restorative-sleep- again" feeling only lasts until the urine carries the nutrients out. I am reluctant to spend money on amino's taken orally because of this observation about my own case. Any thoughts? I think I may be better off with immune modulators like isoprinosine, Thanks for considering my question and comments.
This is exactly what I am doing with my naturopathic doctor. We use my test results to formulate a protocol customized for my exact needs, which has changed over time as I have improved. I go in once a week to do it and have improved greatly with this care, which supports my ability to exercise.

It consists of amino acids, B vitamins, antioxidants, minerals, and mitochondrial nutrients like carnitine.

Some naturopaths do "canned" IVs, with a preset formula of nutrients, like a Myers cocktail, which might be risky in your case - you'd want it formulated for you. Doctors who have been trained by this group would know how to properly help you:

https://www.ivnutritionaltherapy.com/team/

You can PM me if you'd like to discuss it further.
 

Learner1

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what is your take on the newly published study that reports failure to replicate their findings? (If/when you have the chance to take a good look, of course.:)): https://www.nature.com/articles/s41598-019-47966-z

There's a thread on the new paper here on S4ME (but none on PhoenixRising I've seen as yet): https://www.s4me.info/threads/asses...tory-test-aug-2019-morton-newton-et-al.10703/
There were some differences between the original testing and that in this paper if one reads the Methods section.

The original paper claimed that the trst was diagnostic for ME/CFS, which it doesn't seem to be. Still, the trst gave parltients a clue as to how well their mitochondria are working, which would likely vary depending on the etiology and subtype of ME/CFS patient.

In the discussion, people panned patients taking supplements in response to the test. One writer pointed out that "one size fits all" is ridiculous and need to be customizsd to a patient's needs, which makes a lot of sense.

I didn't do that test, instead have done the MitoSwab test here in the US, which measures mitochondrial content and function of complexes I-IV. They are looking into doing complex V as well. The test has been validated with autistic patients at Childrens Hospital of Philadelphia.

I did two tests 9 months apart, and did a Genova Diagnostics NutrEval and and an HDRI nitrotyrosine test concurrently, with mito repair and support nutrients in between.

As I suspected, this was an excellwnt experiment and validated sone of the theories I read about ME/CFS regarding oxidative and nitrosative stress:
  • Nitrotyrosine was high on the first test, indicating ongoing peroxynitrite production, which impairs complex I and damages mito membranes
  • It was slightly above normal 9 moths later, much lower than before, indicating the nutrient interventions were working (though I tested low in folate which could be why it was still a little high)
  • The first NutrEval showed glutathione and vitamin C depletion with high lipid peroxides (cell membrane damage) and high 8OH-dG (marker of DNA damage)
  • The second NutrEval showed more normal glutathione and vitamin C, lower lipid peroxides and normal 8OH-dG, after upping methylating nutrients and vitamin C, adding liposomal glutathione, and taking NT Factor and phosphatidyl choline to repair membranes
  • The first MitoSwab showed <50% of normal mito content, the second showed 150% of normal. As I'd also become very depleted in asparagine where it had been normal on the first, we believe that old mitochondria were not able to die off due to lack of asparagine, needed for it, and that is why content went up.
  • Complexes II and IV were going at 370% of normal, which seemed to be the "smoking gun" for the oxidative stress. I had been depleted of Mn and B2, used in Mn-SOD which defends peroxynitrites, and B2 is used as FAD in Complex II, so this made sense.
  • With intervention, these complexes were around 115% on the second test, after adding the mito membrane repair and upping support for glutathione which can reverse the damage.
  • Complex I was impaired on both tests, which makes sense given that peroxynitrites are known to impair it.
  • During this 9 month period, my function and ability to exercise gradually improved to where I can exercise more than most women my age. I still have challenges, especially with aerobic exercise, but this experiment brought me to a more normal life.
Mitochondria recycle every 6-8 weeks. It is a slow process to make changes, but my hypothesis that feeding nutrients to repair them and support their function (I also take carnitine, CoQ10, and NMN/NAD) would make a difference.

It is more than just a diagnostic. Diagnostics don't get us well. But, using tests that give actionable information to inform the treatment process is very valuable. I'm thankful to Myhill, Booth, and McLaren-Howard. Without their clues, I would never have pursued this path.
 

Hip

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Hey @Hip - seeing as you seem to be somewhat of an expert on the Myhill, Booth, McLaren-Howard papers :thumbsup:, what is your take on the newly published study that reports failure to replicate their findings? (If/when you have the chance to take a good look, of course.:)): https://www.nature.com/articles/s41598-019-47966-z
I am quite tired at the moment, so have not been able to look into the new Tomas et al study much. I think we will need to wait for the Myhill team to respond.

When the 2016 Lawson study found higher than normal ATP levels the cells of ME/CFS patients, which contradicted the Myhill study finding of lower ATP, Dr John McLaren-Howard of Acumen Labs provided a great explanation of what was likely going on, which resolved this paradox.

So I am looking forward to hearing his analysis of this new Tomas et al study.


The Tomas study found that a delay in processing the blood samples altered the results of their test, and they suggest this delay could account for the differences between patients and controls in the Myhill study:
We suggest that it is potentially the delay between sample collection and cell isolation that is causing the decrease in mitochondrial function previously reported in CFS/ME patients.
But it is worth pointing out that the test at Acumen Labs it not only able to distinguish ME/CFS patients from healthy controls, but also is able to roughly distinguish between very severe patients, severe patients and moderate patients (see Figure 4a from Myhill 2009). In other words, the more severe patients tend to have a worse Mitochondrial Energy Score (MES) on the Acumen test than the less severe.



@Hip, do you think that the people who wrote the recent paper misrepresented Dr Myhill in terms of the fact that she never intended it to be a biomarker?
I think the Myhill group presented the Acumen Lab test as a diagnostic tool, but I don't think they presented it as a biomarker which is unique to ME/CFS (there are other diseases with mitochondrial dysfunction, so these would presumably also show poor mitochondria functioning on the Acumen test).
 
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ZeroGravitas

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I am looking forward to hearing his analysis of this new Tomas et al study.
Absolutely. This is also my main response - it should hopefully be very interesting (from an academic perspective) to hear how Dr John McLaren-Howard explains things. And if any new insights come from this.

When the 2016 Lawson study found higher than normal ATP levels the cells of ME/CFS patients
Oh yes, that apparent contradiction stimulated very interesting debate and was how I cut my teeth first posting on this forum, ultimately contacting Xinnan Wang for these direct responses. (A couple months before your post on the response from McLaren-Howard, as you already linked. :))

In other words, the more severe patients tend to have a worse Mitochondrial Energy Score (MES) on the Acumen test than the less severe.
Right. The original Myhill et al papers show the Acumen test to correlate very closely with disease impairment. And their plots showed complete separation between patients and healthy controls. Which is why I've said that the (disapointingly small) sample size in the replication study should still have found a very strong signal (i.e. probably also complete separation) if their lab method and patient selection was sound (and the original studies were correct). Right?


In the discussion, people panned patients taking supplements in response to the test.
Right. I'm not sure how much the recent paper misframes the context of the use of the Acumen test by the Myhill group. Or if the criticisms it levels are all justified (and appropriate) given the reported findings. Or if there is bias against Myhill via the funding bodies, which commissioned the PACE trial, or directly from the researches, which I know not of...

But it certainly highlights the philosophical disparity between approaches: the conventional medical approach (e.g. of the NHS) to do nothing when there's no proven test/treatment and let patients suffer (and die). Verses the more compassionate and pragmatic overall approach of Dr Myhill (and others here). A kind of tinkering and learning by trial and error experience of what helps.

While I know that this has definitely helped a lot of patients significantly (and is something I support), I'm still sceptical of some of her explanations when it comes to the scientific specifics. On occasion, her reported views on things have seemed dogmatic, given a lack of supporting evidence - explanations probably more tailored to convincing patients to implement difficult but helpful changes.

Similarly I'd be staggered (pleasantly surprised) if McLaren-Howard was, in relative isolation, perfectly 100% correct about such novel technical findings. Given how science is such an iterative, conversational process of decreasing misconceptions, etc (and how messy biology is, specifically). Although the Acumen tests seem to have been a ahead of their time, in correctly looking at reduced mitochondrial energy output, it seems unlikely that he would have pinpointed the correct/entire mechanism(s) of action, there.

At any rate, it doesn't seem to explain the route cause or curative treatments, right? (Compared to a theory like Phair's metabolic trap, etc.) Myhill's treatments only ever seem to remedy/mitigate the worst of the downstream consequences of the illness. Similarly, my expecation is that, if the test is (ultimately) valid, it will only indicate differentiation between severity of ME/CFS disability. (Hmmm, I've rambled on unnecessarily here, sorry.:oops:)
 
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Right. I'm not sure how much the recent paper misframes the context of the use of the Acumen test by the Myhill group. Or if the criticisms it levels are all justified (and appropriate) given the reported findings. Or if there is bias against Myhill via the funding bodies, which commissioned the PACE trial, or directly from the researches, which I know not of...
Acknowledgements were MEA, Afme & MRC. MEA not always our friend but better than Afme which supported PACE & Controversial NICE guidelines. MRC (Medical Research Council) Funders that Wessely has professional links to include The MRC,

Dr Myhill is always under threat from the powers to be. With campaigns against PACE Authors (complaint to GMC) & MAIMES - Medical Abuse in ME Sufferers

So as you can see there may very well be some bias going on, there's more but I'll wait for a response next week
Here is a link below to the funding where it does mention a Comparison paper with muscle biopsy however there is no mention of it -- My poor ME Brain is a little short of Mitochondria atm look forward to the debate to come :)

https://wames.org.uk/cms-english/new-mea-award-for-mitochondrial-research/
 
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Just remembered what it was about the link in my previous comment, I believe the paper that has hit the headlines was testing Dr Myhills test that used neutrophils but that they were problematic and went onto PBMC's but that it wasn't documented (something like that) so the above paper was looking at that but that has been very hush hush. Sorry I'm a bit vague hope someone can peruse them both because basically I'm running on fumes :(
 

ZeroGravitas

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OK, so Myhill and McLaren Howard posted their official responses up here on this web page yesterday.

Dr Myhill essentially doubts the new study managed to perform the lab procedure correctly:
What this means is that we can have little confidence in the ability of the Tomas group to replicate the Acumen test.
McLaren Howard goes into detail about why this explanation for the discrepancies can't be the case:
The Tomas study found that a delay in processing the blood samples altered the results of their test, and they suggest this delay could account for the differences between patients and controls in the Myhill study
Apparently he went to great lengths to look for effects produced by delayed processing time when first setting up the test, being not significantly perturbed up to 48 hours later (provided no major temperature changes). Also explaining that regular patient samples are typically processed within 24 hours and that he does phase-contrast microscopy on every sample to check for changes in storage conditions, discarding any damaged samples.

Plus much more about other aspects. A pretty detailed rebuttal. I wonder if it would be appropriate for us to contact the Cara Tomas et al authors (i.e. Julia L. Newton) for a response in turn...?

Also, I forgot to ask above about the MES score - is that something we could calculate ourselves from data provided by the new study? Do we know the equation? Wondering if that would potentially show some patient/control separation in aggregating the sub-tests together (although I doubt that).

Edit: lol @Georgelis - beat me to posting the link by about 8 minutes.

Oh, also, the Facebook group devs have said to email any (patient/follower) questions through to Myhill, so I could relay any specific technical queries, etc, if you like.:)
 

Hip

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Also, I forgot to ask above about the MES score - is that something we could calculate ourselves from data provided by the new study?
I will have to read Myhill's response when I have more energy.


The Acumen labs test provides figures for the efficiency of the 5 mitochondrial processes they test. These efficiency figures are numbers from 0 to 1, with 1 being 100% efficiency.

The MES is calculated just by multiplying the 5 efficiency figures together.

I tried to calculate someone's MES in this post, but I am not entirely sure I am doing it right.