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Dr Myhill mitochondrial test not repeatable

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6
'We replicated the MES protocol using neutrophils and peripheral blood mononuclear cells (PBMCs) from CFS/ME patients (10) and healthy controls (13). The protocol was then repeated in PBMCs and neutrophils from healthy controls to investigate the effect of delayed sample processing time used by the Myhill group. Experiments using the established protocol showed no differences between CFS/ME patients and healthy controls in any of the components of the MES (p ≥ 0.059). Delaying blood sample processing by 24 hours (well within the 72 hour time frame quoted by the Myhill group) significantly altered many of the parameters used to calculate the MES in both neutrophils and PBMCs. The MES test does not have the reliability and reproducibility required of a diagnostic test and therefore should not currently be offered as a diagnostic test for CFS/ME. The differences observed by the Myhill group may be down to differences in sample processing time between cohorts.'

https://www.nature.com/articles/s41...xPVl8ucL7SWVqJkKJN_tZvXYTTV6VAQS3r6tYgbs0J2ek
 

Hip

Senior Member
Messages
17,824
I think we will have to wait on the response from Dr John McLaren-Howard of Acumen Labs.

I would have been good to get the comments and response of Dr Norman E. Booth on this replication study (along with McLaren-Howard he was one of the three authors of the Myhill studies), but sadly he died not so long ago.

I added a note at the beginning of my article on the Myhill energy metabolism dysfunction studies saying that the results failed to be replicated.
 
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taniaaust1

Senior Member
Messages
13,054
Location
Sth Australia
It is always interesting when different results are gotten. I wonder how many people were in that Myhill study. I did wonder what diagnostic criteria were being used for recruitment for this study and saw "
Ethical approval
Blood samples were obtained from patients fulfilling the Canadian consensus diagnostic criteria for CFS/ME and healthy controls after obtaining ethical approval from the National Research Ethics

"

so I think both used the same ME/CFS patient group.
 

gbells

Improved ME from 2 to 6
Messages
1,491
Location
Alexandria, VA USA
If memory serves dr. Myhill used to follow doctor l e h r n e r's antiviral drug protocol. However the licensing medical authorities in the United kingdom forced her to stop. Does anyone know whether she switched to an alternative regimen we're stop treating CFS patients all together?
 

boolybooly

Senior Member
Messages
161
Location
Northants UK
It is always interesting when different results are gotten. I wonder how many people were in that Myhill study. I did wonder what diagnostic criteria were being used for recruitment for this study and saw "
Ethical approval
Blood samples were obtained from patients fulfilling the Canadian consensus diagnostic criteria for CFS/ME and healthy controls after obtaining ethical approval from the National Research Ethics

"

so I think both used the same ME/CFS patient group.

I don't have any inside information (I am a patient of Dr Myhill and have had anomalous mitchondria profile test results).

If it does not say so explicitly then I don't think its safe to assume that these are the same patients.

None of the existing criteria are definitive so one cannot be sure patient cohorts are equivalent based on these.

If memory serves dr. Myhill used to follow doctor l e h r n e r's antiviral drug protocol. However the licensing medical authorities in the United kingdom forced her to stop. Does anyone know whether she switched to an alternative regimen we're stop treating CFS patients all together?

To the best of my knowledge Dr Myhill is still helping patients with CFS and I am one such though I am not sure how easy it is to become a patient today, I believe she has a lot of patients now.

We need more doctors like her.
 

Mary

Moderator Resource
Messages
17,335
Location
Southern California
Cort writes about this here: The Myhill Mitochondrial Test and ME/CFS Studies Take a Hit @Hip, did you see this article? It just came out today. It talks about responses from Dr. Myhill and Dr. John McLaren-Howard.

Re Dr. Myhill:
Dr. Myhill posted several responses to the paper on her website – none of which, unfortunately, addressed the issues raised in the Tomas paper. She reported that the testing was blinded, that the tests are less expensive than they might have been, that approximately 1000 tests have been run and that the tests are routinely run in quadruplicate, etc.

One statement, “The essence of this paper appears to be that tests of mitochondrial function are not relevant in the assessment of patients with CFS/ME,” is clearly incorrect as the Tomas group has found evidence of mitochondrial issues in ME/CFS and would surely welcome a commercial test that would show that. In fact, in the paper Tomas suggested that, “Other tests of energetic dysfunction (in ME/CFS) could be developed using the Seahorse extracellular flux assay,” (but advised caution until it was clear what role cellular energy production problems play in ME/CFS).

Re Dr. McLaren-Howard:
Dr. McClaren did respond to the central issue. He reported that during the initial testing he explored the effects that sample storage might have using samples that were processed within minutes and re-tested 6, 12, 24, 48 and 72 hours later. He stated that, provided that the samples were kept in the original “vacutainer” tubes and not subjected to extremes of temperature, there were only minor changes in the test results up to the 48 hour point. After that, some samples began to degrade, and he uses phase-contrast microscopy to separate out samples which have signs of cell damage.

His statement, “Test situations regarding time since venepuncture and storage/delivery methods continue to be explored” suggests, though, that not all the issues regarding sample processing have been explored.
Cort concludes:
with the publication of the Tomas paper, the burden of proof now appears to fall on the Myhill group to find a way to rebut the Tomas finding – probably with a peer-reviewed paper which validates their current testing regimen (using PBMC’s).
 

Hip

Senior Member
Messages
17,824
Cort writes about this here: The Myhill Mitochondrial Test and ME/CFS Studies Take a Hit @Hip, did you see this article? It just came out today. It talks about responses from Dr. Myhill and Dr. John McLaren-Howard.

Yes, I read it today. As Cort says, looks like we will have to wait for a response from the Myhill group and Acumen labs to see if they can rebut the Tomas finding or not.

This Tomas et al study was the long-awaited replication study funded by the ME Association. They have an article on it here. I think everyone was hoping it would replicate the Myhill results, as that would have then provided good evidence for mitochondrial issues in ME/CFS. But unfortunately they were not able to replicate.

I have not actually spent much time looking into the details of the Tomas paper, so I can't really comment any further on it at the moment.
 

boolybooly

Senior Member
Messages
161
Location
Northants UK
To declare my interests I am a patient of Dr Myhill and I have had the mito tests in question and used them in evidence for disability assessment at one time but no longer do and my last successful appeal for PIP 2016 did not involve them but did involve Dr Myhill's diagnosis.

Further reading, a summary of seahorse results in relation to PWME shows conflicting results, including a Thomas finding of reduced ATP production which appears contrary to Stanford's finding of increased ATP production though one has to wonder if they are experimenting with the same condition. Which is a problem related to ill defined criteria.

http://simmaronresearch.com/2019/08/me-cfs-seahorse-energy-production-study-shows-surprises/

Also Stanford found increased glycolysis and Thomas and Hanson found reduced.

Also Fisher hypothesised that compensatory glycolysis is increased if memory serves but Thomas and Hanson apparently found reduced according to Simmarons write up.

Fisher et al
https://www.preprints.org/manuscript/201909.0043/v1

To be perfectly frank I am not confident that diagnostic criteria are sufficiently strict to prevent different conditions being diagnosed as ME and believe this may be a significant factor in the different results being reported by different labs

Also I am not convinced by the tone of language used in the write up of Thomas et al, which goes beyond simple factual reporting and veers into pejorative implication which exceeds the level of certainty in their results and gives the impression of competitive hyperbole.

The suggestion that seahorse can provide testing services to supplant McLaren Howard's Acumen tests indicates a competitive interest which could be a source of unconscious bias and makes me reluctant to put my faith in Thomas et al's null finding regarding the lack of replicability for the Acumen tests and I would like to see the Acumen tests replicated by a disinterested third party before coming to any conclusions.
 

gbells

Improved ME from 2 to 6
Messages
1,491
Location
Alexandria, VA USA
This is a good puzzle. I think the reason that the MyHill mitochondrial deficit test wasn't sensitive is because it is a static test, not under exercise, while the problem occurs functionally after. Static state is akin to rest so the ATP is easy to replace and you don't have an ATP (energy) deficit. Two day exercise testing is where you see oxidation problems, not on the first day but the second. Exercise upregulates Nf-kB. Herpesviruses upregulate Nf-kB. Nf-kB must be carefully controlled. Overdose causes excess nitric oxide, which has been found in SEIDs patients. So basically, something is causing metabolic changes which impair exercise and trigger fatigue and painful muscle inflammation which then triggers avoidance behavior. Viagra causes nitric oxide release and when overdosed causes rhabdomyolysis, painful breakdown of muscle tissue. So the problem here is probably that you need to do the test after sufficient exertion. This could be a problem for Ron Davis' nanoscalpel test which tests at rest.

Reference
Chronic Fatigue Syndrome: Exercise Performance Related to Immune Dysfunction. JO NIJS et al. CLINICAL SCIENCES 2005. https://bit.ly/2okIBs4
 
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Hip

Senior Member
Messages
17,824
So basically, something is causing metabolic changes which impair exercise and trigger fatigue and painful muscle inflammation which then triggers avoidance behavior.
So the problem here is probably that you need to do the test after sufficient exertion.

The Myhill group detailed a very interesting mechanism by which they propose mitochondrial blockages lead to PEM — a mechanism is described in this post. I think irrespective of whether the Acumen lab tests are valid or not, this theorized mechanism may still be a viable explanation for PEM.

If you look at this Myhill PEM theory, you realize that the mitochondrial blockages can be ever-present, but it is only when the body is pushed through higher levels of exertion do the consequences of those blockages appear — as PEM. But even without PEM occurring, the blockages are still there, and thus should be measurable in tests, according to this theory.

In brief, the Myhill PEM theory is this:

The ATP molecule can viewed like a wooden delivery cart that is stacked up with energy. When ATP delivers the energy into the cell, this wooden cart is then sent back to the mitochondria for recycling and refilling with energy. But if the mitochondria are blocked in any way, as is believed is the case in ME/CFS, this wooden cart refilling process becomes much slower. This blockage is not an issue when body energy expenditure is on tick-over, but becomes a problem when energy expenditure rates increase.

When energy expenditure is increased, ATP cannot be recycled quick enough (ie, the wooden carts cannot be refilled fast enough) to meet energy demands because of the blockage; but the body has a back-up system that can temporarily help out: this back-up system involves burning the wooden carts themselves to create energy!

This burning of the carts works fine in the short term, but the long term consequences are that you now have no wooden carts (ATP molecules) to delivery energy. And it is this that creates the PEM state, according to the Myhill group. It's only when the body makes some new wooden carts to carry energy do you get over PEM. But because it takes days to rebuild these wooden carts (rebuilding is called de novo synthesis of the ATP molecules), PEM itself often takes days to clear.

This is only a theory of PEM, it has not been empirically proven; but it is the only theory I have seen which can neatly account for how higher energy expenditure leads to PEM.

As I say, even if the Acumen lab "ATP Profiles" blood test is not correct, this theory of PEM may still turn out to be right.
 

gbells

Improved ME from 2 to 6
Messages
1,491
Location
Alexandria, VA USA
As I say, even if the Acumen lab "ATP Profiles" blood test is not correct, this theory of PEM may still turn out to be right.

So why was she testing it at rest if the problem occurs after effort? It makes no sense.
My theory has better support from research.
 

Hip

Senior Member
Messages
17,824
So why was she testing it at rest if the problem occurs after effort? It makes no sense.

The blockages in energy metabolism are ever-present, including at rest. As far as I am aware, exertion does not affect these blockages, so it does not matter if you test for the blockages at rest, or during exertion.

The theorized loss of ATP molecules during exertion, which the Myhill group posit is the cause of PEM, is not measured by the Acumen lab ATP Profiles blood test.

There are 5 aspects of cellular energy metabolism which are measure by the Acumen test, and are those detailed in this long post, and labelled (1) to (5).
 

gbells

Improved ME from 2 to 6
Messages
1,491
Location
Alexandria, VA USA
The blockages in energy metabolism are ever-present, including at rest. As far as I am aware, exertion does not affect these blockages, so it does not matter if you test for the blockages at rest, or during exertion.

The theorized loss of ATP molecules during exertion, which the Myhill group posit is the cause of PEM, is not measured by the Acumen lab ATP Profiles blood test.

There are 5 aspects of cellular energy metabolism which are measure by the Acumen test, and are those detailed in this long post, and labelled (1) to (5).

Her theory is not supported by the Tomas study. They didn't find any difference between normal and SEIDs patients.
 

Hip

Senior Member
Messages
17,824
Her theory is not supported by the Tomas study. They didn't find any difference between normal and SEIDs patients.

We know that, but you are changing the conversation.

You asked me why Myhill was testing it at rest if the problem occurs after effort. I then explained to you why.