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MEA RRF to fund study into tests for mitochondrial dysfunction

Hutan

Senior Member
Messages
1,099
Location
New Zealand
I suspect that most people are not aware of this very interesting research that was carried out by Professor Mina Behan in Glasgow many years ago which demonstrated structural abnormalities in skeletal muscle mitochondria

Part of my thigh muscle was used in this research and I still have a large scar to prove it!

Paper: http://link.springer.com/article/10.1007/BF00294431#page-1

Thanks. This study seemed to show a very clear difference between healthy people and people with long standing post-viral syndrome. Has it been replicated? If not, surely replication is a priority.

Will the proposed mitochondrial studies (sorry, have not looked in to them in detail) go any way towards evaluation of this study's result?
 

Research 1st

Severe ME, POTS & MCAS.
Messages
768
This small MEA study in my view, would not be published with great scientific fanfare to help approve or disaprove of Dr Myhill's test, which, is not expensive considering how much tests cost on the market.

The major study design issue, is this:

The novel Dr Myhill test is on Lymphocyte ATP - white blood cells. This is interesting as its white blood cells that are linked to all manner of immune dysfunction in CFS research. Note this is blood, not tissue. The tissue in desperate need of research in neuro sign severe ME is lymphatic tissue - biopsies. Here may lie a pathogens reservoir, including prions.

But:

Those who don't want people to link low ATP in WBC with chronic infection in PWME, will perhaps attempt to discredit the WBC ATP findings in patients as 'unproven' using any method they can.

Historically, the pro BPS lobby (who deny ME is an organic disease, distinct from CF) would love to crush the sale of any biomedical test that exposes the huge gap in science, BPS CFS is based on - no science remember, only beliefs.

Yes, the classical way to measure Mito function in Mito disease is a muscle biopsy, but ME is an aqquired disease (like AIDS or MS), not a congenital muscle weakness disorder, hence most (not all) PWME muscle biopsies are negative apart from the odd non specific virus plenty PWME never get nailed by. (There's an issue of disease latency, subsets, length of disease - all variables unable to be controlled for by the researcher). Then you need to add in which patients have inflammation, then types of inflammation (CRP/ESR vs Oxidative Stress etc).

Combined, its too complex without the kind of budget the MRC would grant ME denial researchers.

So, comparing two different areas of biology to conclude which is best in a paper is impossible, because they are different areas of biology and no method is right or wrong, they are complimentary exclusionary or (theoretically) inclusionary.

Yet the BPS CFS guru's will revel in potential to cite 'research evidence' that challenges clinical usefullness of Dr Myhill's test, should this occur.

To prove which test is better you need to do bloods and biopsies on the same research participants. (Arm biopsies aren't generally sufficient, you'd need thigh surgery to get good mitochondrial muscle samples).

Yet an 'open' mitochondria muscle biopsy is very painful (can't anethatise muscle as it ruins sample) and is somewhat risky (nerve damage, infection, blood loss is possible). Ethical approval is thus going to be challenging in a bunch of presumed 'tired people'.

I would then remember, that a simple blood test, such as Dr Myhill's carries much less risk to a patient, even if the results are not muscle centric, they are still cellular ATP based.

In my view, I would let Dr Myhill sell her test and not interfere on the grounds of worries over cost/which is more suitable etc, because by potentially stopping it, you reduce patient legitimacy in the community, who otherwise have zero proof of organic weakness (unexpected low WBC ATP go a sceptical GP etc).

Cohorts won't accurately reflect which test is more appropriate anyway due to heterogeneous issue:

Some accuracy occurs using ME-ICC or CCC CFS. Yet,
no one with the confusing CFS/ME need complain of, or display, any medical sign of muscle weakness or any other medically verifiable sign of disease.

How then, one determines which research group had 25% or 85% of probable 'ME' patients in a muscle study Vs a Lymphocyte ATP blood test, using British CFS/ME diagnostic criteria...is anyone's guess.

This is a massive problem when determining any test validity in CFS or ME, meaning few robust conclusions can be made, especially when selecting assays.

As long as weak diagnostic criteria is allowed, the more tests, the merrier. More tests = more data. Once subgroups are identified, then we can decide fairly, which test is more suitable for whom.
 

charles shepherd

Senior Member
Messages
2,239
Thanks. This study seemed to show a very clear difference between healthy people and people with long standing post-viral syndrome. Has it been replicated? If not, surely replication is a priority.

Will the proposed mitochondrial studies (sorry, have not looked in to them in detail) go any way towards evaluation of this study's result?

I don't think anyone has tried to properly replicate the very significant structural abnormalities in skeletal muscle mitochondria that were found and reported by Mina Behan

On a personal basis I find this very disappointing (and I have tried to create interest here) having used part of my own muscle in this research!
 

charles shepherd

Senior Member
Messages
2,239
This small MEA study in my view, would not be published with great scientific fanfare to help approve or disaprove of Dr Myhill's test, which, is not expensive considering how much tests cost on the market.

The major study design issue, is this:

The novel Dr Myhill test is on Lymphocyte ATP - white blood cells. This is interesting as its white blood cells that are linked to all manner of immune dysfunction in CFS research. Note this is blood, not tissue. The tissue in desperate need of research in neuro sign severe ME is lymphatic tissue - biopsies. Here may lie a pathogens reservoir, including prions.

But:

Those who don't want people to link low ATP in WBC with chronic infection in PWME, will perhaps attempt to discredit the WBC ATP findings in patients as 'unproven' using any method they can.

Historically, the pro BPS lobby (who deny ME is an organic disease, distinct from CF) would love to crush the sale of any biomedical test that exposes the huge gap in science, BPS CFS is based on - no science remember, only beliefs.

Yes, the classical way to measure Mito function in Mito disease is a muscle biopsy, but ME is an aqquired disease (like AIDS or MS), not a congenital muscle weakness disorder, hence most (not all) PWME muscle biopsies are negative apart from the odd non specific virus plenty PWME never get nailed by. (There's an issue of disease latency, subsets, length of disease - all variables unable to be controlled for by the researcher). Then you need to add in which patients have inflammation, then types of inflammation (CRP/ESR vs Oxidative Stress etc).

Combined, its too complex without the kind of budget the MRC would grant ME denial researchers.

So, comparing two different areas of biology to conclude which is best in a paper is impossible, because they are different areas of biology and no method is right or wrong, they are complimentary exclusionary or (theoretically) inclusionary.

Yet the BPS CFS guru's will revel in potential to cite 'research evidence' that challenges clinical usefullness of Dr Myhill's test, should this occur.

To prove which test is better you need to do bloods and biopsies on the same research participants. (Arm biopsies aren't generally sufficient, you'd need thigh surgery to get good mitochondrial muscle samples).

Yet an 'open' mitochondria muscle biopsy is very painful (can't anethatise muscle as it ruins sample) and is somewhat risky (nerve damage, infection, blood loss is possible). Ethical approval is thus going to be challenging in a bunch of presumed 'tired people'.

I would then remember, that a simple blood test, such as Dr Myhill's carries much less risk to a patient, even if the results are not muscle centric, they are still cellular ATP based.

In my view, I would let Dr Myhill sell her test and not interfere on the grounds of worries over cost/which is more suitable etc, because by potentially stopping it, you reduce patient legitimacy in the community, who otherwise have zero proof of organic weakness (unexpected low WBC ATP go a sceptical GP etc).

Cohorts won't accurately reflect which test is more appropriate anyway due to heterogeneous issue:

Some accuracy occurs using ME-ICC or CCC CFS. Yet,
no one with the confusing CFS/ME need complain of, or display, any medical sign of muscle weakness or any other medically verifiable sign of disease.

How then, one determines which research group had 25% or 85% of probable 'ME' patients in a muscle study Vs a Lymphocyte ATP blood test, using British CFS/ME diagnostic criteria...is anyone's guess.

This is a massive problem when determining any test validity in CFS or ME, meaning few robust conclusions can be made, especially when selecting assays.

As long as weak diagnostic criteria is allowed, the more tests, the merrier. More tests = more data. Once subgroups are identified, then we can decide fairly, which test is more suitable for whom.

I think we are going to have to agree to disagree here on the potential value of this small research study which, as I keep saying, is an important first step in trying to assess whether this commercial test is of value in detecting and measuring the degree of mitochondrial dysfunction in ME/CFS.

The design was agreed after prolonged discussion with a muscle and mitochondrial research group here in the UK who have an international reputation and who are also very involved with muscle and mitochondrial research into ME/CFS.

They believe that we are dealing with a complex biomedical illness which also involves mitochondrial dysfunction.
 

Scarecrow

Revolting Peasant
Messages
1,904
Location
Scotland
@charles shepherd I understand that the pilot study at Newcastle, which indicated impaired oxidative phosphorylation, used muscle cells but as the ATP profile test uses neutrophils, will the MEA funded study also use neutrophils when assaying oxidative phosphorylation?

I've looked thoroughly through the MEA announcement - sorry if it's mentioned, I just can't see it.
 

charles shepherd

Senior Member
Messages
2,239
@charles shepherd I understand that the pilot study at Newcastle, which indicated impaired oxidative phosphorylation, used muscle cells but as the ATP profile test uses neutrophils, will the MEA funded study also use neutrophils when assaying oxidative phosphorylation?

I've looked thoroughly through the MEA announcement - sorry if it's mentioned, I just can't see it.

There are a number of 'small print' technical queries arising which I think would benefit from input from Dr Boulton in Newcastle

I will lump them all together next week and ask her to comment as well

When I have time I will go through the quite detailed grant application protocol that I have from Newcastle but not right now - because other work is piling up!
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
@charles shepherd, I wonder if you or Dr Boulton would mind answering another question about the study you are funding...
I've been wondering how will they determine which mitochondrial test (the novel test or the 'gold standard' test) is most accurate at detecting abnormalities?
 
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Scarecrow

Revolting Peasant
Messages
1,904
Location
Scotland
The novel Dr Myhill test is on Lymphocyte ATP - white blood cells. This is interesting as its white blood cells that are linked to all manner of immune dysfunction in CFS research. Note this is blood, not tissue. The tissue in desperate need of research in neuro sign severe ME is lymphatic tissue - biopsies. Here may lie a pathogens reservoir, including prions.
The ATP profile test uses neutrophils not lymphocytes. The study that I linked to above, which measured oxidative phosphorylation directly, used a group of cells that includes lymphocytes and they found no difference between Fukuda patients and controls. They concluded that the impairment demonstrated by 2 day CPET was due to limited oxygen transport capacity.

The Myhill et al study, which also used Fukuda patients, had already acknowledged that the reduced ATP production they measured could be due to lack of cellular oxygen.

Our observations strongly implicate mitochondrial dysfunction as the immediate cause of CFS symptoms. However, we cannot tell whether the damage to mitochondrial function is a primary effect, or a secondary effect to one or more of a number of primary conditions, for example cellular hypoxia [30], or oxidative stress including excessive peroxynitrite [54-58].

To prove which test is better you need to do bloods and biopsies on the same research participants. (Arm biopsies aren't generally sufficient, you'd need thigh surgery to get good mitochondrial muscle samples).
Fair point but why do you think that they won't be using the same research participants for both tests?
Some accuracy occurs using ME-ICC or CCC CFS. Yet, no one with the confusing CFS/ME need complain of, or display, any medical sign of muscle weakness or any other medically verifiable sign of disease.

How then, one determines which research group had 25% or 85% of probable 'ME' patients in a muscle study Vs a Lymphocyte ATP blood test, using British CFS/ME diagnostic criteria...is anyone's guess.
The Myhill et al. study itself used Fukuda patients. I think that Newton uses Fukuda also. Because PEM is a requirement for a clinical diagnosis in the UK, you wouldn't expect idiopathic fatigue patients to be included. I know that isn't your point but your criticism is unfair if you're not including Myhill in it.
 

Scarecrow

Revolting Peasant
Messages
1,904
Location
Scotland
There are a number of 'small print' technical queries arising which I think would benefit from input from Dr Boulton in Newcastle

I will lump them all together next week and ask her to comment as well

When I have time I will go through the quite detailed grant application protocol that I have from Newcastle but not right now - because other work is piling up!
And you thought no one was interested in mitochondrial dysfunction!

Thank you.
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
@charles shepherd, I'm certain there are many on this forum who are particularly interested in mitochondrial dysfunction, and would love to see it investigated in well-funded research studies. So you're far from alone with regards to your interest in this subject. Personally, I think it should be a top priority. But I think any potential mitochondrial dysfunction might potentially have an autoimmune, genetic or pathogenic cause.
 

charles shepherd

Senior Member
Messages
2,239
@charles shepherd, I'm certain there are many on this forum who are particularly interested in mitochondrial dysfunction, and would love to see it investigated in well-funded research studies. So you're far from alone with regards to your interest in this subject. Personally, I think it should be a top priority. But I think any potential mitochondrial dysfunction might potentially have an autoimmune, genetic or pathogenic cause.


Thanks Bob

Post-infectious mitochondrial myopathies are well recognised and this was the initial diagnosis that I received in relation to my post chickenpox encephalitis ME. The MM diagnosis was made by Professor John Morgan Hughes at the National Hospital for Neurological Diseases in Queens Square, London. At the time John was one of the leading experts on muscle disease in the UK and he had seen a number of people with a very similar muscle symptomatology following an acute infection.
 

SOC

Senior Member
Messages
7,849
I'm very pleased to see any (decent) research in mitochondrial dysfunction in ME/CFS. :thumbsup:

I wonder if some of the confusion here is due to the varying nature of "studies" in the scientific arena. Conventional, rigorous scientific research starts with a valid hypothesis which is proved or disproved by the research. Many rules and procedures are in place to (theoretically) minimize the impact of unintentional (or intentional) bias on the part of the researcher. That's what we usually think about when we talk about scientific research. This is the high-powered stuff.

There are also, however, other types of studies. This one looks like an exploratory study. Exploratory studies are small, early, relatively low-powered studies whose intention is to get a feel for the lay of the land, so to speak. They are mostly used to take a complex picture and try to figure out where to focus more limited rigorous studies. It's kind of a "Let's take a look and see what we've got here, then move on from there" idea. Exploratory studies often don't have a clear hypothesis or single specific goal. For that reason, they are not considered rigorous scientific studies, but that doesn't mean they aren't valuable in moving forward the science.

For all their value, though, they are incomplete in and of themselves. They are clearing-the-ground studies. They lay the groundwork for justifying more extensive, and expensive, research. Without rigorous follow-up studies, the results don't mean much. My guess is that Newcastle is using this as a way to figure out where to direct efforts for further in-depth research on the topic. I certainly hope so. :)
 

charles shepherd

Senior Member
Messages
2,239
I'm very pleased to see any (decent) research in mitochondrial dysfunction in ME/CFS. :thumbsup:

I wonder if some of the confusion here is due to the varying nature of "studies" in the scientific arena. Conventional, rigorous scientific research starts with a valid hypothesis which is proved or disproved by the research. Many rules and procedures are in place to (theoretically) minimize the impact of unintentional (or intentional) bias on the part of the researcher. That's what we usually think about when we talk about scientific research. This is the high-powered stuff.

There are also, however, other types of studies. This one looks like an exploratory study. Exploratory studies are small, early, relatively low-powered studies whose intention is to get a feel for the lay of the land, so to speak. They are mostly used to take a complex picture and try to figure out where to focus more limited rigorous studies. It's kind of a "Let's take a look and see what we've got here, then move on from there" idea. Exploratory studies often don't have a clear hypothesis or single specific goal. For that reason, they are not considered rigorous scientific studies, but that doesn't mean they aren't valuable in moving forward the science.

For all their value, though, they are incomplete in and of themselves. They are clearing-the-ground studies. They lay the groundwork for justifying more extensive, and expensive, research. Without rigorous follow-up studies, the results don't mean much. My guess is that Newcastle is using this as a way to figure out where to direct efforts for further in-depth research on the topic. I certainly hope so. :)

Thanks for a very helpful contribution

With the benefit of hindsight I should have made some of these points about the very important role of preliminary/exploratory research studies at the start of this discussion
 

charles shepherd

Senior Member
Messages
2,239
@charles shepherd, I wonder if you or Dr Boulton would mind answering another question about the study you are funding...
I've been wondering how will they determine which mitochondrial test (the novel test or the 'gold standard' test) is most accurate at detecting abnormalities?

I don't think I can go any further than saying we all very open minded about what conclusions will be drawn from this small study and where this may then take us. We are hoping that the results will provide an indication as to whether the commercial test is of some value in assessing mitochondrial function in ME/CFS. It's a short study (5 months) that has already started (in May) - so it won't be too long before we have some results to consider.
 

Kati

Patient in training
Messages
5,497
Great new, thank you.

i wonder how much it costs for the Dr Myhill test? Patients are willing to pay because they want to show proof of illness. Too often, out of despair, patients would do a lot of things. The stigma and neglect out there is absolutely unbelievable.

i understand Dr Myhill's test and practice is more of the alternative side and not recognized by medical systems.

I am pleased that this will be a quick affair, hopefully peer-reviewed and published just as quickly.

Myself, I have had a muscle biopsy. The local mito clinic is more focused on the genetic mito dysfunction so my Mt DNA was sequenced and said to be normal with no major deletions or mutations. Microscopy of my muscle fiber showed atrophy of the slow twich fibers, but they didn't seem to care about that. This was perhaps 2-3 years into my illness. i would undergo another muscle biopsy if needed but personally, I think mito dysfunction is just downstream of the cause of the disease.
 
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charles shepherd

Senior Member
Messages
2,239
Great new, thank you.

i wonder how much it costs for the Dr Myhill test? Patients are willing to pay because they want to show proof of illness. Too often, out of despair, patients would do a lot of things. The stigma and neglect out there is absolutely unbelievable.

i understand Dr Myhill's test and practice is more of the alternative side and not recognized by medical systems.

I am pleased that this will be a quick affair, hopefully peer-reviewed and published just as quickly.

Myself, I have had a muscle biopsy. The local mito clinic is more focused on the genetic mito dysfunction so my Mt DNA was sequenced and said to be normal with no major deletions or mutations. Microscopy of my muscle fiber showed atrophy of the slow twich fibers, but they didn't seem to care about that. This was perhaps 2-3 years into my illness. i would undergo another muscle biopsy if needed but personally, I think mito dysfunction is just downstream of the cause of the disease.

Details about the commercial test can be found here:

http://www.drmyhill.co.uk/wiki/Mitochondrial_Function_Profile

The cost (test + letter) comes to £370

You may have seen that we are also funding some research (also in Newcastle) which is looking at mitochondrial DNA in ME/CFS