A new hypothesis of chronic fatigue syndrome: Co-conditioning theory.

Dolphin

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I'm starting to consider that the "blame" for the efforts of all these psychologizers, CBTers, GETers, actually does not lie with them, but with the people who know it's really physiological and who aren't doing anything about demonstrating it.

We know that the cell and mitochondrial energy metabolism is deranged in CFS, and Myhill has a test for that. Why isn't this test more widely available? Why won't they make it available to anyone outside the UK? Why won't anyone outside the UK develop a similar test? That's the problem. If that test were more widely available, it would definitely provide a reasonably reliable marker for CFS.

Once that were the case, it could then be easily demonstrated that CBT, GET, or any of that cr4p doesn't change the results of the test one bit, and that therefore they are not effective therapies. Maybe even the opposite of effective in GET. Then the psychologizers would have absolutely nothing to say.

The blame for this predicament is on the people who, for whatever reason - whether a failure of imagination or initiative, or a desire to continue making money off of CFS patients - refuse to standardize a mitochondrial profile test that would not only provide a marker for CFS, but would finally shut up the psychologizers for good. We already have a model for it in the ATP Profile test. There is absolutely no reason why a test like that can't become more widespread and adopted as a standard test for CFS. That would end the entire debate.
Biotech companies and the like would probably be the normal sorts of people who might make something like that happen.
 

Dolphin

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Hi TomK.

It was not a research trial, but an outpatient rehabilitation program at a hospital. It used GET but did not specialise in CFS. A clinical psychologist was available too, but suggested there was no need for psychotherapy, so I was just allocated a physiotherapist.

The lead doctor felt "very optimistic" about my recovery, probably because most of his patients had serious physical injuries while I had a diagnosis which he believed would respond well to exercise. I eventually pulled out of the program because it was difficult establishing a meaningful baseline and the increased activity was having an impact on the rest of my life.

As you know, some patients simply cannot tolerate walking for 6 minutes, while many others can walk 6 minutes if they have to, but they pay for it later rather than immediately by the end of the 6th minute. If the PACE trial is using the 6 minute walk test in a similar way to measure the "fitness" and (immediate) "exercise tolerance" of a patient, then I have serious doubts about the usefulness of this test, especially if patients aren't even "deconditioned" in the first place.

A few physiotherapists I have talked to over the years have this idea that graded activity should be maintained while tolerating as much symptoms as possible, because there is some positive breakthrough point after 4 weeks. Not sure if that is something commonly taught to them about sedentary healthy people or if it just a ploy to increase the adherence of CFS patients?

All the times over the years I have tried regular exercise, "graded" or otherwise, there has never been any wonderful breakthrough point to justify the hype.
Thanks.

Regarding the 4 weeks, I'd say that's a more standard thing taught for "healthy" sedentary people. Physios generally get people, who have been immobile or had an operation, up and moving. CFS patients would only be a tiny proportion of most of their work (unless they are part of a CFS service). With a lot of their non-CFS patients, they have to be like personal trainers or sergeant majors or whatever and really push people.
 

jeffrez

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Biotech companies and the like would probably be the normal sorts of people who might make something like that happen.
Exactly. The point I'm making is that they're not going to develop some test for which there is no demand, are they? Maybe they could make and offer a test that didn't require a doctor's order, but it's doubtful. The CFS docs really need to get involved and make it happen, imo.

Maybe we could prod them with an email campaign, e-petition, etc. Myhill has such a test, so we know it's not impossible. And I don't think the test was extraordinarily expensive, either - a couple hundred dollars at most, I think. It seems so doable.
 
G

Gerwyn

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If you take that stance, then CFS does not exist. There is no objectively measurable parameter in CFS.
If you really believe that then you dont understand the illness or are buying into propaganda Excercise tolerance can easily be meaured over a twenty four to 48 hours and always shows a deterioration IF patients are PROPERLY DIAGNOSED.

Measuring someone over a 6 minute period,and then subjectively,is just a scam.

Now I am on the subject does anyone know how improvement is defined in the CBT studies?? because if impovement measures in GET are a con what about CBT.Any answers gratefully recieved
 

Dolphin

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Exactly. The point I'm making is that they're not going to develop some test for which there is no demand, are they? Maybe they could make and offer a test that didn't require a doctor's order, but it's doubtful. The CFS docs really need to get involved and make it happen, imo.

Maybe we could prod them with an email campaign, e-petition, etc. Myhill has such a test, so we know it's not impossible. And I don't think the test was extraordinarily expensive, either - a couple hundred dollars at most, I think. It seems so doable.
Remember that there is no proof that that test is ME/CFS-specific test. The same abnormalities could exist in other conditions.

It also didn't correlate well on individual factors - it only did well when one multiplied the factors. The paper can be seen at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/

I imagine the inventor (McLaren-Howard) who is connected with Acumen labs (he was formerly Biolab I believe) would like it to be available outside the UK.
 

richvank

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Remember that there is no proof that that test is ME/CFS-specific test. The same abnormalities could exist in other conditions.

It also didn't correlate well on individual factors - it only did well when one multiplied the factors. The paper can be seen at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/

I imagine the inventor (McLaren) who is connected with Acumen labs (he was formerly Biolab I believe) would like it to be available outside the UK.
Hi. Tom and the group.

It's true that Dr. Howard has encouraged labs outside the UK to offer the mitochondrial testing, and he has freely given the test procedures to anyone who asks for them. So far, I don't know of any other labs that have begun to offer this testing. I think it is a rather specialized type of testing, and not so easy to start doing on one's own. Dr. Howard is a very talented person, and he spent several years developing the test procedures and becoming familiar with them. Also, as has been mentioned, specialty labs have to be able to stay in business, and it takes an investment to set up to offer a set of tests like this. The demand would probably not be very large at first, because most conventional doctors would not be familiar with this type of testing and would not be likely to order it.

Dr. Howard has run these tests on quite a few samples from the U.S., and it is possible for people in the U.S. to order it directly from his lab.

I think it's also true that any disorder that involves chronic glutathione depletion will show abnormal results on the mito testing. My view (which I don't think is fully shared by Dr. Howard or Dr. Myhill (yet!) ) is that ME/CFS involves glutathione depletion coupled with a partial block in the methylation cycle, and that these are the fundamental issues that result in the mito dysfunction in CFS. So I would advocate using the methylation pathways panel offered by Vitamin Diagnostics and the European Laboratory of Nutrients as the basic test to define cases of CFS. Unfortunately, the Vitamin Diagnostics lab has been down for several months because of a move to a different building. I hope to find out soon whether they are back up in operation.

Note that Dr. Howard does measure red blood cell glutathione as well as the activities of the glutathione peroxidase enzymes in his set of tests, and often finds abnormalities there. In the more severe cases of glutathione depletion, it shows up in the red blood cells, but this is not the most sensitive place to look. Vitamin Diagnostics measures the plasma glutathione levels, both reduced and oxidized, and this is a more sensitive (and more difficult) test. It also requires special enzyme blockers to be included in the sample vials so that the reduced glutathione is preserved during shipping and storage of samples. As far as I know, these enzyme inhibitors are a proprietary development of Vitamin Diagnostics lab, and other labs don't use them. The specialty lab business is very competitive in the U.S., and patents and proprietary information are very much a part of the picture. After all, these are for-profit labs, and if there were not a profit incentive, they would not exist. This is just economic reality.

I do want to add that I think that Dr. Howard's work is brilliant, and I have found his testing to be very helpful in analyzing what is going on in cases of ME/CFS. His testing is about the best direct evidence of the involvement of mito dysfunction in this disorder. It's just that the mito dysfunction is not the most fundamental, root issue in the biochemistry of this disorder, in my opinion. That is to be found in the vicious circle mechanism that involves glutathione depletion, a partial methylation cycle block, and draining of the folate metabolites out of the cells via the methyl trap mechanism.

Best regards,

Rich
 

dannybex

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Thanks Rich as always for your comprehensive overview here (as well as your comment on Cort's latest article/blog post).

I'm stunned that Vitamin Diagnostics is still not reopened. I don't have the methylation kit yet, but the KPU kit. I'll call them on Monday to see if they can tell me when they expect to be back in business. They probably have run into some sort of regulatory red tape that they have no control over...
 

jeffrez

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Remember that there is no proof that that test is ME/CFS-specific test. The same abnormalities could exist in other conditions.

It also didn't correlate well on individual factors - it only did well when one multiplied the factors. The paper can be seen at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/

I imagine the inventor (McLaren-Howard) who is connected with Acumen labs (he was formerly Biolab I believe) would like it to be available outside the UK.
The fact that it correlates strongly on multiple factors strengthens the findings, imo, not weakens them. Someone could have some minor or isolated metabolic defect for some other reason -- genetic, etc. -- and not have CFS. It's when you take the factors together that you show the biomarker.

Thinking that there has to be just one single abnormality is, in my opinion, part of the outdated way of thinking that is keeping everyone stuck back in the Dark Ages. ME/CFS are relatively new disorders -- at least it being this widespread is new -- and these illnesses don't conform to the old models of disease. We need new models to be able to "see" them, and I think this mito test is one way, maybe an early way, but it seems very accurate, according to their reports, which I think showed something like 70 people out of 71 who scored in this range on the test had CFS. That's a very strong correlation, and I think even the 1 person who didn't test in the "cfs zone" was still really close.

It's true theoretically that the same abnormalities could exist in other conditions. But let's be honest: we all know experientially that they don't. If they did, those people would have CFS, too. Or possibly fibro, GWS, etc. which perhaps share some of the same profile. But they don't. Even when they're really, really sick with something else, like cancer or AIDS. It's not the same. We all know that. And when someone with CFS improved, whether through ampligen, GSH, some other means, we most likely also would see the results of their test change. That would be more strong support for the validity of the test. Based on their reported findings, at least, and what we seem to know about CFS so far, I think it would be a much better marker than the XMRV obsession, which imo is a red herring.
 

jeffrez

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richvank: that's all very interesting. Thanks for posting it. I am going to try to remember to look into the Vitamin Diagnostics testing when they get their website back online.

About the glutathione ideas, hasn't Cheney somewhat abandoned those? Are people still seeing improvements with taking whey and other glutathione precursors?
 

richvank

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Thanks Rich as always for your comprehensive overview here (as well as your comment on Cort's latest article/blog post).

I'm stunned that Vitamin Diagnostics is still not reopened. I don't have the methylation kit yet, but the KPU kit. I'll call them on Monday to see if they can tell me when they expect to be back in business. They probably have run into some sort of regulatory red tape that they have no control over...
Hi, dannybex.

Please see my update on the Vitamin Diagnostics thread.

Best regards,

Rich
 

richvank

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richvank: that's all very interesting. Thanks for posting it. I am going to try to remember to look into the Vitamin Diagnostics testing when they get their website back online.

About the glutathione ideas, hasn't Cheney somewhat abandoned those? Are people still seeing improvements with taking whey and other glutathione precursors?
Hi, Mr. Kite.

You're welcome, and I'm glad you found it interesting.

I just posted an update on the Vitamin Diagnostics thread.

On glutathione and Dr. Cheney, that's an interesting situation. Here's the story: In 1999, Dr. Cheney gave a couple of public talks (in Austria and in Texas) in which he reported that essentially all his CFS patients had glutathione depletion, and that he was trying various approaches to building it up, including whey protein. That is what got me interested in glutathione, and I studied it quite a bit and became convinced that glutathione depletion is behind many of the features of CFS. I also encouraged PWCs to try to build up their glutathione in various ways. Over the course of time I found that while these measures did help many PWCs (while some could not tolerate them), the benefits were temporary. I began to believe that there was a vicious circle operating that was holding glutathione down in PWCs. I presented a poster paper stating this at the 2004 AACFS conference. Shortly after this, Jill James and colleagues published their work in autism, which showed that glutathione was also depleted in that disorder, and that it was associated with a problem in the methylation cycle, which lies upstream of glutathione in the sulfur metabolism. When I read this, I immediately suspected that the same thing must be true in CFS, and I began encouraging PWCs to try the treatments that had helped the methylation cycle in autism. This turned out to be true, and these types of treatments have been able to restore glutathione without directly supplementing it or its precursors. I've written additional papers about this, which you can read at www.cfsresearch.org by clicking on CFS/M.E. and then on my name.

Meanwhile, Dr. Cheney also found that boosting glutathione directly was not all he had hoped it would be. In addition, I think he ran some lab tests that were unfortunately misinterpreted, and he began to believe that the problem with glutathione in CFS was not that it was depleted, but that it was oxidized. He then reasoned that building glutathione directly would simply raise the level of oxidized glutathione, which would not be beneficial. So he abandoned glutathione boosting. Meanwhile, he had his heart failure and transplant, and he became very interested in the heart in CFS. He got an echocardiograph machine, and focused his diagnosis on using it. He also moved more into using cell signalling factors from animals, and then eventually into incorporating stem cell treatments, which he is focussing on now, and it's looking very good at this point.

So he and I differ with regard to glutathione at this point. I think that we have good evidence that glutathione depletion and the partial methylation cycle block are at the root of CFS, and that they are the cause of the mito dysfunction, which in turn causes the diastolic dysfunction of the heart that he observes by echocardiography. I think his current view is that the mito dysfunction is caused by oxidative stress, which is brought about perhaps by a virus inhibiting the antioxidant enzymes. We continue to have constructive dialogue, and perhaps eventually our views will converge again. In any case, I owe a lot to Dr. Cheney for stimulation of my thinking, and I continue to root for his stem cell therapy patients.

If you go to the site I mentioned above, you can read about the Simplified Treatment Approach for CFS, which is based on the hypothesis I've adopted from the autism people, and which has been very helpful for many PWCs.

Best regards,

Rich
 

PoetInSF

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You can't say that they didn't do what they were asked to. They may well have increased the length of their walk but decreased the activity in the rest of their lives - that might not have been consciously decreased the rest of their activity.
The total amount of activity should be what matters. (As anti-GET folks often notes, all activities are exercises.) The only thing you can conclude from this study is that: CBT showed improvements and there was no increase in activities; therefore, the improvement was not mediated by the increased activities. Would they have achieved even bigger improvement if they increased activities as well? No way to tell from this study either. In other words, this study is irrelevant regarding GET.
 

Dolphin

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The total amount of activity should be what matters..
I agree.
(As anti-GET folks often notes, all activities are exercises.)..
Yes
The only thing you can conclude from this study is that: CBT showed improvements.).
Well, my point is that we should question whether these are real "improvements" at all and how significant they are.

Such studies are sometimes reported as showing that CBT can restore the ability to work or lead to full recovery because of the improved scores on the physical functioning or fatigue questionnaires, even though as you say, these people aren't doing anymore.

So I think that we should not have much faith in the results from these questionnaires in a lot of studies including where people are encouraged to go for walks. The authors put a different spin on the results but then it was their studies they tested but they choose not to report the actometer which publishing the studies - the Prins study was published in 2001 but they are only publishing the actometer data now.
 

PoetInSF

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Graded exercise therapy is carrying on with the incremental increase in exercise no matter how bad you feel or how much pain you are in. They do not believe that such pain is related to a disease process, they think it is normal sensations (their word) which we think is pain.
Do you have a link to a GET guideline that says this? Most official guidelines I've seen seemed quite reasonable. I remember only one (it might have been from Warwick) recommending walking off PEM. I quickly dismissed it when I first saw it, eventhough it recommended to cut back, not increase. Later I figured, what the heck, I'd give it a try. To my surprise, I DID feel better. Since then I've been walking off mild case of PEM. Will that work for everybody? I have no idea.

Happily resting after walking off PEM with 1.9mi trek to Chinatown...
 

PoetInSF

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by Poet in SF
You have missed the point. All scientific studies should try to be objective. Asking someone if they feel better is very subjective and liable to bias so a study with an objective measurement carries much more weight.
What do you suggest? If you have a way to objectively measure and qualify fatigue in CFS, you've found a diagnostic marker. You can't blame GET study for failing to measure what is not objectively parameterized for CFS.
 

Dolphin

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Do you have a link to a GET guideline that says this? Most official guidelines I've seen seemed quite reasonable. I remember only one (it might have been from Warwick) recommending walking off PEM. I quickly dismissed it when I first saw it, eventhough it recommended to cut back, not increase.
Here's the Kathy Fulcher and Peter White protocol for GET for anybody interested:

The protocol

The original protocol for GET was based on the improvements in strength, endurance and symptomatology documented for other disorders, notably fibromyalgia and 'effort syndrome' (Fulcher and White 10). The protocol is divided into two parts: assessment and exercise prescription. The assessment is designed to determine the patient's aerobic capacity and involves a graded incremental and continuous test on a treadmill or bicycle ergometer. Heart monitors are used with recordings taken at rest, every two minutes during exercise, at maximum exertion and three minutes after exercise. Post-exercise heart rate (HR) should be monitored for longer if it remains elevated. Alternatively, one can take the pulse manually, and/or use an online ECG system. The exercise test is performed in two minute stages, beginning at a very low work rate. On a treadmill, the speed should be constant and the gradient increased. On a bicycle, the pedal revolutions should be maintained at 40 or 50 revolutions per minute (RPM) and the resistance increased. The aim is to exercise to volitional exhaustion or symptom limited maximum. In addition, the therapist should assess muscle strength. Full isokinetic testing is not recommended but isometric assessment of quadriceps strength using a strain guage system or appropriate dynamometers is useful. Baseline assessment should furthermore include a record of symptoms and disability.

The original protocol recommends fortnightly sessions for clinical practice with ten face-to-face individual sessions over 20 weeks, and weekly sessions for research. All should be carried out by a qualified exercise physiologist or physiotherapist. Patients should be taught stretching exercises to do at the beginning of each session. The intensity and duration of the exercise must be tailored to the individual and negotiated with the patient, but most can begin at an intensity of 40% of their maximum aerobic capacity which equates to approximately 50% of their heart rate reserve (HRR: maximum HR – resting HR). The target exercise zone will be between 50-60% of the HRR (HRR x 0.5). However, if the patient is severely disabled, it may be more helpful to start with two weeks of stretching alone.

Each session includes a time for joint planning and the discussion of the following two weeks' prescription. The initial aim is to establish a regular pattern of exercise (usually walking), which may be only five minutes per day to begin with, and patients are encouraged to exercise at least five days a week and to schedule their exercise into their day. The periods may be broken up into one or two minutes of target pace activity interspersed with one minute at a slower pace. The duration of the home exercise can be increased by one or two minutes a week up to a maximum 30 minutes per session, but must always be based on their previous week’s performance. The intensity of exercise can then be increased to 50% and then 60% of their maximum aerobic capacity but patients must be informed that they should not exceed their target heart rate (measured by a monitor lent by the clinic if possible) or do more on a good day.

If patients progress well after four visits, eight weeks into the programme, strengthening exercises may be added to the routine. This should take the form of local muscle conditioning exercises using their own body weight or hand-held weights (cans of food or bottles of water) as resistance. The weekly exercise programme can then be split into half the sessions of purely aerobic activities as described above, and half with a shorter aerobic warm-up followed by their muscle strengthening exercises, split into sets (of five to ten repetitions) to make them more manageable.

All patients should keep an exercise diary recording the type and duration of exercise, time of day and how they feel. On their fortnightly attendances, the diary should be reviewed and the exercise for the following two weeks should be negotiated. If they complain of fatigue in response to a new level of exercise, they should be advised to remain at the same level for an extra week, rather than progressing the duration, and to increase the exercise when the symptoms regress. They should be reminded that each new level will feel harder initially, until the body adapts. Reassessment should repeat the tests completed at baseline.

The aim of the following analysis is to assess the efficacy of GET using the above protocol or a version consistent with the main principle of GET, i.e. a gradual increase in activity levels according to a pre-determined schedule, where patients are not permitted to stop and rest when they feel fatigued but are encouraged to tolerate a certain amount of discomfort for up to one week.
Note, they only say fatigue but then they don't describe all the symptoms exercise can bring on - they tend to be called "fatigue symptoms" or "symptoms of fatigue".
 

PoetInSF

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If you really believe that then you dont understand the illness or are buying into propaganda Excercise tolerance can easily be meaured over a twenty four to 48 hours and always shows a deterioration IF patients are PROPERLY DIAGNOSED.

Measuring someone over a 6 minute period,and then subjectively,is just a scam.
Feel free to quote a specific study that is a scam. We'll have basis for discussion then.
 

PoetInSF

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The PACE Trial http://www.biomedcentral.com/1471-2377/7/6 uses the 6-minute walking test - that one costs in the region of 5 million pounds so is worth discussing. It will probably be published this year.
It appears to be extensive and well designed study, though it's not yet a part of any systematic GET study evaluations done so far. It's an excellent idea to measure both symptom and disability as outcomes as they are not the one and the same. (I've said this before on Donnica thread: the best way to characterize CFS is with both disability and symptoms, not just with symptoms)

The 6 min walk test measures the exercise tolerance (disability), not the symptoms. I'm assuming it is assessed at the baseline, and then at periodic intervals. I don't see a problem as along as it is done apple-to-apple. If the test, or any treatment, causes them PEM, they'll probably drop out. The study seems to have a plan to take that into account as well.
 
G

Gerwyn

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Hi. Tom and the group.

It's true that Dr. Howard has encouraged labs outside the UK to offer the mitochondrial testing, and he has freely given the test procedures to anyone who asks for them. So far, I don't know of any other labs that have begun to offer this testing. I think it is a rather specialized type of testing, and not so easy to start doing on one's own. Dr. Howard is a very talented person, and he spent several years developing the test procedures and becoming familiar with them. Also, as has been mentioned, specialty labs have to be able to stay in business, and it takes an investment to set up to offer a set of tests like this. The demand would probably not be very large at first, because most conventional doctors would not be familiar with this type of testing and would not be likely to order it.

Dr. Howard has run these tests on quite a few samples from the U.S., and it is possible for people in the U.S. to order it directly from his lab.

I think it's also true that any disorder that involves chronic glutathione depletion will show abnormal results on the mito testing. My view (which I don't think is fully shared by Dr. Howard or Dr. Myhill (yet!) ) is that ME/CFS involves glutathione depletion coupled with a partial block in the methylation cycle, and that these are the fundamental issues that result in the mito dysfunction in CFS. So I would advocate using the methylation pathways panel offered by Vitamin Diagnostics and the European Laboratory of Nutrients as the basic test to define cases of CFS. Unfortunately, the Vitamin Diagnostics lab has been down for several months because of a move to a different building. I hope to find out soon whether they are back up in operation.

Note that Dr. Howard does measure red blood cell glutathione as well as the activities of the glutathione peroxidase enzymes in his set of tests, and often finds abnormalities there. In the more severe cases of glutathione depletion, it shows up in the red blood cells, but this is not the most sensitive place to look. Vitamin Diagnostics measures the plasma glutathione levels, both reduced and oxidized, and this is a more sensitive (and more difficult) test. It also requires special enzyme blockers to be included in the sample vials so that the reduced glutathione is preserved during shipping and storage of samples. As far as I know, these enzyme inhibitors are a proprietary development of Vitamin Diagnostics lab, and other labs don't use them. The specialty lab business is very competitive in the U.S., and patents and proprietary information are very much a part of the picture. After all, these are for-profit labs, and if there were not a profit incentive, they would not exist. This is just economic reality.

I do want to add that I think that Dr. Howard's work is brilliant, and I have found his testing to be very helpful in analyzing what is going on in cases of ME/CFS. His testing is about the best direct evidence of the involvement of mito dysfunction in this disorder. It's just that the mito dysfunction is not the most fundamental, root issue in the biochemistry of this disorder, in my opinion. That is to be found in the vicious circle mechanism that involves glutathione depletion, a partial methylation cycle block, and draining of the folate metabolites out of the cells via the methyl trap mechanism.

Best regards,

Rich
Sorry rich i disagree the symptom comples is more consistant with mito dysfunction glutathione depletion i think is secondary and not causative.that of course is just my opinion