1. Patients launch a $1.27 million crowdfunding campaign for ME/CFS gut microbiome study.
    Check out the website, Facebook and Twitter. Join in donate and spread the word!
The Lipkin Microbiome Crowdfunding Campaign Launches!
An ambitious $1.27m international, patient-led fundraising campaign storms into action. Sasha invites you to join it!
Discuss the article on the Forums.

Dr Myhill publishes second paper

Discussion in 'Latest ME/CFS Research' started by ISAS, Jul 2, 2012.

  1. adreno

    adreno 3% neanderthal

    Messages:
    2,120
    Likes:
    1,157
    Tundras of Europa
    Maybe by taking supps that protect the mitochondria we are preventing further deterioration, without it being a cure.

    I can not claim to have been cured by her supplements either, but at least I'm not deteriorating. Instead, I'm very slowly improving over the years.

    Oxidative stress has been repeatedly found in ME, and whether mitochondrial dysfunction is at the root of ME or not, I feel it is important to protect the mitochondria of the constant oxidative insult.
    Allyson, SJB944, merylg and 1 other person like this.
  2. heapsreal

    heapsreal iherb 10% discount code OPA989,

    Messages:
    6,887
    Likes:
    3,985
    australia (brisbane)
    i agree adreno, i think many supps etc stop further damage. Theres studies showing oxidative stress in cfs me as well as low carnitine and q10 levels but i think before we get improvement we need to get closer to the source rather then fill the cracks with q10 , carnitine etc??
    Allyson and justy like this.
  3. adreno

    adreno 3% neanderthal

    Messages:
    2,120
    Likes:
    1,157
    Tundras of Europa
    I agree, we are just treating symptoms with the supps, but I believe that's the best we can do for now, until we know more about the disease. I would be nice to actually have something left to salvage, if a cure comes along eventually.
    sianrecovery likes this.
  4. xrunner

    xrunner Senior Member

    Messages:
    527
    Likes:
    185
    me four!
    the supps made me worse actually and the test over the years did not correlate that well with my state of health.
    In the long run, supps just created more imbalances because they did not address the cause, in my case chronic infections.
    All in all quite a disappointing and money draining experience for me.
  5. Mula

    Mula Senior Member

    Messages:
    131
    Likes:
    46
    Gangrene may produce familiar symptoms that are reported by those with MECFS but gangrene is distinctly different.
  6. barbc56

    barbc56 Senior Member

    Messages:
    1,244
    Likes:
    625
    The problem with this paper is that thie test used is not validated and has been scientifically discredited. (See below) That's like a house without a good foundation. It's destined to fall apart even if the house is made well.

    The Chief Medical Advisor and Trustee of the ME Association, Dr. Charles Shepherd, when asked about the validity of the Myhill Mitochondrial Function tests.

    https://www.facebook.com/permalink.php?story_fbid=268325576558441&id=171411469583186

    There are several other issues I could go into but probably best not for legal reasons, but I think the above is telling as far as the validity of this paper.

    Barb C.:>)
    Simon likes this.
  7. Aquila

    Aquila

    Messages:
    43
    Likes:
    15
    UK
    Was this tested for blinded? Surely if it was it can't be dismissed as quickly as Charles shepherd suggest. A blood test which can separate healthy people from pwme is surely incredibly useful. But it does need to be replicated by an independent lab. It seems sad to dismiss it particularly as the sample size is relatively large. I was notwell enough to do more than skim the paper. Could you explain barb why it could not be useful as a test for m.e.?
    Allyson likes this.
  8. barbc56

    barbc56 Senior Member

    Messages:
    1,244
    Likes:
    625
    From the following study:
    Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity.
    J Transl Med. 2010; 8: 93. Published online 2010 October 11. doi: 10.1186/1479-5876-8-93http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964609/?tool=pubmed
    This same study also includes criticism of the following Myhill study:

    Chronic fatigue syndrome and mitochondrial dysfunction.
    Int J Clin Exp Med. 2009;2(1):1-16. Epub 2009 Jan 15.
    http://www.ncbi.nlm.nih.gov/pubmed/19436827
    Barb C.:>)
  9. ISAS

    ISAS

    Messages:
    29
    Likes:
    29
    REPOST FROM peoplewithme

    Dr Myhill Press Release on second 'mito' paper


    JULY 2012

    PRESS RELEASE
    Int J Clin Exp Med 2012;5(3):208-220

    Original Article
    Mitochondrial dysfunction and the pathophysiology of Myalgic
    Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
    Norman E Booth, Sarah Myhill, John McLaren-Howard

    Department of Physics and Mansfield College, University of Oxford, Oxford UK; Sarah Myhill Ltd, Llangunllo, Powys UK; Acumen, Tiverton, Devon UK
    Received April 26, 2012; accepted May 21, 2012; Epub June 15, 2012; Published June 30, 2012

    Abstract: The objectives of this study are to test the hypothesis that the fatigue and accompanying symptoms of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis are in part due to defects in energy provision at the cellular level, and to understand the pathophysiology of the defects so that effective medical intervention can be implemented. We performed an audit of 139 patients (ages 18-65) diagnosed with CFS/ME and attending a private practice. The patients and 53 normal, healthy controls had the ATP Profile test carried out on neutrophils from a 3-ml venous blood sample. This test yields 6 numerical factors that describe the availability of ATP and the efficiency of oxidative phosphorylation in mitochondria. Other biomedical measurements, including the concentration of cell-free DNA in plasma, were made. The results of the audit are compared with the controls and a previous cohort of 61 patients. We find that all patients tested have measureable mitochondrial dysfunction which correlates with the severity of the illness. The patients divide into two main groups differentiated by how cellular metabolism attempts to compensate for the dysfunction. Comparisons with exercise studies suggest that the dysfunction in neutrophils also occurs in other cells. This is confirmed by the cell-free DNA measurements which indicate levels of tissue damage up to 3.5 times the normal reference range. The major immediate causes of the dysfunction are lack of essential substrates and partial blocking of the translocator protein sites in mitochondria. The ATP Profile is
    a valuable diagnostic tool for the clinical management of CFS/ME. (IJCEM1204005)

    Keywords: Chronic fatigue syndrome, myalgic encephalomyelitis, mitochondria, adenosine triphosphate (ATP), oxidative phosphorylation, cellular energetic, glycolysis, cell-free DNA, exercise

    Address all correspondence to: Dr. Norman E Booth, PhD FInstP, Emeritus Professorial Fellow in Physics, Mansfield College, University of Oxford, UK. E-mail: n.booth1@physics.ox.ac.uk

    Full text available at http://www.ijcem.com/files/IJCEM1204005.pdf

    Dr Norman Booth, Dr Sarah Myhill and Dr John McLaren Howard are pleased to announce the publication of a second paper concerning the link between mitochondrial dysfunction and ME/CFS.

    Comment
    In 2009 we published our first paper looking at mitochondrial function in ME/CFS patients. What we found is that those patients with the worst mitochondrial function had the worst levels of fatigue and vice versa. There was a very clear relationship between the two. The importance of this paper was that it gave backing to certain treatment interventions and also that it clearly established ME/CFS as a physical condition with physical causes. The mitochondrial function can be used as an objective assessment of fatigue and of course this has obvious practical implications. Hitherto any assessment of the level of disability had to be subjective and this created great difficulties for patients in cases where their physicians disbelieved the serious nature of their symptoms. For a detailed explanation of the clinical issues please see
    http://www.drmyhill.co.uk/wiki/CFS_-_The_Central_Cause:_Mitochondrial_Failure

    This second paper further explores the above ideas. In this second paper the size of the patient group is much larger with 138 ME/CFS patients involved. Their mitochondrial function tests were compared with 53 normal healthy controls. The findings of the first paper were repeated and confirmed, but the analysis of this second paper was carried out slightly differently. It was found on careful inspection of the biochemistry that there were various sub-groups of ME/CFS patients with their own characteristic biochemical pattern. In particular, one of the five parameters measured, namely translocator protein function IN, can be higher as well as lower for patients as compared with controls. This second paper also attempts to explain what is happening at the biochemical level to result in such an abnormality. To this end, Dr. Booth provides an alternative method of assessing mitochondrial function. He noticed that the percentage inhibition of ATP closely correlates with TL-in factor – this is probably because the biochemistry of these two measured quantities is so closely associated. So instead of using TL-in to calculate the mitochondrial energy score, he used percentage ATP inhibited – this provided a solution to the problem of translocator protein IN being higher in some patients than in controls, a factor which in itself is abnormal.

    Dr. Booth then went on to plot the relationship between mitochondrial energy score and the number of factors within the normal region to achieve an extremely close correlation. Importantly this test identifies a clean separation between the ME/CFS cases and the healthy controls.

    So this first part of the paper very much confirms the work of the first paper published in 2009 which is that those patients with the worst ME/CFS had the worst mitochondrial function and vice versa.

    It must be remembered that patients attending a clinic for ME/CFS are usually the most severely fatigued – no mildly ill patients were tested. Within these limitations the ATP profile is an exclusive and sensitive test for ME/CFS. However, we cannot claim that it is specific to ME/CFS because there are many other neurological illnesses and metabolic syndrome also associated with mitochondrial dysfunction.

    Dr Booth went on to analyse sub-groups within the main group. When mitochondria are stressed, i.e. energy demand exceeds energy delivery, in the short term they can switch into an alternative means of making ATP, of which there are 2 possibilities identified. Dr. Booth called these patients cohort 1 and cohort 2. In cohort 1, the mitochondria switch into anaerobic metabolism with increased glycolosis in order to produce ATP.

    In cohort 2 there was an alternative process to supply additional ATP. This alternative process involves the adenylate kinase reaction in which two molecules of ADP combine to make one of ATP and one of AMP. The problem with this reaction is that for every molecule of ATP generated, so is one of AMP. This is not recycled, but mainly lost in the urine. So there may be short term metabolic benefits here, but in the longer term metabolic disaster ensues as the energy molecules literally leak away. It takes time to replace these leaked molecules of ADP (leaked in the form of a ‘lost’ AMP molecule) and so this may explain one of the clinical features of ME/CFS, namely delayed fatigue.

    A vital feature of ATP studies is that they identify the mechanisms by which mitochondria ‘go slow’. Essentially they can ‘go slow’ for one of three common reasons, either there is substrate deficiency, i.e. lack of essential co-factors for mitochondria to work such as Co-enzyme Q10, magnesium, vitamin B3, or acetyl-L-carnitine, or secondly, because mitochondria are blocked by toxins. Typically the blockage can be of oxidative phosphorylation and/or translocator protein function. Dr John McLaren Howard has developed several further tests to look at the nature of these blockages. These tests include microrespirometry studies, translocator protein function studies, intracellular calcium studies and so on. The third possible mechanism for mitochondria malfunctioning has to do with membrane function. The membranes of mitochondria need to be of just the right consistency in order to hold the bundle of enzymes in the correct 3D configuration to allow efficient movement of substrate from one enzyme complex to another. To this end, again Dr John McLaren Howard has developed cardiolipin studies which look in more detail at mitochondrial membrane structure and function.

    Many of the above tests have been available in research laboratories, some John has developed through his own brilliance and initiative. What is so wonderful is how he has given these cutting edge research tests a clinical application. This is extremely helpful for patients and clinicians because we can see exactly why mitochondria are ‘going slow’ and thereby correct deficiencies using both nutritional supplements, correct gut function, as well as being able to tailor detoxification regimes to individual patients.

    This second paper also goes on to look at cell free DNA in ME/CFS patients. Cell free DNA is a measure of DNA in the bloodstream that is not bound up within cell membranes. It can only, therefore, come from damaged cells and therefore is a measure of cell damage within the body. What we found is a strong negative correlation with mitochondrial energy scores, ATP levels and the rate of oxidative phosphorylation. What this means is that those patients with mitochondria that perform extremely poorly have the highest level of cell damage and vice versa. This makes perfect biochemical sense – if mitochondria ‘go slow’ one can expect there to be the production of free radicals which have the potential to damage tissues. Therefore addressing these issues of poor antioxidant status is an essential part of the package of treatment for ME/CFS patients. These abnormal results clearly show that the effect on mitochondria is a systemic effect, not just confined to the neutrophils that are being tested. Very often we see levels of cell free DNA of a similar magnitude to those in patients who are experiencing a serious illness such as cancer, stroke, autoimmunity, or severe viral infection. Again this underpins the fact that ME/CFS is a physical condition with clear indications of marked cell damage. This puts ME/CFS firmly in the realm of major organic pathology.

    Implications for the treatment of ME/CFS
    These bio-medical tests have been extremely helpful in the diagnosis and management of ME/CFS patients. This is because they clearly identify the biochemical lesions that underpin the cause of this illness. Furthermore, identification of these lesions has clear implications for management using the standard methods of nutritional and environmental medicine. We are currently preparing a third paper which looks at the efficacy of these interventions in patients by measuring mitochondrial function tests before and after such interventions and correlating these with the clinical picture. For further information as to what these interventions are please see http://www.drmyhill.co.uk/wiki/CFS_-_CFS_Book_published_by_Dr_Sarah_Myhill which is available on line without charge.

    It bears repeating that this paper would not have been remotely possible without the brilliance of Dr John McLaren Howard at Acumen Laboratory who has developed these wonderful tests for looking at mitochondrial function, together with the analytical mind of Dr. Norman Booth who has analysed the data in detail to identify the biochemical metabolic pathways invo
  10. xrunner

    xrunner Senior Member

    Messages:
    527
    Likes:
    185
    Thanks Barbc, that's very interesting. If that is correct then there's quite a flaw in the Acumen test.

    I've always wondered why they test on neutrophils instead of other white cells with a longer life e.g. macrophages, which seem more relevant in a CFS context . Anybody knows?
  11. sianrecovery

    sianrecovery Senior Member

    Messages:
    695
    Likes:
    399
    Manchester UK
    Not that Charles Shephard is exactly a disinterested observer.

    I dont know the science - I do know I admire Sarah Myhill and the fact she has survived years of persecution to keep looking for answers for ME patients. She may not get everything right, but at least she TRIES. How many docs in the UK could say the same?
    peggy-sue, justy and jace like this.
  12. richvank

    richvank Senior Member

    Messages:
    2,717
    Likes:
    735
    Hi, x.

    Neutrophils are most abundant cells in the blood that have mitochondria, and are relatively easy to separate out. I think those are the reasons.

    Best regards,

    Rich
    justy likes this.
  13. Mark

    Mark Acting CEO

    Messages:
    4,459
    Likes:
    1,837
    Sofa, UK
    When you (and Shepherd) point out that the test has not been validated, does that mean that several other scientists have attempted replication of the study without success, or does it mean that nobody else has attempted to validate or replicate it (yet)? There's a big difference.

    And when you say it's been "scientifically discredited", the evidence you cite only shows that another scientist has disputed one aspect of it (which may be a crucial aspect, I don't know whether it invalidates the whole exercise). It's quite strong to say something has been "scientifically discredited": surely quite a lot of evidence would be required to support that claim, not just one paper disagreeing with one aspect?
    Allyson, justy, Enid and 3 others like this.
  14. Aquila

    Aquila

    Messages:
    43
    Likes:
    15
    UK
    Thanks for that paper Barbc that's really interesting. Surely if that's true a fault in oxygen transport shouldn't be too hard to find. My TIBC is very low I wondered if the two are correlated I have a look.

    I had a look at the ME assoication FB page and his comments suggest he is looking to get some one to retest the results.



    Bit weird copying an pasting his comments on fb but as he was quoted it seems fair to give the rest of what he said.
  15. biophile

    biophile Places I'd rather be.

    Messages:
    1,348
    Likes:
    3,973
    I see that barbc56 has beat me too it by quoting Vermeulen et al's commentary, but I will still post my version anyway to provide background for additional points I wanted to make, I probably would have had to quote barbc56 anyway. Regarding Shepherd's (MEA) comments, the Facebook link given does not seem to work, and I'm not into Facebook anyway. I could only find the comments quoted elsewhere on a blog:

    I vaguely remembered that the Myhill et al 2009 paper had been challenged for relying on unvalidated tests that may not reflect mitochondrial function in the areas we should be concerned about. Now I remember where, Vermeulen et al. I noticed that the recent Morris & Maes 2012 review on "a neuro-immune model of ME/CFS" stated this:

    The Vermeulen et al 2010 study (http://www.translational-medicine.com/content/8/1/93) did their ATP synthesis assay on PBMCs and concluded that oxidative phosphorylation was normal, that ATP production was probably reduced because the anaerobic threshold was reached, and that the transport capacity of oxygen is limited in patients. The authors also criticized the Myhill et al 2009 paper:

    Perhaps this is still consistent with other findings suggesting increased apoptosis in CFS patients? Anyway, Booth later posted a comment on the publishing journal's website. He saw value in the study but defended the validity of their own study, and also pointed out their own patients were more severely affected and couldn't have done the exercise test featured in the Vermeulen et al study. I didn't analyse everything he said but he does state that "Neutrophils contain fewer mitochondria than PBMCs but there are sufficient for study purposes." At the end he conceded that "In retrospect, we can see that this work using neutrophils should have been paralleled by similar studies using PBMCs and we have already begun that task." (http://www.translational-medicine.com/content/8/1/93/comments)

    That was over a year ago. However, there is no mention of testing PBMCs in the recent Myhil et al 2012 study:

    So when will they be publishing the results for parallel testing on both neutrophils and PBMCs?
    Simon likes this.
  16. barbc56

    barbc56 Senior Member

    Messages:
    1,244
    Likes:
    625
    I do know that doctors who work with mitochondria disorders don't use this test. Interest would most likely be low because of a priori which means the odds, that this test is measuring what it is suppose to measure are low when taking into consideration what we know about the human body.

    If you read the study and critiqueI cited in my above post, that study shows it's not likely that a mitochrondia disorder is the cause of CFS/ME. It might help to read the whole study that I cited.

    If you know of any studies where the results of the test can be used to predict which samples are the controls and which are patients or in other words a blinded study, I would be interested in reading these.

    I want to add more info here but it's late and will post again tomorrow as there are a lot of issues in general about mitochrondia disorders as well as specific issues surrounding these papers.

    This has nothing to do with whether I like Myhill or not but by the current scientific knowledge.
    Barb C.:>)
    sianrecovery likes this.
  17. sianrecovery

    sianrecovery Senior Member

    Messages:
    695
    Likes:
    399
    Manchester UK
    Yeah, I totally understand that Barb, and have read this with interest and am glad to. My point was that I appreciate her efforts, not that I disliked reasoned critique. I do feel that in the UK many of her critics are not motivated by reason, but by personal antipathy, but I dont for a second think that applies here.
    justy likes this.
  18. justy

    justy Senior Member

    Messages:
    2,313
    Likes:
    1,902
    U.K
    A couple of points from my very unscientific and weary brain.
    1. Myhill et al certainly don't seem to propose that M.E is caused by a mitochondrial disorder, but that cellular energy becomes impaired down the line and it is this which they are testing. Ipresume this is why they use this test rather than the more traditional muscle biopsy that is used to detect mito dosorders as its not a true mitochondiral disorder in the same sense.
    I wish i could explian my thoughts better - to tired right now. Brain is on idle mode.
    Justy.
    Allyson and sianrecovery like this.
  19. sianrecovery

    sianrecovery Senior Member

    Messages:
    695
    Likes:
    399
    Manchester UK
    thats certainly true to how she explained its relevance to me. And I dont define ME as a mito disorder, but lets face it, in a systemic energy dysregulation of this type, the mitos have to in there somewhere
    Allyson, merylg and justy like this.
  20. Allyson

    Allyson Senior Member

    Messages:
    1,684
    Likes:
    666
    Australia, Melbourne
    > >This post was removed to this thread a bit late in the discussion but it includes a succinct summary of the paper so I have left it up.

    re:
    "The ATP Profile is a valuable diagnostic tool for the clinical management of CFS/ME."

    Whether or not this is accurate, let's some of us have the test done so we see the results at least. Here in Australia we PWME are not getting tested for anything, so this is at least one step better than that.
    Lets try it before we knock it out of the water.





    For years, sufferers of chronic fatigue syndrome (CFS), also known as
    > > myalgic encephalomyelitis (ME), have been subjected to the abuse of
    > > modern medicine, which has claimed that it’s a mental disorder, that
    > > it's all in their heads. Now, a clinical study clearly documents that
    > > these people, ... suffer from a dysfunction of mitochondria,
    > > the cells' energy production centers.
    > > Published 30 June 2012 in the /Journal of Clinical and Experimental
    > > Medicine, /the study

    > > <http://sacfs.asn.au/download/IJCEM1204005.pdf>^

    (1) investigated the
    > > use of biomedical tests to diagnose and expand knowledge of CFS/ME.
    > > They tested 139 patients diagnosed with CFS/ME and 53 normal healthy
    > > people. The subjects donated blood samples for an ATP Profile test
    > > carried out on neutrophils from a 3 milliliter blood sample. In a
    > > press release^(2) , the authors state they found:
    > >
    > > * All patients tested have measureable mitochondrial dysfunction
    > > which correlates with the severity of the illness.
    > > * The patients divide into two main groups differentiated by how
    > > cellular metabolism attempts to compensate for the dysfunction.
    > > * Comparisons with exercise studies suggest that the dysfunction in
    > > neutrophils also occurs in other cells. This is confirmed by the
    > > cell-free DNA measurements which indicate levels of tissue damage
    > > up to 3.5 times the normal reference range.
    > > * The major immediate causes of the dysfunction are /lack of
    > > essential substrates/ and /partial blocking of the translocator
    > > protein sites in mitochondria/ .
    > > * The ATP Profile is a valuable diagnostic tool for the clinical
    > > management of CFS/ME.
    Wonko, taniaaust1, Enid and 1 other person like this.

See more popular forum discussions.

Share This Page