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

Discussion in 'Latest ME/CFS Research' started by Hip, Oct 21, 2016.

  1. Hip

    Hip Senior Member

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    The ME/CFS Energy Metabolism Studies of Myhill, Booth and McLaren-Howard

    With recent metabolomic studies from Fluge and Mella as well as Robert Naviaux et al finding defects in the energy metabolism of ME/CFS patients, perhaps now we should more closely examine the three very incisive studies of Dr Sarah Myhill, Norman E. Booth and John McLaren-Howard (published in 2009, 2012 and 2013) on the dysfunctional energy metabolism of ME/CFS.

    The research of Myhill, Booth and McLaren-Howard on defective energy production in ME/CFS has not been covered in any great depth on these forums, particularly not on the theory side. Hopefully we can rectify that in this thread.

    Dr Sarah Myhill is a GP with a great deal of research interest and expertise in treating ME/CFS.
    Dr Norman E. Booth is a retired academic physicist with two family members who have been affected by ME/CFS.
    Dr John McLaren-Howard is cofounder of Biolab Medical Unit, and medical director of Acumen Labs, UK.



    Summary Points

    • The experimental results of these studies strongly implicate mitochondrial dysfunction as an intermediate cause of ME/CFS symptoms (by "intermediate," I think the authors mean not the primary cause of ME/CFS, which may for example be viral and/or autoimmune, but an intermediate pathophysiology that is induced by the primary cause).

    • The studies used the "ATP Profiles" test (Acumen Laboratory, UK) to measure the efficiency of five metabolic processes involved in energy production. The "ATP Profiles" test provides five numerical figures that indicate the functional efficiency of each of the five energy metabolism processes.

    Using this "ATP Profiles" test in their studies, the authors found that almost all ME/CFS patients in their cohorts had defective energy production (the studies examined ~200 ME/CFS patients). However, out of the five energy metabolism processes, each patient had their own particular processes that were at fault (ie, running at low efficiency), and their own particular processes that were working fine (running at normal efficiency). So all ME/CFS patients had defective energy production, but there were patient subsets according to which particular energy metabolism processes were dysfunctional.

    • Because the studies discovered that defects in energy metabolism are not found in just one process, but found in up to five different processes, the authors combined the individual efficiency figures for each of the five processes into one single efficiency figure, which they call the Mitochondrial Energy Score (MES). The MES is thus a single numerical value that gives the overall efficiency of a patient's energy production.

    • The authors found there is a high degree of correlation between the Mitochondrial Energy Score and the degree of severity of ME/CFS (severity as measured on the Bell scale).

    • Furthermore, the Mitochondrial Energy Score value was able to successfully distinguish between ME/CFS patients and healthy controls in nearly all cases. So the Mitochondrial Energy Score could be a good potential biomarker for ME/CFS (although the authors do not claim a low MES is unique to ME/CFS, because there are other neurological illnesses and metabolic syndromes which are also associated with mitochondrial dysfunction).

    • The authors do not mention this in their studies, but other research I came across indicates that defects in two energy metabolism processes found at fault in ME/CFS (namely the two translocator protein energy metabolism processes) may be caused by an autoantibody that targets and disables translocator protein. This translocator protein autoantibody appears to be triggered by coxsackievirus B, as the autoantibody has been found in CVB myocarditis. As far as I can see, this virally-associated autoantibody may well in part explain how viral infection causes ME/CFS.

    • Most impressively, the authors pinpoint what may be the physiological mechanism behind post-exertional malaise (PEM). Briefly, they suggest PEM occurs when adenosine triphosphate (ATP) molecules, whose role it is to convey energy, inadvertently get broken down and ultimately flushed out of the body in the urine, via a particular set of metabolic circumstances; this results in a temporary shortage of ATP molecules, and thus a temporary inability to transport energy in the cell — a situation which they posit causes PEM. Full explanation coming up next.



    The Myhill, Booth and McLaren-Howard Theory of PEM

    Rather than jumping straight into the 5 energy metabolism processes that were found at fault in ME/CFS, we are going to start with Myhill, Booth and McLaren-Howard's biochemical explanation of how PEM arises, as this is quite easy to understand, and makes a nice introduction to the studies.

    So we begin with the studies' findings that ME/CFS involves a poor, low efficiency energy metabolism. There are knock-on effects arising from this poor energy metabolism — knock-on effects that occur in periods of exertion when the energy demands of the body are high, and the blocked energy metabolism is thus overtaxed and put under stress. On her website, Dr Sarah Myhill explains:
    In other words, Dr Myhill is saying that because of the poor energy metabolism and mitochondrial inefficiencies found in ME/CFS patients, during physical exercise, there is an acute shortage of energy and the mitochondria cannot recycle ADP back to ATP fast enough, so there is a build up of ADP molecules.

    In a desperate attempt to harvest more energy, some of the ADP molecules, which are normally recycled back to ATP, instead get converted to AMP (this conversion to AMP occurs by what is known as the adenylate kinase reaction, in which two molecules of ADP combine to make one of ATP and one of AMP).

    However, because AMP is not easily recycled, this AMP is flushed right out of the body, thereby causing a permanent loss of the ADP molecules that the AMP was derived from.

    (The exact way AMP is flushed from the body is this: AMP is first changed into inosine monophosphate plus ammonia, the inosine monophosphate is then degraded to inosine, and then to hypoxanthine, then to xanthine, and finally eliminated in the urine as uric acid. Ref: Myhill 2012).

    So you get a temporary acute shortage of ATP and ADP molecules, which is major problem, because ATP/ADP recycling is the main basis of the body's energy distributing system, responsible for carrying more than 90% of our cellular energy. So now your body is short of energy, simply because you do not have the means to transport it: the ATP and ADP molecules. The theory states that this temporary shortage of ATP and ADP molecules, which are needed to transport the energy from the mitochondria into the cell, causes PEM.

    As a consequence of this temporary shortage, more of these ATP/ADP molecules have to be manufactured by the body from scratch, to replace the lost molecules. And efficient energy distribution can only be resumed once these lost molecules are manufactured.

    But it takes 1 to 4 days for the body to rebuild its stock of ATP/ADP molecules, as it takes a lot longer to manufacture the ATP molecule from scratch (this called de novo synthesis), rather than the more usual and easier process of creating ATP by recycling ADP.

    Myhill, Booth and McLaren-Howard think this 1 to 4 days of novo synthesis of ATP may explain the PEM period: you get PEM for several days after physical exertion due to the acute shortage of ATP/ADP molecules; and you remain in PEM until your body finishes rebuilding its stock of ATP and ADP molecules.


    Note: to be clear, when Myhill, Booth and McLaren-Howard are referring to a shortage of ATP/ADP molecules during the PEM period, this not so much a shortage of energy in the mitochondria (although mitochondrial energy supply may be poor as well), but rather an acute temporary shortage of ATP/ADP molecules with which convey the energy generated in the mitochondria to where it is needed in the cell. In other words, PEM is an acute problem of transport of energy, where you temporarily do not have enough ATP/ADP energy transportation molecules.

    If you want an analogy: imagine that the mitochondria are like oil refineries making energy in the form of gasoline; and imagine that the ATP molecules are like gasoline trucks filled with gasoline and transporting this fuel to where it is needed, and that the ADP molecules are like empty gasoline trucks that have delivered their fuel, and are returning back to the refinery to be refilled again.

    Myhill, Booth and McLaren-Howard are saying PEM arises when the body inadvertently temporarily loses many of its gasoline trucks, so it does not have enough trucks to distribute the fuel energy to where it is need. You only get over the PEM period when your body manufactures some brand new gasoline trucks to replace the lost ones (manufactures more ATP/ADP molecules), so that you can start efficiency delivering the fuel energy again.

    So this is a compelling theory of how PEM may arise.


    I was thinking that Myhill, Booth and McLaren-Howard's ATP/ADP molecule restocking theory of PEM suggests that D-ribose supplementation specifically during the PEM period might help mitigate PEM, since they point out that the ATP molecule is easily synthesized from D-ribose (by de novo synthesis). So taking D-ribose specifically during PEM may help you to more quickly rebuild your stock of ATP molecules.

    Dr Sarah Myhill then goes on to explain how in ME/CFS, high levels of lactic acid arise during physical exertion, as a direct result of this ATP molecule shortage:
    So Myhill, Booth and McLaren-Howard are saying that as a consequence of this shortage of ATP/ADP molecules (the gasoline trucks), the body desperately tries to manufacture new ATP molecules (manufacture more gasoline trucks) by any route it can. And one route of manufacturing ATP is via the conversion of glucose to lactic acid (anaerobic glycolysis), which takes place in the cell cytosol rather than the mitochondria. But by making ATP in this way, you get a build up of lactic acid.

    So this would explain why ME/CFS patients generate far higher levels of lactic acid during physical exertion: it is just a result of the desperate attempt to make more ATP, which the body needs in order to convey the energy generated by the mitochondria.

    This lactic acid build-up then further compounds the energy shortage problem of PEM, because to clear lactic acid by converting it back to glucose, it requires considerably more energy than was originally gained from the conversion of glucose to lactic acid (glucose to lactic acid yields two molecules of ATP for the body to use, but the reverse process uses up six molecules of ATP).

    Obtaining energy by the conversion of glucose to lactic acid is a bit of an act of desperation by the body: it's like being desperate for money and going to a loan shark, only to find that you have to pay back a lot more than you were originally lent.

    So Myhill, Booth and McLaren-Howard are theorizing that the production of lactic acid further contributes to the energy shortage issue that we know as PEM.


    Incidentally, the idea that lactic acid build up further exacerbates PEM in this way nicely ties up with the fact that nearly all the "PEM Buster" supplements (which members of this forum have found significantly mitigate PEM) appear to reduce lactic acid. This seems to support the idea that lactic acid build up is part of the problem in PEM.

    In summary: Myhill, Booth and McLaren-Howard are theorizing that PEM may be due to an acute shortage of ATP/ADP molecules (due to these molecules being broken down and ultimately dumped out of the body in the urine), which is then further compounded by the body desperately lending energy from the lactic acid loan shark.

    So a combination of D-ribose (to help restock the body with ATP molecules) plus some of these PEM Buster supplements (to neutralize lactic acid) might work for combating PEM.



    The Dysfunctional Energy Metabolism at the Root of ME/CFS

    Let's now delve into the five energy metabolism processes whose efficiencies are measured by the "ATP Profiles" test, and which were found to be poorly functioning in ME/CFS.

    These five energy metabolism processes are as follows:

    (1) ATP Concentration = the quantity of ATP present in the cell

    This one is very straightforward: ATP is created in the mitochondria (recycled from ADP), and created in the cell cytosol via glycolysis. This ATP then supplies energy to the cell. Mitochondria supply around 90% of the cell's ATP energy needs; whereas glycolysis only supplies around 10%. The ATP Concentration measured in the "ATP Profiles" test is simply the total amount of ATP molecules present in the cell.

    In terms of the amount of ATP molecules present in the cells of ME/CFS patients, the Myhill 2009 study found ME/CFS patients only have around 60% of the ATP of healthy controls. Thus there is a major ATP energy shortage in the cells of ME/CFS patients.

    (You can derive this 60% figure from Figure 2A of the study, where you see that on average, healthy controls have ATP concentrations of around 2 fmol per cell, whereas on average ME/CFS patients have around 1.2 fmol per cell, with some patients having as little as 0.9 fmol per cell.)


    (2) ATP Ratio = the fraction of ATP in the cell that is complexed with magnesium

    The majority of ATP molecules present in cells are bonded onto magnesium ions, to create a complex known as Mg-ATP. This bonding to magnesium is necessary in order for ATP to yield its energy; ATP molecules that are not bound to magnesium are not able to liberate the energy they carry. Thus an important factor in energy metabolism efficiency is the percentage of ATP in the cell that is bonded to magnesium, as only this percentage can supply energy. This percentage is given by the ATP Ratio. The ATP Ratio is also an indication of the amount of magnesium in the cell.

    One study found ME/CFS patients have low levels of intracellular magnesium, which may cause a shortage of magnesium for ATP to bond to, and thereby reduce the amount of ATP in the cell available to supply energy.

    I wonder if this may in part explain why magnesium injections or high dose transdermal magnesium cream has been found helpful in ME/CFS. Presumably, though, such magnesium treatment might only be useful for ME/CFS patients who have a poor ATP Ratio, as measured by the "ATP Profiles" test.

    Note that if you are going to try magnesium injections or high dose transdermal magnesium cream, it might be an idea to also take cofactors that promote the absorption of magnesium into cells, such as: vitamin B6 and vitamin B1 (see this post and the subsequent posts).


    (3) Oxidative Phosphorylation = efficiency of oxidative phosphorylation

    Oxidative phosphorylation is the mitochondrial process by which ADP is recycled back to ATP. This recycling is achieved by adding phosphate to the adenosine diphosphate (ADP) molecule, which has two phosphates, to convert it to adenosine triphosphate (ATP), which has three phosphates.

    Myhill, Booth and McLaren-Howard found that around half the ME/CFS patients in their studies had oxidative phosphorylation running normally (these they labelled Group A patients); but the other half of patients had their oxidative phosphorylation partially blocked and running at low efficiency (these they labelled Group B patients).

    In ME/CFS patients whose oxidative phosphorylation is running normally (Group A), they found cellular metabolism uses increased glycolysis to partially compensate for the overall energy metabolism dysfunction.

    Whereas for patients whose oxidative phosphorylation was partially blocked (Group B), these patients use an alternative route to increased glycolysis, most likely the adenylate kinase reaction in which two molecules of ADP combine to make one of ATP and one of AMP. This adenylate kinase reaction is the same process which it is theorized leads to PEM, via the break down and loss of the energy-carrying ATP/ADP molecules. Ref: Myhill 2013.

    D-ribose may be an especially important nutrient for Group B patients. Ref: Myhill 2013.

    In Myhill 2012 the authors state:
    Note that co-enzyme Q10 is a vital factor in oxidative phosphorylation, and deficiency in Q10 may cause oxidative phosphorylation to go slow.


    (4) Translocator Protein Out = efficiency of ADP transport out from the cell

    One job of translocator protein, which is located on the mitochondrial membrane, is to transport ADP in the cell across the mitochondrial membrane, and into the mitochondrion, for recycling back to ATP.


    (5) Translocator Protein In = efficiency of ATP transport into the cell

    The other job of translocator protein is to transport the energy-carrying ATP molecules created in the mitochondria (from recycled ADP) across the mitochondrial membrane and into the cell, where their energy is used for cellular functioning. The efficiency of this ATP transport process across the mitochondrial membrane is another important factor in the efficiency mitochondrial energy production.

    Dr Myhill says that translocator protein could be malfunctioning as a result of xenobiotic stress (e.g. organochlorine or organophosphate pesticide exposure), poor antioxidants status (lipid peroxides), and various other factors. See: Translocator protein studies - DoctorMyhill for a list of factors that can disrupt translocator protein.

    Out of the five energy metabolism processes, Translocator Protein In (TL IN) is unusual, as in some ME/CFS patients its efficiency is actually higher than it is for all of the control group. Thus some ME/CFS patients appear to be transporting super-normal amounts of ATP from their mitochondria into the cell cytosol. In Myhill 2012 they say that these super-normal values of TL IN are:
    Note that the Krebs cycle substrates are: citrate, isocitrate, alpha-ketoglutarate, succinyl-CoA, succinate, fumarate, malate, oxaloacetate. Replenishing any one substrate will replenish all of them.

    In Myhill 2012 they state:
    Note that translocator protein is also referred to as the adenine nucleotide translocator (ANT), and the ATP-ADP-translocator.



    Could Enterovirus-Triggered Autoantibodies Be Blocking The Mitochondrial Translocator Protein in ME/CFS?

    I came across a very interesting connection between coxsackievirus B, autoimmunity and translocator protein: this study found autoantibodies which target and disable translocator protein in patients with viral myocarditis and dilated cardiomyopathy, which they then reproduced in a murine model infected with coxsackievirus B3.

    This seems very significant, because the chronic infections in coxsackievirus B myocarditis and dilated cardiomyopathy are very similar to the chronic coxsackievirus B infections found in ME/CFS. The study authors said:
    Note that the adenine nucleotide translocator (ANT) is just another name for translator protein.

    So the authors are proposing a molecular mimicry-type autoimmunity, where antibodies that target the virus VP protein also unfortunately cross-reactive to translocator protein — thus in fighting the virus, the immune system antibodies inadvertently attack and block the crucial translocator protein on mitochondria.

    And indeed, it is known that energy metabolism in myocarditis and dilated cardiomyopathy is running at low efficiency, due to translocator protein dysfunction. The same autoimmune-mediated disruptions to translocator protein could thus also be happening in ME/CFS.

    As long ago as 1985, ME/CFS researcher Prof Peter Behan stated in this paper that he thought something like may be the case in ME/CFS:
    Anti-mitochondrial autoantibodies of various sorts have been found in a number of diseases, including lupus, Sjögren’s, myocarditis, cardiomyopathy, tuberculosis and leprosy. See: Anti-mitochondrial antibody - Wikipedia.

    If ME/CFS does indeed involve an energy metabolism dysfunction caused by mitochondrial autoantibodies, and if those autoantibodies do indeed derive from an autoimmune state triggered by viral infection, that would neatly tie together and explain three known features of ME/CFS pathophysiology:

    (i) the fact that ME/CFS is associated with infection from certain viruses, particularly coxsackievirus B
    (ii) the fact that ME/CFS likely involves autoimmunity
    (iii) the fact that energy metabolism appears to be dysfunctional in ME/CFS

    A coxsackievirus B-triggered translocator protein autoantibody could explain all these features.

    More detailed info on Prof Peter Behan's translocator protein (ANT protein) autoantibody theory of ME/CFS is found in this thread.


    In terms of treatment possibilities, it occurred to me that since translocator protein autoantibodies need to cross the cellular membrane in order to get into the cell and disable the translocator protein, any supplements or drugs that can modify the cellular membrane or its receptors in a way that inhibits the ferrying of antibodies across the cell membrane may have the potential to treat ME/CFS, because this would block the ill effects of these translocator protein autoantibodies.

    Perhaps that could be one reason why supplements like fish oil (especially high EPA fish oil such as VegEPA®) which affect cellular membranes benefit some ME/CFS patients.



    Study Results: Defects in 5 Energy Metabolism Processes in ME/CFS

    For the 71 ME/CFS patients in the Myhill 2009 study, figure 2 below shows how their five energy metabolism processes (labelled A to E) were operating in terms of efficiency, as determined by the "ATP Profiles" test.

    If you glance at the second column, you can see that the blue bars, which represent ME/CFS patients' energy metabolism process efficiencies, are generally lower down (= less efficient) on the vertical axis of energy efficiency, compared to the gray bars in the third column, which represent the energy metabolism process efficiencies of the healthy controls.

    This shows that these 5 energy metabolism processes in ME/CFS patients are generally operating at a reduced output compared to healthy people. Similar low energy metabolism process efficiencies were found in the 138 ME/CFS patients of the Myhill 2012 study.


    The Five Energy Metabolism Process Efficiencies of ME/CFS Patients and Healthy Controls
    Figure 2.png
    Figure 2 from Myhill 2009​

    The Mitochondrial Energy Score (MES)

    As the above figure 2 shows, defects in ME/CFS patients' energy metabolism are found not just in one area, but in up to five different processes of energy metabolism. So in the study, the authors combined the efficiency figures for each of the five energy metabolism processes into one overall efficiency figure, called the Mitochondrial Energy Score (MES). The Mitochondrial Energy Score thus provides a single numerical value that indicates the overall efficiency of energy production.

    In the Myhill 2009 study, in figure 4a shown below, they plot a graph of the Mitochondrial Energy Score against the severity of ME/CFS, as measured by the Bell scale.


    Mitochondrial Energy Score vs ME/CFS Severity
    Figure 4a.png
    Figure 4a from Myhill 2009
    It is immediately apparent from this graph that the Mitochondrial Energy Score clearly separates ME/CFS patients from healthy controls in almost all cases; and furthermore, that the MES strongly correlates with the severity of ME/CFS.



    Some References and Further Reading

    Sarah Myhill, Norman E. Booth and John McLaren-Howard's three studies on mitochondrial failure in ME/CFS:
    Dr Myhill's book (2014):
    A summary of Myhill, Booth and McLaren-Howard's energy metabolism defect research can be found on Dr Sarah Myhill's website:
    Video in which Dr Sarah Myhill explains the mitochondrial dysfunctions in ME/CFS, and (at timecode 20:53) details the "ATP Profiles" test:
    An example of the results of the "ATP profiles" test can be seen in this post, from a forum member who took this test.

    A summary of Myhill, Booth and McLaren-Howard's mitochondrial dysfunction ME/CFS research, testing and treatment can be found on www.me-ireland.com.
     
    Last edited: Aug 24, 2017
  2. justy

    justy Donate Advocate Demonstrate

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    Thanks for this excellent run down on the work of Myhill Et al. I agree this work has been most overlooked by nearly everybody.

    I had the test done when I was a patient of Dr Myhill back in 2010 and my results showed all of the above, with an overall score of 30% which was very consistent with where I was at on the Bell scale - and still am to a large degree, slipping in and out of severe, but at times a little more functional.

    Dr Myhills proposed treatments are supplements and dietary and pacing. Unfortunately many of us were not able to tolerate the many supplements prescribed, for example many of us have reactive hypoglycaemia and candida and for this reason don't tolerate D Ribose. I got a lot of help from selenium originally and B12 injections, but they stopped working after a year or so. Her advice re resting, pacing and management is very helpful and allows the patient to manage their condition better.

    I also did the Translocator protein studies and found they were not that useful. I did have significant blockages, but not with anything they had seen before - it was steroids blocking and McLaren Howard was asked to comment - they said they had never seen this result before and didn't know what it meant.

    In the end I felt that the Mito test and the TLP test were good in the early days when Drs, family and even myself thought I might have a mental health issue - they verified it was a real physical illness. However until the tests have been replicated against other disease states such as MS or Lupus, all I feel they are really telling us is that we are ill, and we know that already.

    We need to dig deeper to get to the heart of why we are ill, what caused this in the first place, to effect any real change. Supplements and diet will help some of the people a little, a few a lot, but for most of us it is not a cure.

    I was interested in the idea of the autoantibodies. I wonder why Myhill et al don't follow this up?
     
  3. trishrhymes

    trishrhymes Senior Member

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    This is excellent stuff, thank you. Will need several goes to take it all in.
     
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  4. CCC

    CCC Senior Member

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    I've read through her stuff a few times (as recently as last week), but thank you so much for pulling it all together.

    It seems like all the work is starting to come together in some sort of idealised scientific paradigm kind of way.
     
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  5. themjay

    themjay

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    Thank you for your excellent work. I had the mitochondrial profile tested and it came out at a very low 5% of normal which does correlate with my severe M.E. My TL Protein tests show signs of an autoimmune response so your proposals are very interesting. Unfortunately like justy I had little success with the treatments suggested by Dr Myhill
     

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  6. Sidereal

    Sidereal Senior Member

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    It's important to keep in mind in case people haven't read the cited study (which Myhill et al are referring to where the psychiatric explanation for Group B's impaired performance was proposed and GET recommended as treatment for this subgroup) that it was done by Julia Newton's group. Here we have a good example of the kind of catastrophe that typically occurs when you have a poor grasp of biochemistry and you design a project where you measure only two metabolites, as they did in that study, and then overinterpret the results. When those two metabolites come back normal in some patients, it's concluded that the problem is psychiatric and that graded exercise is the appropriate treatment, something which would likely just maim the patient further. Which is why involvement of supposed biomedical ME researchers like her and others in MEGA is so very worrisome. If they measure just a few things, as the Q&A is already preparing us for, because all the money is wasted on recruiting unrealistic numbers of patients from fatigue clinics and getting them to fill out anxiety and depression questionnaires, then we could have a very damaging situation where absence of evidence of physical findings will set us back another 20 or 30 years.
     
  7. barbc56

    barbc56 Senior Member

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    Since Myhill doesn't even get many basic medical concepts correct , I would look at her studies very very closely.

    Maybe they are good oid studies as I haven't looked at hers very closely yet.

    She is not highly regarded by most medical professionals and imho, for good reasons.l, and I would be wary in her participation in advocacy for us.

    I know patients swear by her but that's a much different scenario than actually having her included in studies.
     
  8. justy

    justy Donate Advocate Demonstrate

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    what specifically are you referring to? Something to back up these accusations would be good. Have you canvased 'most medical professionals' to ask them what they think of Myhill and her work, and have they all been given the chance to assess her work on its own merits.

    As you well know the UK medical establishment is not keen on anyone who treats people with ME with anything other than CBT and GET, or who views it as a biomedical illness. She has never been found guilty of anything by the GMC despite many vexatious claim made against her by other GP's.
     
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  9. barbc56

    barbc56 Senior Member

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    I think it's not as simple as that. Many of her ideas go against best medical practices in other countries where cbt and get are not emphasized.

    One thing that comes to mind is that she says babies should be placed on their stimachs when sleeping. This is not only an outdated practice but studies have shown babies put on their backs are less likely to die from SIDS.

    I will certainly make a list of things. You make a good point about backing up my statements.but it may not be today.

    Please understand I am not criticizing those who go to her. That is personal choice.

    But I have reservations about her representative for patients.
     
  10. justy

    justy Donate Advocate Demonstrate

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    Do you have a link to the advice re sleeping positions for babies?
     
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  11. skipskip30

    skipskip30 Senior Member

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    http://www.drmyhill.co.uk/wiki/Cot_death_-_what_every_parent_needs_to_know

    Perhaps she did advocate putting babies on their tummies in the past but she doesn't anymore. Its good to fact check before posting quite serious allegations.
     
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  12. Hip

    Hip Senior Member

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    Thanks. Actually, it has taken me all week to read through and write up the 3 Myhill et al papers!

    But I thought it was important to do, since now other ME/CFS metabolomic studies are emerging, showing energy metabolism dysfunction in ME/CFS. So the hypothesis that ME/CFS is fundamentally due to a failure of energy metabolism is gathering momentum — and evidence.

    It is beginning to look like the lack of energy of ME/CFS patients might actually be due to... a physical lack of energy. It really could be that simple and straightforward.


    I like Myhill et al's approach to focusing in on multiple sub-systems in the energy generating and distributing metabolism. It's very interesting that Myhill and her co-researchers found that ME/CFS patients can have normal functioning in some area of their energy metabolism, but have major defects in other areas.

    So you will only see a full picture when you examine the various sub-systems of the energy generating and distributing machinery.



    That's very interesting. You're referring to the translocator protein studies test shown at timecode 32:12 of Dr Myhill's video (I've copied this below), and the translocator protein test that @themjay posted above?

    And they found that steroid hormones were blocking your translocator proteins, is that what you mean by steroids? Did they say what particular steroids might be involved?

    That's really amazing that they were able to discover this, though, via the translocator protein study test.


    Example of an ME/CFS Patient's Translocator Protein Studies Test (Acumen Labs)
    Translocator Protein Study Example.jpg



    I am not sure if Dr Myhill and her fellow researchers are aware of the autoantibody possibility. I just found this autoimmune connection when, on a hunch, I Googled for "translocator protein autoantibody".
     
    Last edited: Oct 21, 2016
  13. Hip

    Hip Senior Member

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    Your translocator protein studies test looks very interesting, @themjay: the fact your test results say they found stuck on to your translocator protein a "Large protein complex on membranes; Probably an immune complex".

    So it appears as if your mitochondrial translocator protein is being attacked by autoantibodies.


    Although I believe by definition, an "immune complex" is where an antibody binds to a soluble antigen (soluble antigen = a free-floating antigen, as opposed to an antigen that is fixed in position at some location). This then creates a free-floating complex of antibody bounded to antigen. Free floating immune complexes can get deposited in organs, as occurs in rheumatoid arthritis in the joints; though I don't know much about this.

    But maybe what you have is not actually an immune complex, but simply an antibody that binds directly to the translocator protein, as was found to occur in the coxsackievirus B myocarditis study. Did you have any viral tests done, such as coxsackievirus B tests?


    By the way, translocator protein goes by a number of different names, including:

    adenine nucleotide translocator
    adenine nucleotide translocase

    ATP/ADP translocator
    ADP/ATP translocator

    ATP/ADP translocase
    ADP/ATP translocase

    ATP/ADP carrier
    ADP/ATP carrier
     
    Last edited: May 1, 2017
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  14. themjay

    themjay

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    Thank you so much for your looking at my results - I have posted them several times but no one has commented before. Dr. Myhill also did not comment - the test was 4 years ago but I have no reason to believe anything has changed. In his brief notes, the tester did suggest the possibility of an autoimmune response. This was so vague and I had no one to interpret but I have always had the nagging suspicion it may be important.

    I tried to see an Immunologist at St James Leeds, but as soon as he read my CFS diagnosis he was reluctant to carry out any blood tests and referred me to the bad joke that was Seacroft Fatigue Clinic. So no, I have not had any virus tests.

    Dr. Myhill was adamant my gut needed fixing and this is one of my worst symptoms. Earlier she administered EPD injections as she believed I was having allergic reactions. These made me very ill - a reaction she said she had never observed before.

    As I mentioned none of her treatments has made any impact. I did not even get relief from injecting B12 and Magnesium which Justy said helped her on a temporary basis.
     
  15. Hip

    Hip Senior Member

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    Well that is often the norm in ME/CFS. Of the hundreds of treatments I have tried, including those used by ME/CFS doctors, very few have had any effect, and some made me worse.

    I don't think at this stage we should be looking at the Myhill / Booth / McLaren-Howard energy metabolism research in terms of a road to treatment. In specific patients, I imagine the energy metabolism test results might, if the patient is lucky, lead to some useful interventions.

    In Myhill 2013 they say that mitochondrial function is typically impaired in two ways: substrate or co-factor deficiency, and inhibition by chemicals, exogenous or endogenous.

    So for example, if the tests determined that your translocator protein was disrupted as a result of accumulation of organochlorine pesticides in your body, then organochlorine detoxification may help.

    Or if you are a Group A2 patient (= Group A patient who has high TL IN values), they think these patients have Krebs cycle substrate deficiencies, or electron transport chain (ETC) substrate deficiencies (= deficiency of ADP and inorganic phosphate), and can be treated with supplements. Ref: Myhill 2012.

    However, if autoantibodies are causing translocator protein dysfunction, then interventions such diet, supplements and detoxification are probably not going to help much; you'd need to address the autoimmunity, with for example something like rituximab treatment.


    It looks from this research that there may be several different ways in which energy metabolism can become dysfunctional in ME/CFS. And a given ME/CFS patient may have more than one defect in their energy production systems. So this research should be seen as a starting point for further in depth studies on ME/CFS energy metabolism, and on the factors (like autoantibodies) that may throw a spanner in the works of the energy machinery.
     
    Last edited: Oct 21, 2016
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  16. themjay

    themjay

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    thank you again for taking a look - it is a very frustrating situation when we are all acting as our own researchers and guinea pigs....
     
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  17. barbc56

    barbc56 Senior Member

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    @skipskip30

    She has indeed changed her website about placement of babies in the crib. Whether this is one of the issues she was ordered to change by the GMC or something she changed herself, I don't know.

    That's the crux of the problem, it's hard to tell how much she has changed her website because the GMC ordered her to or how muuch are now her personal beliefs.

    However, to be honest, I may have misread the intention of this thread.

    My point which is more in keeping with this thread probably should have read that whether it is Crawley, Myhill or any researchers that have perspectives which aren't science based, we need to be extra viligent about any analysis of their research.

    She still has medical beliefs that I think are outdated or not backed by science. That's my personal view but may not be relevant here. Whether patients choose her as a doctor or not is a personal decision.

    As far as her mitochondrial studies, I'm not knowledgeable enough about this issue to comment.
     
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  18. Barry53

    Barry53 Senior Member

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    UK
    I really do not think it right to bundle Dr Myhill as being the of same ilk as Esther Crawley. Nor that Dr Myhill's work is not science based.
     
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  19. Hip

    Hip Senior Member

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    In fact, if you read the full story about the GMC case, Stuart Jones, the scientist who originally reported Dr Myhill to the General Medical Council (GMC) and who made disparaging remarks about Dr Myhill on the "Bad Science" forum, ultimately was disciplined for misconduct in this affair, whereas Dr Myhill was vindicated, with the GMC case against Dr Myhill being dropped.

    Dr Myhill said of Stuart Jones:
    Certainly from your none-too-well researched but nevertheless disparaging comments about Sarah Myhill on this thread, it seems that aphorism about mud is true. If you are going to criticize someone online, at least get your facts right. It is irresponsible not to.
     
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  20. ash0787

    ash0787 Senior Member

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    This is probably the best theory I have seen so far, it fits in with my feeling that its fundamentally caused by a shortage of energy, however I do have some ways to critique it :D

    If the AMP was really being dumped into the urine this would be really easy to test for, and this paper was published a few years ago now, yet hasn't been followed up despite proposing a really convincing argument, as you said it hasn't even been mentioned much by people here. Perhaps the researchers could shed light as to why this is.

    Also with the coxsackievirus B thing, I was going to say antibodies dont usually cross the cell membrane so they couldn't possibly interfere with mitochondria, but then I realized it said "translocator protein" not "protein transcripter"
    and it actually says its located on the membrane surface, so yes I guess your idea is valid, however again this explanation just seems too straightforward that if it were true it would have been picked up by researchers like Dr Davis, however I understand thats more of a 'feeling' I have more than a valid counter argument.
     
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