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A BIOMARKER FOR MYALGIC ENCEPHALOPATHY/cfs

Discussion in 'General ME/CFS News' started by Gerwyn, Apr 24, 2010.

  1. Gerwyn

    Gerwyn Guest

    If the CAA want to look for a simple biomarker here it is.Why aren't they working on this?

    January 18, 2009

    [Note: The report abstracted here presents evidence that chronic fatigue has a physical basis - a dysfunction of the cells energy (ATP)-generating mitochondria - and that an ATP profile blood test is useful to measure degree of mitochondrial dysfunction and severity of illness. To read the full text of this free-access article, click here. And to read Dr. Myhills patient handout on CFS as a symptom of mitochondrial failure, click here.]

    This study aims to improve the health of patients suffering from chronic fatigue syndrome (CFS) by interventions based on the biochemistry of the illness, specifically the function of mitochondria in producing ATP (adenosine triphosphate), the energy currency for all body functions, and recycling ADP (adenosine diphosphate) to replenish the ATP supply as needed.

    Patients attending a private medical practice specializing in CFS were diagnosed using the Centers for Disease Control criteria. In consultation with each patient, an integer on the Bell Ability Scale [a measure of activity/function was assigned, and a blood sample was taken for the ATP profile test, designed for CFS and other fatigue conditions.

    Each test produced 5 numerical factors which describe the availability of ATP in neutrophils, the fraction complexed with magnesium, the efficiency of oxidative phosphorylation, and the transfer efficiencies of ADP into the mitochondria and ATP into the cytosol where the energy is used.

    With the consent of each of 71 patients and 53 normal, healthy controls the 5 factors have been collated and compared with the Bell Ability Scale.

    The individual numerical factors show that patients have different combinations of biochemical lesions.

    When the factors are combined, a remarkable correlation is observed between the degree of mitochondrial dysfunction and the severity of illness (P<0.001). Only 1 of the 71 patients overlaps the normal region.

    The ATP profile test is a powerful diagnostic tool and can differentiate patients who have fatigue and other symptoms as a result of energy wastage by stress and psychological factors from those who have insufficient energy due to cellular respiration dysfunction.

    The individual factors indicate which remedial actions, in the form of dietary supplements, drugs and detoxification, are most likely to be of benefit, and what further tests should be carried out.

    Source: International Journal of Clinical and Experimental Medicine, Jan 15, 2009:1, 1-16.Myhill S, Booth N, McLaren-Howard J. Sarah Myhill Limited, Llangunllo, Knighton, Powys, Wales; Department of Physics and Mansfield College, University of Oxford, Oxford UK; Acumen, Tiverton, Devon, UK [E-mail: Norman E Booth n.booth1@physics.ox.ac.uk]


    NOW THAT WOULD BE A WORTHWHILE USE OF FUNDS.
     
  2. Alexia

    Alexia Senior Member

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    Aren't this biomarkers from the Mitochondria tests that Dr. Myhill and a few other practitioners use in UK? I have had that test and I find I got a lot of information that clearly shows that my body is producing 30% of the energy and some of that energy is blocked by chemical toxins in the mitochondria.
     
  3. Gerwyn

    Gerwyn Guest

    yes Alexia they are mine was less than that
     
  4. jace

    jace Off the fence

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    How does the cost of the mito test compare to the thyroid/blood/liver function standard NHS provided tests? Anyone know?
     
  5. Alexia

    Alexia Senior Member

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    Hi Jace, I can search how much I payed for the mitochondria tests but I don't understand the relation you make to those standart tests on the NHS. The mitochondria tests are very different.
     
  6. usedtobeperkytina

    usedtobeperkytina Senior Member

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    Clay, Alabama
    As I read this, I thought that tests on other fatigue illnesses need to be tested before it can be a biomarker. And that's the rub. There are so many illnesses that cause fatigue.

    There are many other possible biomarkers, Light study results, the Sakudo spectrograph test and the lactate levels. And now we have interferon alpha levels, as reported by WPI. Not to mention, of course, possibility of XMRV tests.

    I think one of the problems with modern medicine is that they look for just one marker. You can diagnose CFs today using a combination of objective tests put together to see if the pattern is there. But this is not the way medicine today thinks. Just as they want to classify illnesses as a type and only one type. CFS is dysfunction of many systems, not just one.

    Tina
     
  7. Gerwyn

    Gerwyn Guest

    Hi tina the test differentiates those with fatigue due to mito dysfunction from those with tiredness from psychogenic conditions.The spectro stuff looks interesting though
     
  8. Tammie

    Tammie Senior Member

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    I agree with most of what you wrote, but mitochondria are in every cell - they are like the battery for each cell.....and as such, if they are not working rt, EVERY system in the body will not work rt - this theory completely fits in with CFS being a "dysfunction of many systems"....it also fits very well with most of the other theories already proposed, inc the possibility that XMRV is causing all this.....definitely fits in with Rich VanK's theory, too
     
  9. usedtobeperkytina

    usedtobeperkytina Senior Member

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    Clay, Alabama
    oh yeah, I accept that this might be good biomarker. My point is they already have enough differences that can be tested if they look at many, put together. We don't need just one, the ones we already know about, put together, tell the story.

    But, that's not the way modern science thinks.

    Gerwyn, I understand this will show difference between those just tired and psychogenic diseases from the CFSers. But have other diseases been tested to see if they show abnormality in similar area? I remember this was concern with Sakudo test. He found difference between CFS and healthy, but he needed to test other diseases to know if it is biomarker for just CFS or if other diseases show similar results. (And then we never heard another word. All we know is patent has been applied for. HUH, maybe he lacks funding too. I sure would love to hear from him. Anyone know Japanese? Wasn't there someone posting here from Japan? Maybe he could call the man.) I think the same study needs to be done for Light study results, make sure other illnesses don't show same thing. Are they doing Light study on fibromyalgia patients now? I thought I heard they were.

    Tina
     
  10. Jenny

    Jenny Senior Member

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    See below for more on the thinking behind the Acumen test.

    Jenny


    Summary of a Talk by Dr John McLaren Howard of Acumen Laboratory, Tiverton
    To South Molton ME Support Group (www.mecfssupportdevon.org.uk)

    Given at South Molton Hospital, South Molton, North Devon, UK

    On 25th June 2008



    South Molton ME Support Group in November 2007 instigated a project part-funding 20 group members to have CFS-profile testing, including ATP testing by Acumen Laboratory, which would give indications which supplements they needed on an individual basis. Because the laboratory is local to us, we have been most fortunate to be offered a preferential rate for this testing, and are most grateful to the laboratory’s director, Dr John McLaren Howard (JMH), for coming to talk with our group and answer any questions that have arisen from this project. The following is a summary of that talk and selected questions. We also have an MP3 recording of the talk. For further information about our group’s project, you can contact the group at info@mecfssupportdevon.org.uk or phone Jacqui Footman 01769 572207. Contact details for Acumen Laboratory are: POBox 129, Tiverton, Devon, EX16 0AJ, Tel 07707 877175. Acumen tests can be requested only by registered medical practitioners.



    Dr John McLaren Howard’s talk
    This summary comes with apologies in advance to JMH for any of my own misunderstandings of the scientific material. JMH did a fantastic job of explaining complex science in simple terms that held our group riveted throughout, but nevertheless, I, without his brilliant biochemical brain could well potentially have reported something somehow incorrectly below. Thank you for your understanding – Jacqui Footman, Information Officer, South Molton ME Support Group.



    JMH started by giving a little background to explain why he has come to the kind of tests he is now doing at Acumen.



    Background


    In the 1960’s and 70’s it was noticed that some people just didn’t recover from an infection in the way that other people did and subsequent to Royal Free disease, people were starting to recognise that this was some kind of syndrome. At that time (1955-70’s), although not now, all cases of what is now called CFS followed an infection. JMH first got involved about 40 years ago, and his involvement as a biochemist was trying to explain why some people got better and some people didn’t - from what seemed to be exactly the same infection process. So he looked at what the residual symptoms were, and there was one that as a biochemist interested him more than all others at that time, myalgia (muscle pain). At that time myalgia was an unusual feature of chronic illness and hence worthy of further investigation.



    Simplified explanation of how muscles work, eg to lift arm: the brain sends a signal and at the end of the nerve the electrical signal is translated into a simple chemical signal - calcium passes into muscle cells. Muscle cells don’t like calcium so try to squeeze it out. As they squeeze muscle cells get smaller and cause contraction that lifts arm. The interesting observation was that people with myalgia following infection didn’t have difficulty lifting the arm but did have difficulty relaxing again afterwards. What has to happen for the muscle to relax after contracting is magnesium passes into the cell and pushes out the calcium. So JMH looked for ways to test whether people had difficulty with magnesium deficiency or magnesium transport. When you measure serum magnesium it is always normal unless someone is very seriously ill, so to detect lesser levels of deficiency it was necessary to develop a new test for intracellular magnesium levels. The test showed that virtually all people with this problem relaxing muscles had low intracellular magnesium, so there was clearly something biochemical that had happened in these people, something very definite, but not the whole answer. Over the next years, this led to a lot of work on how magnesium got into cells, some of which JMH was involved with, including some work with vitamin B1, thiamine. About 15% of people who took vitamin B1 got better within a few weeks, but unfortunately there were still 85%.



    Some years on, work in the USA researching cancer, using cytokines to reduce tumours, although beneficial for the cancer, produced chronic fatigue. This gave a useful clue for those researching CFS at the time. Simple perspective: when you have flu and symptoms come to an end there are a few days when you feel dreadful, then suddenly one day you feel back to normal. The difference between these residual days after the flu and the day when you feel well again is that on the residual days before the cytokines that were turned on to deal with the flu were still turned on, then get switched off. Cytokines are very difficult to measure and levels vary from day to day or even within days, but it has been possible to measure high levels in people with CFS/ME. A classic feature of ME/CFS is that is varies from day to day – if not it is something else, not ME/CFS. Even those who are severely affected will find the odd day when they can do quite a lot more. So this raised the next question. Why would some people leave their immune system switched on after an infection and others turn it off? Was it mental control? - No, doesn’t explain the differences, even when after you account for the effect of mood on the immune system.



    Recent Situation


    JMH, working with Dr Sarah Myhill, had got little further than the above and were at a loss for where to go next. Six volunteers underwent every possible test imaginable – remarkably few abnormalities were found; many small ones but few big. There were 2 frequent findings:



    1 A decrease in an enzyme called Super Oxide Dismutase (SOD). SOD is what protects every cell in your body from damage of all kinds so if it is low those cells will be damaged much more easily, so if you get an infection more cells will be damaged, it will take longer to get over it and as you do so a viscious circle can be started and you get stuck in chronic fatigue syndrome.



    2 These people also had a marked B3 deficiency; B3 in the form nicotinamide was the major clue because it has only one function, to feed mitochondria. Energy comes from mitochondria, the energy factories in the cell. A single white blood cell could have up to 2,000 mitochondria.



    So they wanted to look at mitochondria in action; but mitochondria are very small. So JMH looked to very new developments. He explained how advances in fluorescent microscopy enabled you to see working mitochondria and observe what happens when you take away the nicotinamide or magnesium or SOD. Having developed the tool, he was able to look at mitochondria in a big way and develop the tests he and Sarah Myhill are now doing and using.



    An ATP test measures the amount of ATP (Adenosine TriPhosphate) in white blood cells.

    ATP is based on a sugar, ribose with 3 phosphate groups (triphosphate). Phosphate has enormous energy. If you knock off a phosphate group and go from ATP (triphosphate) to ADP (diphosphate), all that phosphate energy is available to you. This is how mitochondria provide the body with quick energy for any activity – physical movement, thought, anything. So if people have a problem with ATP they will have problems having enough energy. In CFS 80% of people have low overall ATP levels; they will never achieve the same as those with normal ATP. However it is not just that – there was a connection with the earlier work on magnesium: mitochondria need available magnesium to process ATP. So here is a link between the early work in the 1960s and the cutting edge work today, because if magnesium is also low, you will make even less use of the ATP that is available.



    Another (reserve) way we can get energy is from ADP (diphosphate) If desperate we can knock off another phosphate group and get more energy. But then you are left with AMP (monophosphate). Unfortunately AMP cannot be reconverted into ATP and you have to start again from scratch producing ATP through oxidative phosphorylation, which is the way mitochondria make energy but a very slow process. Nature has a wonderful trick – if you have ATP, use it to produce energy and leave ADP, you don’t have to start from scratch, there is a special protein in the wall of the mitochondria that grabs ADP, adds a phosphate group and then makes it available again in the cytoplasm of the cells to produce energy all over again. If you can’t reconvert ADP into ATP, after a while you are stuck – which is exactly what happens in CFS; it is not that you can’t do things, it is that if you do things for a while there isn’t the energy to sustain them, and do them for too long and the energy doesn’t come back for several days – that is because you have taken the process through from diphospate to monophosphate and it takes a long time to produce new ATP from scratch.



    In the test an inhibitor (azide) is used to stop the process in isolated cells, then washed away, then it is observed how quickly the cells recover. If they don’t bounce back, that must reflect chronic fatigue. The test measures how much ADP is reconverted to ATP and how quickly. If you can reconvert 60% within a specific time, you will get away with it and be able to live a reasonably normal life. If 55% you are to some extent disabled; if 25% you are more disabled, if 10% you are in bed all the time. So, we have a marker. We could hypothesise that this test would tie up with the levels of illness severity. It has now been applied to hundreds of ME/CFS patients and it does, with a 95% confidence indicator, which satisfies all scientific and statistical standards. Undoubtedly we are moving in a direction of understanding, understanding why this illness has the effects on energy that it does.



    To investigate further JMH looked at mitochondrial DNA. It is easy to separate mitochondria from cells. Every mitochondria has in the wall thousands of translocator proteins (TL). Each TL is wonderful because it turns round 180 degrees and looks into cell cytoplasm and into mitochondria – when looking into mitochondria it picks up ATP and transports it into the cell, when looking into cell cytoplasm it picks up the ADP, left over from when the cell has used phosphate to produce energy, and transports it back to the mitochondria for recycling. The only reason why you can move at all, even breathe, is because the TL does this. There is a website showing this happening with the latest flourescent microscopy – magic to watch. For most of us this TL process goes on smoothly all the time.



    JMH needed to study how the body builds up ATP inside mitochondria. It starts with ribose, normally made from glucose; from ribose we can start to build on phosphate groups, by the process of oxidative phosphorylation, using the oxygen that we breathe. Our energy therefore comes from the oxygen we breathe and the foods we eat. The ingredients needed were phosphate, which we have loads of from diet and also stores in bone, and also other things of which we have no body stores so these are more significant to consider:



    - Magnesium

    - B3 nicotinamide (B3 deficiencies are very common – if you go back to 1920s and 1930s when people died from these following fatigue, but when it was remedied all were fine. This clutch of diseases were identified treated and forgotten but no-one asked what happens to those who have the milder deficiency; could it be contributing to chronic ill-health?)

    - Electrons needed to pass; there is lots of electrical activity in mitochondria. What takes the electrons into the mitochondria is Co Enzyme Q10, previously known as ubiquinone. It’s most important function is to prevent congestive heart failure, because if the mitochondria in the heart can’t produce enough energy that is what happens. It is provable because people get better – the ultimate test! The heart has the largest number of mitochondria.



    Another test JMH uses is one for DNA adducts. He first attended a conference on DNA adducts in 1992. If DNA is doing its job and something sticks on the side of it, it won’t do its job properly anymore. DNA codes for the proteins of the body; it functions like a zip-fastener. Those who have ever got something stuck in a zip will know what DNA adducts are about – how difficult a situation it is. So imagine how difficult it is for DNA; you have a gene and the reading of that gene is interrupted by something stuck there. That something is likely to be a chemical something, mostly environmental although can be something made in the body. The 1992 conference was all about cancer because there is a very high chance of a mutation in this circumstance and the beginnings of cancer. JMH asked if an onco-gene can be blocked and cause cancer, what about DNA adducts causing any other disease? Could it block any other gene? The answer was yes, but that yes was not taken any further; the conference was focussed only on cancer. At that time, 268 chemicals that could adduct to DNA had already identified. Most of us are generating 500 mutations a minute just as we sit here and we depend on DNA to put those right for us. DNA adducts could be causing any disease, especially chronic disease because we have interfered with the coding of genomic DNA, and every cell except red blood cells have DNA and are hence subject to changes all the time, subject to nature and nurture and we need to nurture them. In 1998 there was another conference on DNA adducts, but still only about cancer. There had been marvellous discoveries in the interim about adducts, what genes they effect and so forth, but nothing of the wider implications. JMH went back to his own drawing board, spent 3 years working out methods for testing for DNA adducts and published in 2002. The method has since been adopted by 5 labs.



    When you have put right the nutrient deficiency, many people get better, some a bit, some not at all. The answer is that the same can happen to TL proteins as happens to DNA, something locks on to them and prevents them working. If this happens to 50% of sites then you have 50% of energy – simple. Some of the things that can adduct to DNA also can adduct to TL protein. The stage that JMH is at now is being able to connect up the nutritional side (needs of mitochondria) with reasons why putting that right doesn’t work, with the environment that we live in and the toxins that we are exposed to. The answer lies in the individual because we are all nutritionally different and exposed to different products we buy or are surrounded by. Also some of us are more susceptible to chemical exposure than others, some of us have very exposed genes, ie genes that are not well protected by our DNA repair system, they get damaged and will not get repaired.



    CFS/ME – although you can define it, it is different in every single person who has it. Unless you are prepared to investigate individually, you will only get so far in helping them and not get even near all the way. You must consider that person, their disease, what started it, how long they have had it, and many variables.



    There is every reason for confidence in the fact that more is known now. There is not a great deal of confidence in how that knowledge is applied in treating people because it depends on groups like those present (at the talk) getting things done, badgering their doctors, consultants and actually doing something.



    These are test results you CAN do something about – we don’t know exactly until you start to do something, but we do know that by doing something you will sort the wood from the trees and start to see which parts of the problem in that individual you are answering and the rest will stand out more clearly than it did before; you will know what to look at next. Patients with CFS often have other underlying disorders as a secondary thing, eg under-active thyroid, which may be a protective mechanism to help prevent people using too much energy when they don’t have it.



    Reminder: do half of what you can cope with today so that you can do the other half tomorrow, do half of what you feel you can realistically do; stay within boundaries - the boundaries will gradually extend on their own; beware programmes that push beyond, do sensible things with life and above all enjoy yourself. That is particularly important as endorphins (hormones produced when we are happy) do so much and benefit the immune system, contributing positively to the cytokine aspect of the disease.



    Selected Questions


    Will supplements take longer to work if you have had ME for a longer time?

    Generally possibly, but you must look at the individual case because if you do just get everything right biochemically, recover can be within a few weeks. However, if you have been unwell for years you will be conditioned to adapting in certain ways, so you need to be open to change.



    Do you need a retest at some stage?

    If you don’t get better, yes, there may be something else to consider that will be revealed by further testing, like peeling the onion. Again, the individual approach is important; you need to consider what has changed and hone in on specific tests, not do the whole lot of tests again.



    Several members have not been able to tolerate Magnesium supplements in any form. What do they do?

    This is an example of individuality. These people will have some reason why they can’t get magnesium into cells, so supplements just increase the serum level, which the body tries to reject and produces symptoms to prevent the level going too high. There will be individual reasons why. It has always been a puzzle but a possible answer recently occurred, and JMH’s hypothesis is that there is too much calcium in cells that is bound to proteins. If calcium has been leaking into cells for a long time, the body has learnt it needs to produce more calcium-binding protein to make the calcium in cells safe, because ionic calcium can damage or kill the cells. Unfortunately however magnesium cannot push calcium bound to protein out of cells, it can only shift ionic calcium, so the magnesium cannot get into the cells. The hypothesis is still being tested, but fits the picture. The calcium overload can however cause early cell death – apoptosis - (which is already known to be a feature of ME/CFS). In the case of early cell death, if that cell has a DNA adduct, the new replacement cell takes on the DNA from the old cell and hence also the damaging DNA adduct. If a cell reaches the end of its normal programmed lifetime, the new cell has new pristine DNA without damage, so it is important to maintain cellular systems. In the past we have tended to think it doesn’t matter if you lose a few thousand extra cells a day, but actually it does if the DNA is damaged.






    Does it make a difference to our treatment if we for some other reason have to take a large amount of drugs?

    That depends on the individual’s detoxification mechanisms and the extent to which it is stressed and the body’s levels of glutathione, which is the enzyme most needed for detoxification of eg painkillers. L-Glutathione complex should help.



    What is the natural way of getting magnesium?

    It is held in the centre of green vegetables. However, one of the most difficult digestive processes is that which digests the chlorophyll at the centre of green vegetables. Watercress is a fantastic source; the Victorians used to eat masses of it.



    GLA a brilliant anti-inflammatory for inflamed muscles – you can use it locally as evening primrose oil massaged into the skin, which is very quickly absorbed.



    Are we any closer to a test for CFS/ME?

    - I believe there is a test for CFS/ME. That is the cell-free DNA test. It would be easy to use, but you have to exclude just a few other things first. Most of the cell-free DNA present in blood plasma is associated with cell degradation. Very low levels are present in healthy people and increases are associated with serious illnesses such as malignancy, stroke, auto-immune diseases, severe infections and CFS. So you can use the cell-free DNA test for CFS if you exclude these other causes of cell-free DNA, which are comparatively easy to exclude.

    The ATP test would not be a test for CFS/ME since there could be other causes such as problems with cell respiration and uncoupling of oxidative phosphorylation.




    South Molton ME Support Group would like to express most grateful thanks to Dr John McLaren Howard for all the time, attention and testing he has freely provided, for his most informative talk and for his helpful answers to people’s questions both in the plenary and privately. Many members of the group involved in the project report improvements in their ME/CFS, but we have not been able as yet to quantify the improvements scientifically in a way that we could report. We hope however to take this further in the future.



    Postscript: Dr Sarah Myhill and Dr John McLaren Howard published a paper on the ATP testing in a peer-reviewed journal in January 2009 http://www.ijcem.com/files/IJCEM812001.pdf



    Disclaimer: South Molton ME Support Group does not accept any responsibility for the consequences of actions taken on account of any information given in this summary or our newsletter or for any advice, information or help given by any member of the group.



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