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Professor Julia Newton: Research Presentation: Transcript and Video: November 2012

Discussion in 'General ME/CFS News' started by Firestormm, Jan 15, 2013.

  1. lansbergen

    lansbergen Senior Member

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    Cleaning the terminals of a corraded car battery could be a description of what I mean.

    I concentrate on the neuromusculair junction but a7 nAchRs are almost everywhere in the body.

    http://en.wikipedia.org/wiki/End-plate_potential


    .
  2. jimells

    jimells Senior Member

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    Firestormm - thanks for your monumental effort to create the transcript. It must've been exhausting.

    I share some of Research 1st scepticism of Dr Newton's work:
    I don't need rehabilitation - I need treatment for whatever causes the inflammation shown by blood tests and/or whatever causes symptoms such as night sweats, sore throat, lethagy and lack of appetite. Dr. Newton's work smells like more of the "you just need exercise" rubbish.

    I readily admit that what I know about biochemistry wouldn't fill a thimble, but the idea of treating 'excess lactic acid' without understanding the reason behind it seems wrong-headed:

    http://en.wikipedia.org/wiki/Lactic_acid#Brain_metabolism
    I recall reading somewhere (Dr Cheney, perhaps??) that lactic acid can be utilized by the heart muscle in place of adequate ATP. Doesn't it seem plausible that excess lactic acid might be a reaction designed to keep us alive?
    Valentijn and ukxmrv like this.
  3. alex3619

    alex3619 Senior Member

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    Excess lactic acid is important to keep us functioning and alive, provided it is not too much for too long. In some cases it could lead to lactic acidosis, though I have never heard of this for ME or CFS patients, only diabetics. We really do need to understand the cause, and also the mechanism whereby test subject acidity is too low when at rest, and the connection between this and brain blood flow. At the moment we have association, causation is still illusive. Until we have that, we cannot test for it in pure ME patients, or a broad CFS patient.

    This research is just one more step in a long path. The big reason its major news is that its not very often such research comes out of the UK, the home of the BPS approach to CFS.

    Personally I really want to know if the abnormal muscle findings are in muscle infected with enteroviruses particularly coxsackie viruses. Given that lactic acid is due to inadequate oxygen processing (typically) I want to know why this is the case.

    This research has a long way to go before being considered central to ME. At the moment its more about OI. NK research has been around for decades, and we are now only getting to the point where its being seriously investigated as a potential biomarker. This kind of muscle research is likely to be the same.

    I would also not knock having a biochemical intervention that allows us to exercise. If we can exercise under the effects of a drug without consequences, then we can improve our fitness - presuming of course that this means our muscles and cardiovascular system can make adaptations. Just because the treatment prevents relapse may not magically restore the full training effect. It depends on what else is wrong. If it can work, I would rather be a fit person with ME than an unfit person with ME. On the other hand, this needs proof, including a properly designed placebo controlled double blinded RCT. This can be placebo controlled if a drug is involved, as well as double blinded. Such a study would also have to be very specific about biomarkers for the subset involved.

    Again let me emphasize that this is all about subsets. Removing treatable subsets one by one is one way to eliminate CFS. When the last subset is a differentiable and treatable disorder, the term CFS will properly belong in the wastebasket of history. Of course the BPS movement might try to keep it alive anyway ... they need somewhere to throw the too hard cases.
    Morgaine, jimells and Valentijn like this.
  4. beaverfury

    beaverfury beaverfury

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    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139492/#R10
    Benjamin Natelsons earlier work on cerebal blood flow in cfs patients also used the fukuda definition.
    Protocol

    Eleven patients who fulfilled the 1994 case definition [10] for CFS and ten age matched (±5years) healthy volunteers were scanned for this study
    Results

    The patients as a group had significantly lower global CBF than the controls. The reduction in CBF occurred across nearly every region assessed. Nine of the 11 patients showed these reductions compared to the average control data, while two patients showed actual increases relative to the controls.
  5. taniaaust1

    taniaaust1 Senior Member

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    I wouldnt mind at all rehabilitation if I could pop a pill and then exercise without symptoms making me want to stop. Thing is if there was such a pill for us to take, we then wouldnt even need rehab as we'd then just do more ourselves!!! and become fit and healthy again anyway.
    Valentijn, Firestormm and alex3619 like this.
  6. alex3619

    alex3619 Senior Member

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    If we had such a pill, it would put CBT and GET practitioners out of a job.
    biophile and Valentijn like this.
  7. Firestormm

    Firestormm Senior Member

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    I don't suppose they would mind, Alex :)
    jimells likes this.
  8. Firestormm

    Firestormm Senior Member

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    As you've 'tagged' me jimells, I thought I would reply. It did take some considerable time and effort to transcribe and I appreciate your recognition of that. I am not 'sold' on Newton - I don't think we need to be. Similarly I don't think it's helpful to have a preconception that any research coming from Newton or her colleague at Newcastle - will answer all the questions for everybody.

    I don't think this is realistic in regard to any research. I also don't think it helpful to have a preconception as to what we might think our condition is or is not. But that's just me trying (and probably failing) to remain objective.

    Julia Newton is a specialist in Syncopy (feinting and/or black-outs) and Ageing. It is her research that has helped shine a light on the significant proportion of patients with our condition who suffer from Orthostatic Intolerance/Autonomic Dysfunction/Low blood pressure/POTS. A proportion that outshines those with other chronic conditions.

    In slide 8 she showed that nearly 90% of patients in her study with CFS/ME had symptoms of OI when standing up, and this was significantly more than in other diseases used as comparisons in several of her studies such as Fatty Liver Disease 56% and Primary Biliary Cirrhosis 69%.

    She also, in slide 7, indicated how CFS/ME compared to 'Controls, NAFLD, PBC, PSC, OLT, VVS, ITP and Sjorgen’s' all of which are regarded similarly as 'fatigue-associated' conditions. This also demonstrated how highly and similarly CFS/ME patients reported symptoms associated with OI.

    For a long time now I have been hearing from people who had great difficulty getting those symptoms attributed to POTS recognised as a legitimate complaint - let alone being tested or indeed treated for it. This area of her research (and the grant from the MRC) will help these people and it will lead (hopefully) to more people (and doctors) who did not realise that this issue could be causing their difficulties, to receive acknowledgement and treatment.

    Newton is not a neurologist. However, Newton's research has suggested to her that for those people who do lack this 'head of steam' i.e. low blood pressure, when compared to other chronic conditions whose other symptoms also feature fatigue - it could if treated perhaps relieve them of this additional impairment.

    Slide 4 did feature Multiple Sclerosis and this fatigue association as well as a paper in the Journal of Neurology:

    So, poor 'head of steam' = orthostatic intolerance = cognitive problems = possible link to fatigue. I mean it seems to me (a layman) that if my body is not able (for whatever reason - the heart?) to generate sufficient blood pressure to see blood reach all my organs as quickly as I need it to - then my organs (my body) is going to be 'starved' of esp. oxygen.

    This isn't especially new either. She pointed to an original article/paper appearing in the Lancet Rowe et al; Is neurally mediated hypotension an unrecognised cause of chronic fatigue? Lancet. 345(8950):623-4, 1995 It just hasn't been well recognised.

    If I lack oxygen I am going to feel fatigued, to have problems concentrating, to experience recall issues, and even forget stuff and might describe all of this as 'brain fog'. One silly example I might use is this:

    Sat in a sealed room with a real fire. The fire takes the oxygen out of the air I breathe. The longer I am there the sleepier I feel. I am in effect oxygen-starved. If I was to conduct cognitive challenges then the longer I was there the poorer the results would be. Eventually, if the fire kept being replenished, I would die.

    Quite what effect, if any, this lack of oxygen has on the muscles and on the brain itself - long-term - I don't know. But could it account for 'inflammation'? It might be interesting to ask Julia for her thoughts on this. What causes the low blood pressure in the first place? I don't know either but she cites and talks about cardiac function - and several papers are listed below that I should probably read.

    The other study I thought of particular fascination, was what she had completed on muscle and exercise function. The exercise inside an MRI and then taking muscle cells and 'exercising' them in a laboratory 'gym'. I mean that is so cool and the first time I have ever heard this happen.

    Having been around for a while, I know that people - including Dr Charles Shepherd of the ME Association - have endured muscle biopsies. Professor Behan (now Patron of the ME Association) has taken muscle biopsies from patients with ME in the past I understand.

    What hasn't happened previously to my knowledge, is an explicit acknowledgement from 'the establishment' in the way that the MRC has done that this line of research - in the way it has been done and is proposed by Julia - is well worth following and funding.

    If a drug can one day be developed which will relieve me of not only the autonomic dysfunction, but the fatigue, and the constant pain in my muscles exacerbated by exercise - I will be chuffed to bits.

    It might not work out like that. It might not solve all my problems. But it is one of the best and most hopeful presentations I have ever listened to and a research direction that I think holds promise for a lot of people. It will also serve (has served) to gain greater recognition for our condition and link it to and place it above the symptoms experienced by other chronic illnesses. And that can't be bad news either.

    I also look forward to hearing from her colleague, Dr Wan Ng and his immune system work. It may complement Julia's work or it might conflict or it might provide some answers for different people in the 'pot'. Whatever the outcome of it I hope some 'fingerprint' can be found. What the effects long-term of 'fatigue' and of the symptoms we attribute to ME are on the body, I don't think anyone has ever looked into and perhaps someone should; but if a biomarker of some description is forthcoming in relation to the immune system it would further help quantify matters.

    I said earlier I'd list all the papers Julia cited in her presentation. She said at the beginning there were over 200 papers relating to CFS/ME and problems with the vascular or autonomic nervous system. I will come back and add links to the actual papers listed below. Unhelpfully she didn't cite them in full so I'll need to dig a bit I expect and I'm knackered now:

    As I said I'll complete the links to the actual papers later today perhaps though if anyone else wants to lend a hand I'd appreciate it. Thanks :)
    voner and Valentijn like this.
  9. Firestormm

    Firestormm Senior Member

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    Can I add that Simon has blogged here about the Cardiac work from Newton and colleagues 'New study hints at biological roots of mental and physical fatigue in ME/CFS'
    peggy-sue likes this.
  10. Research 1st

    Research 1st

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    If there is excessive lactate in the brain (from mitochondrial dysfunction), won't that theoretically reduce brain blood flow and thus possibly explain the finding of cerebral hypoperfusion that was found in the late 80's early 90s by Dr Costa in London, UK in ME sufferers?

    Dr Newton proposes to find a medication to reduce excess acids.First of all one would have to find the route cause of the mitochondria not working that is leading to this. E.g. immune/genetic/viral/retroviral practically anything messing up the Creb cycle.

    Past CFS papers reveal very brain high lactate using neuroimaging and wondered if this can be tied in with excessive lactic acid in muscles and the heart in Dr Newton's 'CFS/ME' cohort?

    What do you think.
    peggy-sue, Enid and Valentijn like this.
  11. beaverfury

    beaverfury beaverfury

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    Too hard basket.
    Is Lactate in the brain a goody :angel: ,or a baddy:ninja: ?

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC327204/

    The nature of the link between cerebral blood flow (CBF) and energy metabolism is of great interest and importance but remains controversial despite decades of research and debate.

    Although CBF augmentation is still considered to be a hallmark of intensified neural activity, previous assumptions that behaviorally induced increases in local blood flow reflect similar local increases in oxidative metabolism have been contradicted by brain imaging studies with positron-emission tomography (PET) and MRI .

    Fox and his colleagues demonstrated that in normal, awake adult humans, stimulation of the visual or somatosensory cortex results in dramatic increases in CBF but minimal increases in oxygen consumption. Increases in glucose utilization are similar to changes in CBF . Although it is often assumed that the increase in CBF in neural activation is driven by a need for increased delivery of oxygen or glucose, it has been demonstrated in human subjects that the CBF response to physiological activation is not altered by either stepped hypoglycemia or hypoxia.

    These results suggest that increased CBF during physiological brain activation does not occur to prevent a shortage of these metabolic substrates.

    Ido et al. recently reported that CBF in activated rat brain is modified by changes in the plasma lactate/pyruvate ratio: CBF was augmented when lactate/pyruvate ratios were raised and attenuated when the ratios were lowered. Specifically, immediately after lactate bolus injection, the magnitude of the CBF increase associated with sensory stimulation approximately doubled.


    http://www.ncbi.nlm.nih.gov/pubmed/22186669
    Brain lactate metabolism: the discoveries and the controversies

    Abstract
    Potential roles for lactate in the energetics of brain activation have changed radically during the past three decades, shifting from waste product to supplemental fuel and signaling molecule. Current models for lactate transport and metabolism ...... are highly debated, owing, in part, to discordant results obtained in different experimental systems and conditions.....

    Lactate utilization by the adult brain increases during lactate infusions and strenuous exercise that markedly increase blood lactate levels. Lactate can be an 'opportunistic', glucose-sparing substrate when present in high amounts, but most evidence supports glucose as the major fuel for normal, activated brain.

    Monocarboxylate transporters . wiki http://en.wikipedia.org/wiki/Lactic_acid

    In animals, L-lactate is constantly produced from pyruvate via the enzyme lactate dehydrogenase (LDH). It does not increase in concentration until the rate of lactate production exceeds the rate of lactate removal, which is governed by a number of factors, including monocarboxylate transporters, concentration and isoform of LDH, and oxidative capacity of tissues.

    Monocarboxylate Transporters and Lactate Metabolism in Equine Athletes: A Review

    http://www.actavetscand.com/content/43/2/63#B16
    In the muscle, lactate is used for oxidation and energy production,

    This small increase in muscle oxygen consumption will also double the utilisation of lactate in muscle, seen as faster disappearance.

    It can be speculated that an individual with a high lactate transport capacity may produce more ATP from glycogen/glucose before the critical pH inside the cell is reached than an individual with a low lactate transport capacity. This is supported by two lines of evidence: First, some elite athletes have exceptionally high MCT activities, and second, human beings with a deficiency in MCT also suffer from exercise intolerance.


    Since few ME/CFSers play extreme sport, you could expect the oxygen carrying capacity of our muscle tissues to be low, and therefore not efficient at removing lactate.
    I guess this is where the deconditioning argument comes in, but it doesnt take into account that there is some mechanism far more debilitating to effort that stops ME/cfsers from increasing their activity.

    Sorry if this post is a bit lengthy (and lacking direction)
  12. alex3619

    alex3619 Senior Member

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    They wouldn't mind the entire basis of their theories, built over decades, being proven wrong? The end of their research in this direction? The loss of funding and prestige?
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  13. Emootje

    Emootje Senior Member

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    "And our preliminary experiments using something called dichloroacetate have shown that we can reverse that accumulation of acid in patients with CFS/ME by adding dichloroacetate to the cell culture where the muscle cells have been exercising" (dichloroacetate is a pyruvate dehydrogenase complex activator)

    Inflammation (lipopolysaccharide infusion) in rats causes a down regulation of the pyruvate dehydrogenase complex (PDC) which results in depletion of Acetyl-CoA:

    Inflamation PDC.JPG



    Temporal changes in the involvement of pyruvate dehydrogenase complex in muscle lactate accumulation during lipopolysaccharide infusion in rats

    Inflammation mediated PDC down regulation may explain our accumulation of lactate...
  14. Emootje

    Emootje Senior Member

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    Therapeutic options?

    dfgfdh.jpg
  15. lnester7

    lnester7 Seven

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    As a side note, Did you all noticed she recommended Tilt Training???? I am trying it, I put it on blog as OI training but it does help to train the body to react correctly. I first struggled doing 4min. Today I am up to 20min twice a day!! Worth reading about it.
    jimells likes this.
  16. Sasha

    Sasha Fine, thank you

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    That's interesting, because in the study she published, the increase in standing time was barely anything (it might have been statistically significant but in terms of practical benefit, it didn't seem worth it). Your results are much more impressive.

    I seem to have delayed OI and wish I knew how tilt training applied to me. I can keep on my feet but I really pay for it later.
  17. lnester7

    lnester7 Seven

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    The way the doctor explain it to me is that the brain is programed to not negotiate the lack of oxygen so we have about 6 seconds (something like that) and then we get the pre-syncope (as Julia mentioned too), So the Tilt training is to train your brain to give you more room for wiggle before you get presyncope symptoms (the nausea, the I have to sit down or die.....)

    All I have noticed in me, is that now I can stand and be more vertical for longer periods of time. Also not as many episodes as before. I am far from cured of OI .
    Firestormm and Sasha like this.
  18. Firestormm

    Firestormm Senior Member

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    I do not think that CBT or GET will disappear as a result of a specific treatment. I do not believe said treatment will result in 'cure' certainly not for ME. I still think that other help will be needed even for those symptoms attributable to autonomic nervous system dysfunction. And yes, if science leads the way to better and more targeted (drug) interventions I do believe the practitioners who use CBT and GET will be delighted to see patients getting greater relief. They are health professionals after all. And I am writing with a straight-face believe it or not :)
    barbc56 likes this.
  19. Valentijn

    Valentijn Activity Level: 3

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    So why do at least some of them directly discourage GPs from giving ME patients any medication or referrals for managing symptoms? In light of the overwhelming evidence of physiological problems that are not treatable by CBT/GET, the only conclusion I can draw is that they value their own careers far more than our well-being.
    jimells likes this.
  20. peggy-sue

    peggy-sue

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    Research1st, just a tiny nit-picking point :) - you referred to "British" when you meant English (and probably Welsh). The NHS is Scotland is completely seperate from the NHS in England.
    In Scotland, we have completely different, published "Good Practice Statement for gps on ME/CFS".
    But nothing to back it up apart from one trained nurse somewhere in Fife.
    NICE guidelines do not apply in Scotland.
    Valentijn likes this.

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