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Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in ME/CFS - 2020 - Schreiner

Discussion in 'BioMedical ME/CFS Research' started by Kalliope, Apr 24, 2020.

  1. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Yes, I find the whole field very confusing. If we think the problem is a soluble factor in plasma making mitochondria abnormal then studying cells that have been activated in culture would not be expected to show a difference between PWME and controls because the original soluble factor would have long ago been washed out of the culture system. If Newcastle did find changes after activation that suggests that we are not looking at a soluble factor but something built in to the white cell epigenetics.

    Much the same issues arise with Fisher creating lymphoblasts.
     
  2. strategist

    strategist Senior Member (Voting Rights)

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    What does fatigue and weakness caused by problems with the brain's motor centers feel like? Assuming that this causes these symptoms.
     
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  3. cassava7

    cassava7 Senior Member (Voting Rights)

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    Caniocervical and/or atlantoaxial instability cause brainstem compression (brain's motor center) and can result in ME/CFS symptoms. Judging by that example, I would assume the fatigue and weakness to be similar to ME/CFS. Other diseases like Chiari malformation and syringomyelia do cause severe fatigue and weakness too
    @Jonathan Edwards I'm not the one who asked the question behind this reply but I'd like to thank you for explaining these things & other issues with research in layman terms. Really helpful :)
     
    Last edited: Apr 27, 2020
  4. cassava7

    cassava7 Senior Member (Voting Rights)

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    Besides this study and other ones on mitochondrial dysfunction in ME/CFS, there also was an update from NIH on their intramural study in January. While it's still in PBMCs, it hopefully is good quality data -- that would strengthen the possibility of mitochondrial dysfunction in ME.
    Source
     
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  5. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    That would apply in MS. Weakness due to brain motor centre problems tends to be a spastic weakness with stiffness. Paradoxically, the brain motor neurones work mostly by inhibiting the lower motor neurone in the spinal nerves. They work more like a cruise control on a car than an accelerator pedal. It is said that people with MS feel as if a limb whose brain motor feed is damaged feels as if set in cement.

    Stroke also affects brain motor centres but tends to affect the corresponding sensory centres as well, which leads to a loss of awareness of what is happening in that area - an agnosia. The limb may simply not seem to be there - not even not there, just not thought of at all.
     
  6. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Even with the current sample size, the data is still statistically significant. We saw changes in mitochondrial function from before exercise to after exercise in ME/CFS patients, compared to their matched controls. That tells us that there may be something going on at the cellular level.

    I find this sort of finding very hard to interpret. To prepare peripheral blood mononuclear cells for testing one normally needs to separate them using something like a Ficoll-Hypaque gradient, which involves repeated washings. If exercise leads to the production of a soluble factor that interferes with mitochondrial function it should be washed out in this process.
     
  7. lunarainbows

    lunarainbows Senior Member (Voting Rights)

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    I don’t really think the motor weakness like the spastic weakness and agnosia which Jonathan Edwards describes, applies to me at all. I don’t think those are usually part of ME? Or are they?

    From what is described, I don’t think the motor control part of the brain is what causing ME symptoms and weakness. I am very aware of all my body parts and it doesn’t feel like concrete and it’s not the stiffness that’s stopping it moving - there is an overwhelming all body weakness and exhaustion that is very hard to put into words.

    Edit; it’s like my body parts are losing power, I just cannot repeatedly move them. (there is stiffness in my legs but that’s due to not moving as much I think, rather than being causal).
     
    Last edited by a moderator: Apr 28, 2020
  8. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    They have never been reported as features of ME as far as I know. And they come with typical signs on examination that are not found in ME.
     
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  9. strategist

    strategist Senior Member (Voting Rights)

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    I did have stiffness and brisk knee reflexes (according to a neurologist) for some time during and after the POTS onset. I looked up what brisk reflexes meant and it can mean demyelination. In practice it meant I could not move my legs and feet in the same way as I would before while walking. Even with best effort, I just could not replicate the same smooth movement. But that is not part of my flavor of ME/CFS. It's a separate problem.
     
  10. strategist

    strategist Senior Member (Voting Rights)

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    So my flavour of ME/CFS doesn't seem to involve motor centers.

    I asked because sometimes it feels like I can't exert force with a limb and that the problem obviously can't be the muscle per se because it worked fine not long ago. It's similar to how one can lack strength in the morning after waking up. Assuming that is actually a normal thing and not sign of an illness.

    I thought it might be a problem with blood circulation although how exactly that would work is unclear. Is there such a thing as locally low blood pressure? Or blood being concentrated in the areas with vital organs at the expense of things like limbs getting little?
     
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  11. spinoza577

    spinoza577 Senior Member (Voting Rights)

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    I completely agree that there is no good reasoning:
    Why do people feel weak? ... EASY ANSWERE: ... Because there is no energy.
    How can we measure any ATP? ... EASY PROCEDURE: ... We take blood cells.
    How does this go together? ... IMPLICIT SUGGESTION: ... It´s simply all the same.

    Popular ideas tend to be thought through badly, and there is no difference if it´s in front of a researcher´s eye or of any other person´s eye. Researcher don´t ask the right questions here, I think.

    This may give some clue, I would say.

    If we feel weak from a cold, we should know that there would be enough energy to run away. It would be though at the cost of best healing for now. It is obviously codified by the brain. And then there are other illnesses which - surprise, surprise - affect in any sense such feelings (without that there is anything wrong with ATP).

    That the "something in the blood" idea is directly related to the feeling of weakness is not thought through well, and Davis must be critisized for this suggestion, even if there is something in the blood (which might be the case).

    A further question then is if this something is a downstream effect from such a structure making the feeling of weakness, or if this something makes the structure to induce the feeling. Again, that this something indicates that the something also takes place in muscles (because some patients feel weak in their muscles) is unlikely in view of the illness, at least as described in the CCC or ICC. And how could it come about that there are so many possible symptoms, but e.g. many organs function completely well?


    I think the paper Scheibenbogen, Prusty and Naviaux is interesting, but any suggestion that a virus here and there accounts for symptoms here and there is unlikely to be true - which they indeed also don´t say.o_O
     
    Last edited: Apr 27, 2020
  12. strategist

    strategist Senior Member (Voting Rights)

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    My every day fatigue and weakness is hard to describe but I'm tempted to say it feels like some sort of impairing, sedating poison. I sometimes described it like that even before the whole "something in the blood" idea became popular. It's not a pure fatigue signal, but mixed in there are also some other signals that are quite uncomfortable. Malaise doesn't seem a popular term here but it seems accurate. It's not too dissimilar from the early stages of a flu.
     
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  13. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    The paper did report on the use of a mass spectrometer to look for protein changes on ciHHV6 reactivated U2-OS cells. Unfortunately they did not do that on the other experiments such as with the A549 cells.

    Hopefully they will extend this work to look at cellular protein changes between cells grown for 48 hours in ME serum vs healthy serum. Could the cellular protein changes be a short term lasting effect of the serum signal? e.g. elevated DRP1 protein causing the cell to stay in fission? Dr. Prusty talks about DRP changes in his CMRC presentation but I don't see it discussed in the paper?

    I believe the Fisher/Australia and Otago/New Zealand teams have cellular protein change data from their experiments...............
     
    Last edited: Apr 27, 2020
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  14. spinoza577

    spinoza577 Senior Member (Voting Rights)

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    I really dare to say:

    My dream yesterday, I hardly can remember, but at some point it really got that terrible that I sweated all over - when I woke up.

    Already with dreams there is no intrinsic feeling that distinguish teh dream from reality, there is no sign, no light, no degree, no nothing - search for it! With dreams it´s only that they lack coherence, whereas in normal life coherence appears (at least as long as you don´t get severe Alzheimer or whatever).


    Any bad feeling can have its badness everywhere in the chain:

    the felt thing -- the transmission -- the act of feeling​


    (No, this last one does not mean in itself that it is psychological, really no.)
     
    Last edited: Apr 27, 2020
  15. cassava7

    cassava7 Senior Member (Voting Rights)

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    Other concerns in the study and its associated press release raised by Van Elzakker and Proal (both from the Polybio foundation).



     
    Last edited: Apr 27, 2020
  16. Marky

    Marky Senior Member (Voting Rights)

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    Nothing I ever experienced pre illness was really similar to what ME feels like. The combination of severe fatigue, brain fog, fasciculations, orthostatic intolerance, post exertional malaise - I have never experienced. What do u call that?

    Further complicating the matter is that ME-patients with PEM diagnosed after strict criteria, often have a myriad of subjective symptoms, and we all experience and interpret them in different ways.

    No other diseases i know of have all these core symptoms, and a myriad of others.

    It makes it near impossible without any data to know what the f is going on

    And if researchers research based on what the symptoms in isolation usually come from, its probably a blind alley tbh

    There is a disease process here that is unique producing unique symptoms (especially post-exertional malaise, its different to cancer fatigue and MS post exertional malaise, although the latter is probably one of the most closely related based on what ive read).

    Hence why it is so hard to explain

    Thats the only thing i feel pretty certain about
     
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  17. wigglethemouse

    wigglethemouse Senior Member (Voting Rights)

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    Using model cell lines means that the experiment is controlled in certain ways (1) U2-OS cells prevent virus replication as they didn't want this effect in the HHV6 experiment (2) A549 - virus naive - no other virus in these cells (3) they are just looking at the effect of what is added to the cell culture, in this case serum.

    If patient cells were used they might already have been harbouring embedded virus's, would have different levels of necessary nutrients and proteins, and a different genetic profile, so you wouldn't know what caused the observed effect.

    Let's remember this is a first step. I'm sure Dr Prusty and co have a gazillion experiments they would like to try when and if they get sufficient funding.

    In the meantime other researchers can read and understand the work and dream up their own experiments.

    EDIT : Other researchers are using model cell lines too. For example Dr. Moreau is using Jurkat cells to see what effect patient plasma has on them.
     
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  18. glennthefrog

    glennthefrog Established Member

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    I'm immune to the flu! haven't had one for 22 years since I got ME
     
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  19. Ravn

    Ravn Senior Member (Voting Rights)

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    Thinking out loud.

    On the one hand we have findings showing ME mitos outside the serum act more or less the same as HC when unstressed but can't keep up when extra demand or stress is placed on them. So problems independent of serum.

    On the other hand we have various serum swap studies that show ME serum spells trouble for healthy mitos. So problems due to serum.

    But is this necessarily contradictory? Could ME mitos have some sort of defect that's present all the time but not bad enough to cause clinical trouble - until you add additional stress. That stress could be in the form of a separate serum factor and/or in the form of exercise-induced mito changes (exercise affects the fusion-fission processes in mitos).

    IIRC the ME serum effect on healthy cells does not reduce their functioning as much as ME serum on ME cells. And ME cells in healthy serum get somewhat better but still don't match healthy cells. That would support a two-factor problem in ME.
     
  20. Ravn

    Ravn Senior Member (Voting Rights)

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    More thinking aloud.

    Let's assume for a moment that fission really happens as proposed in the Prusty paper, and in a variety of cells in ME.

    In this case, is the problem (only) excessive fission or (also) an inability to exit fission mode again. As I understand it fission itself is a perfectly normal and necessary process. There's constant fission and fusion going on in healthy mitos in all sorts of cells. Just as examples, the two articles below look at cardiac and muscle cells (haven't fully read them; note that they're not about ME).

    So inducing fission is not necessarily, in itself, a problem. It could be that all mitos, ME and healthy, react to the factor in the serum by inducing strong fission, which would make sense if there was indeed some sort of viral challenge as the Prusty paper suggests. But maybe for healthy cells that's a temporary state and they soon get back to normal fusion-fission processes (or would do so in vivo with all the normal feedback processes functioning)? And maybe ME cells get stuck in high-fission mode for much longer than healthy ones?
    Physiological Mitochondrial Fragmentation Is a Normal Cardiac Adaptation to Increased Energy Demand (2020) Michael Coronado et al
    https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.117.310725
    Stay Fit, Stay Young: Mitochondria in Movement: The Role of Exercise in the New Mitochondrial Paradigm (2019) Jesus R. Huertas et al
    https://www.hindawi.com/journals/omcl/2019/7058350/
     

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