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Lipkin finds biomarkers not bugs

Discussion in 'Phoenix Rising Articles' started by Firestormm, Sep 12, 2013.

  1. Nielk

    Nielk

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  2. bel canto

    bel canto Senior Member

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    Yes, thanks Neilk!
  3. searcher

    searcher

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    As bel canto said, what was interesting about the Montoya et. al study was that leptin wasn't particularly high-- instead leptin levels correlated with fatigue in patients but not in controls. Leptin levels themselves do not appear to be a useful biomarker-- they will be higher in overweight people even without fatigue.
    From Montoya's paper:
    "The relationship we observed between leptin and fatigue existed even though leptin levels were not abnormally elevated, and there was no statistical difference in leptin values between the CFS and control groups. "
    So, although I think Shoemaker's work is interesting and relevant to CFS patients, I don't think he has made the same conclusion about leptin that Montoya and his team has.

    The Montoya paper on leptin can be found at http://www.translational-medicine.com/content/pdf/1479-5876-11-93.pdf
    Firestormm likes this.
  4. HowToEscape?

    HowToEscape? Senior Member

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    By organizing.

    There is a template for that, the AIDS folks were very well organized and targeted specific actions within a plan. If we just wait for "them" to "do something", we'll wait till we're old and eventually dead.
    Antares in NYC likes this.
  5. GcMAF Australia

    GcMAF Australia Senior Member

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    did he look at Lyme??
  6. Simon

    Simon

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    I think it's worth stressing that the 'hit and run' scenario discussed by Mady Hornig is, at this point, only suggeseted as a possiblity for ME/CFS - and they don't yet have any resultf from their work looking for 'shadows' of previous infections.

    I'm not in the US so don't have any idea of how to press for funds - but it might be worth posting something in the advocacy forum (I couldn't see anything there yet). There is probably discussion of it on the CDC phonecall thread too, but it's rather lengthy.

    That seems a pretty weird finding to me too: it almost implies some sort of shift in the illness after 3 years, which is hard to fathom. Hopefully things will be clearer when the new paper is published, which Ian Lipkin said would be 'very soon'.

    He did find some bugs, but said the Anellovirus was not specific to CFS (ie CFS were not greatly different from controls). It sounds like the retroviral thing was the same in that they found it in 'pooled samples'. Hopefully things will be clearer in the full paper.

    Do you have any refs/links re the elevated IL8 findings elsewhere? Would be good to compare.
    I have to admit I took a slight liberty with the title, favouring snappiness over total accuracy - though I think it reflects the gist fo the talk.
    Antares in NYC and Firestormm like this.
  7. Simon

    Simon

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    Wish I could too! Broadly, I think they are signs of immune activation. Intriguingly, when it comes to the cytokine findings in spinal fluid
    He didn't expand on this and I wish knew more, but clearly Ian Lipkin thinks this could be an important clue.
  8. justy

    justy Senior Member

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    The three year marker difference is fascinating and when it is unraveled may explain why it is often said to those newly ill that the best chances of a full recovery are in the first 2-3 years. It is well known that after this (approximate) time period the illness can become chronic/relapsing/remitting.

    Thanks Simon and Firestormm for the article and the transcript - very much appreciated :thumbsup:
    MeSci, Purple, Nielk and 3 others like this.
  9. Simon

    Simon

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    Leptin

    Not surprsingly this has caused a lot of comment
    Leptin appears to have a role in signalling to the brain, is directly affected by the immune system and ties in with the HPA axis too (post by jeffrez). So it ticks all the boxes (but then so do many things).

    The full text of Montoya's new paper (from earlier this year) is here: Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology

    ABSTRACT


    Background
    ...Studies have demonstrated elevated levels of inflammatory factors in patients with CFS, but findings are contradictory across studies and no biomarkers have been consistently supported. Single time-point approaches potentially overlook important features of CFS, such as fluctuations in fatigue severity. We have observed that individuals with CFS demonstrate significant day-to-day variability in their fatigue severity.

    Methods
    ...we implemented a novel longitudinal study design to investigate the role of cytokines in CFS pathophysiology. Ten women meeting the Fukuda diagnostic criteria for CFS and ten healthy age- and body mass index (BMI)-matched women underwent 25 consecutive days of blood draws and self-reporting of symptom severity. A 51-plex cytokine panel via Luminex was performed for each of the 500 serum samples collected. Our primary hypothesis was that daily fatigue severity would be significantly correlated with the inflammatory adipokine leptin, in the women with CFS and not in the healthy control women. As a post-hoc analysis, a machine learning algorithm using all 51 cytokines was implemented to determine whether immune factors could distinguish high from low fatigue days.

    Results
    Self-reported fatigue severity was significantly correlated with leptin levels in six of the participants with CFS and one healthy control, supporting our primary hypothesis. The machine learning algorithm distinguished high from low fatigue days in the CFS group with 78.3% accuracy.

    Conclusions
    Our results support the role of cytokines in the pathophysiology of CFS.

    The obvious problem with this is that it's a tiny sample. In any event 78% accuracy in separating high from low fatigue days in CFS isn't too great - and is tweaked for this specific sample so would probably be lower in an independent sample. And 6/10 isn't stunning either (though could be subgroups).

    However, it is a really interesting approach and could be consistent with the Lipkin results. As ever, replication is needed.

    PR thread discussing this paper
  10. Firestormm

    Firestormm Guest

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    Replication of Lipkin's preliminary work?

    It is unclear at this point, the extent to which this might (at least in part), represent some means of replication for the Lipkin Study we reported on above; but the NIH grant to the UK Biobank team, led by Luis Nacul, does show some similarity to those areas studied by Lipkin's team:

    It will be a 3 year longitudinal study I believe, ending in 2016, and a significant one at that - though only using plasma and no CSF but the controls will comprise MS patients (as well as healthy) and the ME patient cohort will include those in the severe category:

    Simon and Sasha like this.
  11. Simon

    Simon

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    Thanks

    Hope they take a good look at Lipkin's work first! He looked for several herpes viruses and found almost nothing. He was looking at plasma not NK cells, but if NK cells were infected I would have thought that some of the herpes virus would have been detectable in plasma. Lipkin also didn't include the severely-affected, but he has looked at 285 samples already with another 200 to go. IF they come back negative too that would surely be a concern for the biobank team?

    But still good to see so many chunky studies appearing, and I'm sure the biobank study will generate lots of valuable data and should confirm (or not) the Lipkin findings, even if they, like he, find no herpes.
    Antares in NYC and Firestormm like this.
  12. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    I dont think thats correct in that he found almost none of the herpes viruses. From what i heard of the talk, hhv6 was mentioned but im not sure if he is referring to active infections or not.

    Another thread people have said that its not 'the' cause, which is what he means. Im not even sure if he is referring to a particular test as in spinal fluid? herpes viruses do tend to favour nervous tissue? I think we need some clarrification on this as it does go against what alot of other cfs experts have found and although not everyone has had benefits from treating herpes viruses, it does seem to be a stand out sub set that seems to show some improvement with treatment.

    I would also like to no if they tested for herpes viral particles and or lytic herpes viruses which are mentioned alot by dr lerner?? to me it makes sense that these viruses would be an issue if ones nk function is low, but??

    The whole study hasnt really told us much other then they think theres some infectious cause and there are possible cytokine markers and they need to do alot more work and dont have the money to do it yet.
  13. Firestormm

    Firestormm Guest

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    Yeah, but if NK cells are not infected then it will serve to also rule out Herpes virus. So another confirmation of a poor theory - at least in so far as current infections go. Doesn't rule out this 'shadowing' or trigger concept of course.

    And I think it is pretty safe to say that the UK Team are aware of Lipkin's presentation by now :)

    If their study is really only 3 years (I took that figure from the NIH link but it isn't certain and is not mentioned in the actual text), it would be a shame; as they have said they will be looking to:

    And that could have resulted in a similar differential to what Lipkin was tentatively suggesting at the 3 year point. That's my presumption of course - because as you know I ain't no scientific nerd :alien: :D
    Simon likes this.
  14. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    Serology, which is looking for evidence of previous infections, which I think much of what we need to do in the future must focus, is not part of this report that I am making to you today.

    This is in relation to all the viral testing done by lipkin and his crew which might explain the low incidence of viruses??
    Rereading the lipkin report it also says that the agent must be present in the plasma or spinal fluid as well as not being able to detect historical infections(whatever that means).

    http://www.mecfsforums.com/wiki/Lipkin_presentation,_CDC_Conference_Call_9/10/2013
  15. Firestormm

    Firestormm Guest

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    The point about HHV-6 was made very clear in both the transcript and Simon's review (see above).

    From the transcript:

    They found in the serum from ME patients and controls forwarded by Montoya:

    And in the CSF from Peterson:

    That's the only references to HHV-6 in the presentation.
  16. heapsreal

    heapsreal iherb 10% discount code OPA989,

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    I understand hhv6 but not much is mentioned of other herpes viruses. As mentioned in my last post it appears that he thinks theres more to learn from serology which they didn't do during these tests. Hhv6 may get a different result if serology testing was used??
  17. Simon

    Simon

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    Hi heapsreal

    Serology is testing for antibodies against a virus, 'looking for shadows', as Lipkin put it. Primarliy they are using this technique to find signs of prior infection - however, I think if an active infection is in a particular tissue, but not blood, the anti-virus antibodies (eh anti-HHV6) could still be in the blood. However, I'm not sure if herpes virus are generally not detectable in the blood - I'd just assumed they were.

    Firestormm has already mentioned the low levels of HHV6 found in patients and controls (nb this was a very large and well-characterised cohort, probably much bigger than anything that has gone before). However, they also specifically tested for 4 other human herpes viruses: Cytomegalovirus, Herpes Simplex 1 & 2, and Epstein Barr virus (see transcript). HHV7 and Varicella zoser virus are the only other 2 human herpes viruses they didn't test for specifically, but the hightroughput 'unbiased' testing they did should have detected those if they were there (as I understand it).

    Personally, I think we are learning a lot from this study because it is so large and robust - and there is much more to come, in the serology results and the unbiased search for fungi and bacteria.
    SOC and Firestormm like this.
  18. alex3619

    alex3619 Senior Member

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    I think Lipkin looked for active infections for something like five herpes viruses, which are listed in his transcript. The point is he is looking for signs of acute infection. Serological evidence of past infection can be problematic, and typically this means looking for antibodies I think.

    None of these address non-acute infections which are part of the lifecycles of some viruses, including herpes and enteroviral families. These are the tissue infections that keep being mentioned. From my current understanding, nearly all these types of viruses can infect B cells.
  19. alex3619

    alex3619 Senior Member

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    On Leptin and Serpin I am starting to look into this more closely, though I looked at leptin more than a decade ago. There are many links here with ME pathophysiology. Two that intrigue me at the moment is that leptin can induce hypothalamic inflammation and insulin resistance. If you are obese, have high insulin, glucose or triglycerides; or have disordered stress response or sleep, then leptin could be involved. Its worth some more investigation.

    Serpin is a family I think and not one hormone? It can be involved in regulation of other factors, including energy production. I have barely read anything on this though.
    snowathlete and roxie60 like this.
  20. Gijs

    Gijs Senior Member

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    Business as usual. Nothing has been found. Sound familiar to me. I think the cause of this disease will never been found. It is to complicated. The cytokins Lipkin found are not consistent with earlier findings in other reports.

    For example IL17 are not different by CFS patients compared with controls.

    J Transl Med. (2012) 10(1): 191 Cytokine expression profiles of immune imbalance in post-mononucleosis chronic fatigue
    Broderick G, Katz BZ, Fernandes H, Fletcher MA, Klimas NG, Smith FA, O’Gorman MR, Vernon SD, Taylor R

    There are more reports with different outcomes then Lipkin e.a.

    I do not think Lipkin has found a usefull biomarker or profile.

    Sorry.

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