A New Decade of ME Research: The 11th Invest in ME International ME Conference 2016
Mark Berry presents the first in a series of articles on the 11th Invest in ME International ME Conference in London ...
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Naviaux et. al.: Metabolic features of chronic fatigue syndrome

Discussion in 'Latest ME/CFS Research' started by A.B., Aug 29, 2016.

  1. Barry53

    Barry53 Senior Member

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    I think it is great that these people are exploring different avenues, and no matter whether right or wrong, will help to advance knowledge as truly good science should.
     
    Last edited: Dec 17, 2016
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  2. wastwater

    wastwater Senior Member

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    Dauer is related to FOXO genes so research that I think.
     
    merylg likes this.
  3. roller

    roller wiggle jiggle

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    @Ben Howell

    i would like to know if the studies findings have been cross-checked with other diseases, that show similar patterns.

    if so which ones?

    thx!
     
    merylg likes this.
  4. Murph

    Murph :)

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    I did this a little while ago.

    I was interested in the key metabolites that Naviaux mentioned in the paper, but couldn't help wondering about the hundreds of others that were tested. When the data was released on the metabolomics workbench site I made a few graphs, but didn't have an account to post it here.

    It is a very simple analysis of the raw metabolomic data in the Naviaux paper. Each blue column represents a different metabolite. Data is presented using ratio of average of sick patients to average of healthy patients; and without measuring variance or statistical significance. (nb the authors do more sophisticated analyses than this to obtain their fold change scores published in the paper.) Nevertheless some patterns can be seen.

    The fact people have more metabolites low than high is a decent sign of hypometabolism, although most are not very very low. I find it interesting that men have more metabolites lower, but also more *just* below normal levels.

    Male metabolite ratios.png Female metabolite ratios.png
    Male metabolite ratios.png Female metabolite ratios.png

    [Note axis truncation in the male results. The very high result is nicotinamide n oxide, which is all driven by one absurdly large outlier among male patients. Who knows what's going on there. What's especially odd is nicotinamide n oxide drives the lowest result (0.37) in females. It just seems like a non-normally distributed variable.)
     
    Last edited: Jan 2, 2017
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  5. Learner1

    Learner1 Forum Support Assistant

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    I'm a little new here and haven't yet gotten the hang of all the nuances of this site, so please excuse my butting in here like this.

    I'd created another thread this week about my experiences with B6 deficiency an the relationship to heme and sphingolipid production and immune function. I was asked to copy what I posted there into this discussion, so here goes... I'll look forward to hearing if you all think this might be important in light of Naviaux's findings...


    This describes PLP (P5P or B6) and it's importance in sphingolipids and immune function.

    http://www.folk.uib.no/mfapu/Pages/papers pdf/2013/paul_2013_nr_71-239.pdf

    I extracted this from the PDF:

    PLP-dependent metabolism of sphingolipids

    Reduced availability of PLP is associated with reduction
    in several components ofthe immune response, includ-
    ing significant decreases in lymphocyte numbers, espe-
    cially T-helper cells and IL-2 production in humans.6
    Lymphocytes isolated from vitamin B6-deficient subjects
    also show reduction of lymphoproliferative responses to
    mitogens that activate both T and B cells when grown in
    a culture medium containing adequate concentration of
    PLP.6 This has been attributed to the lower numbers of
    T-helper cells in the lymphocyte population from vitamin
    B6-deficient subjects. Maturation and egress of lympho-
    cytes, especially T-cells, from thymus and lymph nodes
    relies on the gradient of sphingosine-1-phosphate (S1P).
    PLP-dependent enzymes play a major role in the synthe-
    sis and breakdown of S1P, which is a potent metabolite
    that regulates inflammation and immune response pro-
    cesses such as cell growth, survival, differentiation, lym-
    phocyte trafficking, vascular integrity, and cytokine
    and chemokine production.58,59 PLP is required for the
    activity of serine palmitoyl transferase that catalyzes the
    condensation of serine and palmitoyl CoA into 3-keto-
    dihydrosphingosine, which is then converted to S1P
    in a series of reactions.58–60 PLP is also a cofactor for
    sphingosine-1-phosphate lyase, which irreversibly cleaves
    S1P to regulate its concentration.58,59,61 A gradient of S1P
    is required for lymphocyte egress from thymus and
    peripheral lymphoid organs, which is maintained by S1P
    lyase.62 Administration of vitamin B6 antagonist 4’ deoxy-
    pyridoxine interferes with the S1P gradient, results in
    accumulation of mature lymphocytes in the thymus, and
    depletes B- and T-lymphocytes from lymph causing lym-
    phopenia.62 These conditions can be reversed by provid-
    ing excess vitamin B6 in the diet.62 During inflammation,
    S1P concentration increases in the inflamed peripheral
    tissues,63 which functions as a chemoattractant for the
    inflammatory cells.
    One of the intermediate products during the synthe-
    sis of S1P from 3-keto-dihydrosphingosine is ceramide,
    which plays an important role in inflammatory processes.
    Ceramide functions as a second messenger mediating the
    effects of tumor necrosis factor-a and interferon-g on
    programmed cell death and regulating senescence.64,65 An
    increase in cellular ceramide concentration is observed in
    cystic fibrosis, experimental autoimmune encephalomy-
    elitis, and diet-induced insulin resistance, all of which are
    marked by chronic inflammation.66–68 The importance of
    ceramide in these diseases is demonstrated by the fact
    that manipulation of ceramide concentration via inhibi-
    tion of serine palmitoyl transferase or mutation of sph-
    ingomyelinase, reverses the pathology of the disease.66–68
    Ceramide-1-phosphate, which is derived from ceramide,
    activates mast cells that mediate inflammation.69
    Thus, it is possible that is a higher demand exists for
    PLP during inflammation due to the role of PLP in the
    synthesis of S1P and ceramide, and maintenance of S1P
    gradient.
     
  6. Kati

    Kati Patient in training

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    i meant to post the following on this post but did so by mistake in another thread.
    There has been new correspondance in PNAS for Naviaux et al:

    A commentary from Roerick et al. (Including van der Meer) has been published here

    There is a new reply from Dr Naviaux to their comment on the PNAS website. You can access the response here.
     
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  7. BurnA

    BurnA Senior Member

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    Naviaux certainly knows how to reply, I'll give him that.
     
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  8. Neunistiva

    Neunistiva Senior Member

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    Thank you @Kati. This is really good to have as I have seen similar criticism here on forum and elsewhere online, and I didn't feel nearly equipped to even begin answering them.
     
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  9. Mel9

    Mel9 Senior Member

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    I just found a paper :


    Microglial activity in people at ultra high risk of psychosis and in schizophrenia; an [11C]PBR28 PET brain imaging study

    Authors: Peter S Bloomfield, Sudhakar Selvaraj, Mattia Veronese, Gaia Rizzo, Alassandra Bertoldo, David R Owen, Michael AP Bloomfield, Ilaria Bonoldi, Nicola Kalk, Federico Turkheimer, Philip McGuire, Vincenzo de Paola, and Oliver D Howes.

    It was published in Am J Psychiatry. 2016 January ; 173(1): 44–52. doi:10.1176/appi.ajp.2015.14101358.

    They used the following method to test for elevated microglia activity in the brain:


    "Elevations in microglial activity can be measured in vivo with positron emission tomography (PET) using radioligands specific for the 18kD translocator-protein (TSPO), which is expressed on microglia (14). Investigations using the first generation radiotracer (R)- [ 11C]PK11195 have revealed an increase in TSPO binding in medicated patients with schizophrenia when compared to healthy controls (6, 7). The first investigation of microglia using PET in schizophrenia, in a cohort of 10 patients, revealed a total grey matter elevation of microglial activity in the five years following diagnosis (6). The most recent investigation in seven chronically medicated patients with schizophrenia using (R)-[11C]PK11195 demonstrated an elevation in hippocampal binding potential and a non-significant 30% increase in total grey matter binding potential (7)."

    Just wondering if any of the ME CFS researchers have used this method?
     
    picante likes this.
  10. wastwater

    wastwater Senior Member

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    If cytokines are driven high enough it can give a schitzoid like presentation
     
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  11. Kati

    Kati Patient in training

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    There has been a 'correction' posted on the PNAS website which reads as following:

    Link: http://www.pnas.org/content/early/2017/04/18/1703858114.full
     
    Marky90, moosie, Snowdrop and 18 others like this.
  12. GreyOwl

    GreyOwl Dx: strong belief system, avoidance, hypervigilant

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    If only such frank disclosures were made by all researchers.
     
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  13. sdmcvicar

    sdmcvicar

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    I really should see if I can get a chance to get in some shop talk with the Naviaux lab now that I'm relocated to San Diego. I'm impressed by their transparency and professionalism.
     
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  14. grapes

    grapes Senior Member

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    I am just now reading this string, and I LOVE what you are proposing, Forbin. Because with me, this ALL started with an acute mold inhalation. And I'm part of 24% of the population that needs extra help getting the mold out of me. So all I can do is HOPE that as I get it out, I "might" return to normal...or at least be better than I am now.
     
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  15. John Mac

    John Mac Senior Member

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    For anyone waiting to hear news about the replication study it looks like it's been delayed again.
    It was tentatively scheduled to be published 'this fall' and then 'late this fall' but it's now early next year.
    I was hoping for an early Christmas present.

    Replication Metabolomics Study with Paul Cheney MD – Publication Expected Early 2018
    http://www.sisoh.com/replication-metabolomics-study-with-paul-cheney-md/
     
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  16. hixxy

    hixxy Senior Member

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    @John Mac It says 2018 in the title but still says 2017 in the body of the article.

     
  17. John Mac

    John Mac Senior Member

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    Yes I took it that they edited the title to reflect the delay. I remember the fall being the original timescale and then remember seeing the late fall being an update.
     
  18. Zara

    Zara

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    Hi...see study in japan from 2014...however small sized study..they used PK11195 during Petscan..neuroinflamm. was reported.

    Now, sept 2017, they started on replicating finding in bigger cohort of me cfs patients. And they us [11C]PBR28.
     
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  19. wastwater

    wastwater Senior Member

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    I found this about gene UGT8 catalyzes transfer of galactose to ceramide during biosynthesis of galactocerebrosides which are abundant sphingolipids of the myelin membrane of the CNS and peripheral nervous system
     
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  20. FMMM1

    FMMM1 Senior Member

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    Thanks, I've been waiting for the larger study with the new tracer [11C]PBR28. Taken longer than I hoped to get this second study commenced.
     

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