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Doctors Mc.Clure & Kaye respond to Annette Whittemore in "Expert-Reviews.com"

Discussion in 'Media, Interviews, Blogs, Talks, Events about XMRV' started by thegodofpleasure, Jul 17, 2010.

  1. thegodofpleasure

    thegodofpleasure Player in a Greek Tragedy

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    In this article : http://www.expert-reviews.com/doi/pdf/10.1586/erm.10.54 - which appears to be the latest installment in a very public exchange with Annette Whittemore at the WPI, doctors Steve Kaye & Myra McClure (who were both part of the Imperial College group's failed attempt to find XMRV http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008519)
    conclude that a new, multicenter study of fresh blood from the "Science" paper cohort patients, is needed in order to determine whether the WPI's findings are in fact correct or if, in their words, the presence of XMRV
    They go on to say :
    I don't think that this article adds anything to the debate that hasn't already been said. Instead, it suggests pricked and wounded egos, driven to respond publicly to Annette Whittemore's rapier like criticisms. Some of the comments within it seem to lag well behind what we alreay know to be happening in the research world, which makes the authors look hopelessly out of touch.
    It also seems to me that their comments have already been somewhat undermined by the frailty of the CDC's recently failed attempt to find XMRV and hopefully, the Alter / Lo paper is another torpedo headed their way, very soon.

    Perhaps, rather than continuing their spat with Annette Whittemeore, they woud have been better advised to stay quiet, cut and run - but then their ego's are perhaps just too big to do that.


    TGOP
     
  2. Anika

    Anika Senior Member

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    Thanks for posting this (I've only skimmed it so far).

    Didn't McClure state she never wanted to have anything to do with CFS studies again, or something to that effect, in a recent article (I didn't have access to the article, but read comments about it, so I may not have this right).

    My initial reaction to seeing this article: Is this McClure and company hedging their bets? Did they stake out too strong an opinion before, and are trying to find a face-saving way to get back in the game? Or at least trying to neutralize an over-broad conclusion in their initial paper?
     
  3. thegodofpleasure

    thegodofpleasure Player in a Greek Tragedy

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    They're having at swipe at the WPI

    I think that you are probably right Anika and yes, I too saw that remark about McClure vowing not to have any further involvement with XMRV / ME/CFS. :Retro smile:

    However, I think that this (simplistic) swipe at the WPI exemplifies the true purpose behind them writing the article :

    Whichever way it is, we, the poor sods who are suffering, know that they are now slyly back peddling.

    Regards,

    TGOP :D
     
  4. Bob

    Bob

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    Well, their perspective is quite interesting, but in my opinion it's irrelevant as these researchers were incapable of demonstrating that they can detect the virus, in human blood samples, at all, and have declared that they will no longer be involved in any CFS research anyway.

    They do confirm their opinion that CFS is a biomedical illness:

    So they aren't in the psychological camp at all. They were simply unable to detect the virus. I would guess that there was not originally any agenda on their part, other than to carry out the best science they were capable of.

    The yet-to-be-published NIH/FDA positive study, which confirms the WPI's study, makes their statement even more irrelevant. They acknowledge:

    I'm not sure if I agree with their proposals about other labs testing the WPI's patient cohort because of the implications of the following:

    So this is suggesting that if other researchers can't find XMRV in the WPI's patient cohort, then XMRV doesn't exist in these patients, but is a 'technical artefact' (hmm, an interesting proposal - I'm not sure if HIV would ever be described as a technical artefact?!)

    They do confirm their belief in the existence of XMRV:


    I'm not sure about the accuracy of the following quote (with regards to the WPI methodology):

    And the following explanation, of discrepancies between all of the studies, seems to be unbalanced, as the authors do not admit the possibility that the negative studies were just incapable of finding XMRV (a new type of human retrovirus), however wonderful they think that their testing procedures (based on established HIV testing methodologies) are...

     
  5. pollycbr125

    pollycbr125 Senior Member

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    full text is here you dont need to download pdf http://www.expert-reviews.com/doi/full/10.1586/erm.10.54


    Full Text
    Expert Review of Molecular Diagnostics
    July 2010, Vol. 10, No. 5, Pages 537-539 , DOI 10.1586/erm.10.54
    (doi:10.1586/erm.10.54)

    Can detection of xenotropic murine leukemia virus-related virus be linked to chronic fatigue syndrome?
    Myra McClure† & Steve Kaye
    †Author for correspondence
    Sections:

    Last year, a new retrovirus, xenotropic murine leukemia virus-related virus (XMRV), was reported to be present in the peripheral blood cells of patients with chronic fatigue syndrome (CFS) [1]. This finding has not, as yet, been independently confirmed by a second laboratory but, nevertheless, has attracted a great deal of attention.

    As recently as 2006, Urisman et al., in the USA, first found integrated proviral XMRV DNA in cases of familial prostate cancer (PC) [2]. Although the discovery of a new retrovirus was potentially exciting, no causal link to PC could be demonstrated, since the virus appeared to be restricted to stromal cells and not found within the tumor tissue. The authors built their breakthrough on the link between a genetic mutation in RNAseL (an enzyme key to the cellular antiviral response), implicated in familial PC cases [3,4]. Having identified the virus using a microarray capable of detecting all known virus families, they used a specific PCR to detect XMRV sequences in 40% (eight out of 20) of PC patients with the mutation.

    A subsequent study in 2009, also from the USA, tried to find XMRV in 334 consecutive prostate resection samples [5]. Proviral DNA sequences were detected in the prostate tumor epithelium of 6% of patients, particularly those with high-grade cancers. This opened up the possibility that the virus might play a role in tumorigenesis. In contrast to the original report, infection was independent of the RNAseL gene mutation, implicating the virus in sporadic forms of PC, which are far more common in male populations.

    The designation, XMRV, reveals the group of viruses to which this newcomer is most closely related, namely the xenotropic murine (endogenous) viruses. Genomic-sequence comparisons highlight its independence from its murine ancestor, as well as from any human endogenous retroviruses. This, together with the fact that the first XMRV sequences cloned from infected humans were not identical to one another (suggestive of separate episodes of human infection) underpins its discovery as the third human retrovirus [2], the others being the human T-cell leukemia virus type 1 (HTLV-1) and HIV-1.

    In contrast to the two US studies, three European groups generated quite different results from their search for XMRV in PC by proviral DNA amplification. One German group detected a lower prevalence (one out of 105 patients) [6], while an Irish study failed to find the virus in a sample size of 139 patients [7]. A larger study from Germany also failed to detect the virus in any of 500 PC patients [8]. It is too early to speculate whether XMRV has a selective geographical distribution, as is the case for HTLV-1 [9].

    So, how did a murine virus linked to PC become implicated in CFS? CFS is a condition characterized by unexplained long-term fatigue, chronic inflammation and immune dysfunction, which often appears following an episode of severe virus infection. Upregulation of the RNAseL pathway is a feature of CNS, which is consistent with an activated immunity, and with the idea of virus persistence in the pathogenesis of the condition [10,11]. Indeed, CFS has long been considered to be a multifactorial condition, in which virus infection is likely to play a role. Many viruses, including retroviruses, have been sought in CFS patients; some have been found, but none have been convincingly linked to the syndrome following prolonged scrutiny [12–19].

    The new connection of XMRV with CFS reported from the Whittemore Peterson Institute (NV, USA), was published in Science last year [1], and claimed that, of 101 CFS patients recruited to investigate the virus etiology of the disease, 68 (67%) were XMRV positive by single-round PCR amplification of the proviral DNA from peripheral blood mononuclear cells. When the envelope of a virus related to XMRV (spleen focus-forming virus) was used as the antigen to which to measure an antibody response against XMRV, nine out of 18 patients tested had an antiviral response. Interestingly, eight out of 218 of healthy volunteers (3.7%) were also found to be infected with XMRV. There was no association with the RNAseL mutation in either group.

    As was the case with PC, three European studies have failed to find XMRV in CFS patients. The first from Erlwein et al. used nested proviral DNA PCR amplification to amplify different parts of the genome from the Whittemore study [20], but included amplification of a control gene (B-globin) to testify to the integrity and sufficiency of the DNA being assayed. Despite a sensitivity of detection of a single copy of XMRV, they were unable to find the virus in any of the 186 CFS blood samples.

    The second UK study, by Groome et al., used the PCR primers and protocol described in the Science paper [1], but failed to detect XMRV sequences in the 170 CFS patients tested [21]. In addition, they carried out a real-time PCR able to detect fewer than 16 copies per reaction and, again, failed to amplify the virus, either in their CFS samples or in the 395 controls. When this approach failed, they looked for a neutralizing antibody response, as evidence for virus infection. The fact they were able to detect neutralizing activity in one CFS patient, as well as in a number of control sera, gives some indication of the sensitivity of the assay. Further investigation of the specificity of the neutralizing response, by testing the sera against the envelope proteins of viruses other than XMRV, showed that the sera neutralized other viruses, suggesting that the response from the CFS patient was likely to be one of crossreactivity. Nevertheless, they found that, among their healthy control sera, there were four that specifically neutralized XMRV, which raises questions about the prevalence of this virus in the general UK population.

    A third paper, by van Kuppeveld et al., further weakened the case for XMRV involvement in CFS [22]. Two amplification procedures were used. The first was a gag-nested XMRV PCR, adapted from the Urisman paper [2], and the second a quantitative PCR, identifying conserved XMRV pol sequences described previously in the 2009 USA PC paper. The assays, sufficiently sensitive to detect fewer than 10 copies of XMRV, failed to detect virus in either the previously described 298 Dutch CFS patient cohort [23,24], or any of the controls matched by age, sex and geographical location.

    One technical difference stands out from these studies. PCR was employed to amplify XMRV sequences in all four studies. Only the study from the Whittemore Peterson Institute [1] was able to detect XMRV sequences following single-round PCR, indicating that copies of the XMRV genome were not in short supply. All the others found it necessary to employ a nested PCR, a modification of the standard reaction designed to enhance sensitivity and specificity.

    Is there an explanation for such discrepant findings? It is true that no one study is a replicate of another in the sense that the cohort of patients investigated in each case is not the same. It is certainly not beyond the bounds of impossibility that the patients investigated by the Whittemore Peterson Institute may be quite different in their medical experience, immunological or genetic background, from patients studied in Europe and could, therefore, be more susceptible to this particular virus infection. This remains to be clarified.

    One way to address this is for patient material to be sent to the three laboratories unable to detect virus in their respective cohorts and Mikovits from the Whittemore Peterson Institute has, indeed, offered to do this with at least one of the groups involved. However, retrovirologists know the pitfalls associated with studying retroviral association with disease [25]; therefore, a simple posting of DNA samples and reagents to laboratories capable of carrying out PCR is an insufficiently robust means of executing a definitive study. Despite the CFS patient community being, understandably, impatient to know whether or not XMRV is playing a role in CFS, any informative investigation requires thoughtful planning.

    Who is best equipped to carry out the investigation? It is critical to engage those skilled in dealing with biological or public health controversy. National Monitoring Laboratories, such as the CDC and NIH in the USA, and the Health Protection Agency, National Institute of Biological Standards and Control or the National Institute for Medical Research in the UK are best placed to carry this out. Once an investigator from participating laboratories has been identified, a discussion on practical operational issues can start, the most important being which patients should be tested for the virus? If, as would seem logical, this is to be the same cohort of patients who appear to be carrying the virus, then each patient requires to be recalled to the clinic to provide fresh, multiple, blood samples, one of which should be provided to each participating laboratory for independent DNA analyses. The results of this experiment will demonstrate whether XMRV is undeniably present in those patients, or whether its original detection resulted from a technical artefact.

    Future sample exchange between interested parties is likely. Meanwhile, at least two leading US groups are carrying out similar investigations into the link between XMRV and CFS. Their results are awaited with interest.

    Financial & competing interests disclosure
    The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

    No writing assistance was utilized in the production of this manuscript.
     
  6. eric_s

    eric_s Senior Member

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    With exception of the NIH i would say "no, thanks" to that. And if the authors of this paper had really wanted to cooperate they would have had their chance months ago. They're pretty late...

    If the WPI is really convinced of their findings, then for them there is no reason to go back and redo this. Then they're right to push on make new studies. Because in this case they know that they will be proven right anyway, so why waste time and resources. It's just nerve-wracking for us, because we don't have certainty. If they're not right, then they will have a problem of course.

    And one should not judge people just based on this, but when i see the photos in this paper, i feel like they look like quite close-minded people. The sort that would find it hard to accept new facts, even if they were in front of their eyes, if they contradict what they have been taught or believe in. Just a feeling.
     
  7. ukxmrv

    ukxmrv Senior Member

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    Is there any evidence that these agencies have the expertise to carry out this particular task?

    We need people with open minds, with no agenda other than to help patients. We need people with experience in developing studies that do find things or specific positive experience with XMRV or mouse viruses.
     
  8. Esther12

    Esther12 Senior Member

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    I'm sympathetic to McClure, and think she probably got suckered by Wessely into making unfounded comments as to her certainty that XMRV is not a factor in CFS in the UK. It's sounds like she has been rather taken aback by the fallout, and I want to make it clear that what I'm about to say is certainly not the result of personal animosity for the lady, but rather, the sort of puerile commentary the internet was become known for:

    Did anyone else find themselves thinking of Frankie Howard as soon as the saw McClure's photo? I really thought it was Howard in a wig.

    Carry on.
     
  9. pollycbr125

    pollycbr125 Senior Member

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    totally disagree on that one McClure is no fool she knew exactly what she was getting into and to be honest deserves every bit of flak she has got .Shes now going for the sympathy vote , well sorry love you dont fool me , she can backtrack all she likes it wont make any difference .She might think twice about just what she gets involved in ,in the future and make sure the science is solid . which had she done a bit of homework she would have known it was not
     
  10. natasa778

    natasa778 Senior Member

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    I totally agree with you Polly :Retro smile:

    Notice also how she conveniently forgets to mention that she was behind one of the failed studies. She also forgets to mention that small detail of Kuppenvald's failure to mention positive samples etc etc.

    This whole piece is a nasty below the belt punch from someone who no intentions of playing fair.
     
  11. V99

    V99 *****

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    Havn't the WPI, Cleveland clinic and NCI already done this?

    I emailed the magazine questioning if McClure should not state her involvement in the research.
     
  12. Esther12

    Esther12 Senior Member

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    McClure's already put her money on XMRV =/= CFS so ego wise, she's invested. With no positive replication paper yet published, she's not going to have changed her mind, and it would look strange if she did. She'll be hoping it doesn't work out, and her work will have been confirmed - I think that's a pretty natural response given her situation. If it turns out the WPI's work is validated, it will then be very interesting to see how she responds, and if she talk openly about her conversations with Wessely.

    I think it's likely that the speed of their work, and the forthright manner is which it was promoted were a result of Wessely's belief that the XMRV news will cause psychological damage to his patients which he wants to mitigate. It would be very interesting to hear if this was the case, and if he spoke openly to McClure about this.

    From McClure's point of view, she had no interest in CFS, and was being guided by the man widely seen as a leading expert. It's not surprising she would follow his lead. That doesn't absolve her of responsibility, but we should have a little compassion for our human weaknesses and the way they can lead us all to do things we should not.
     
  13. Rivotril

    Rivotril Senior Member

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    "The assays, sufficiently sensitive to detect fewer than 10 copies of XMRV, failed to detect
    virus in either the previously described 298 Dutch CFS patient
    cohort [23,24], or any of the controls matched by age, sex and
    geographical location."

    detect virus in 298 dutch cfs patient cohort???
    thought kuppeveld only tested about 25-30 oxford selected patients

    for the rest i agree with the thing that mc Clure is just in this for saving her own reputation and has no good incentives in this
     
  14. thegodofpleasure

    thegodofpleasure Player in a Greek Tragedy

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    Isn't Dr. Kaye is just as culpable as Dr. McClure ?

    Hey guys,
    how come Dr. McClure is coming in for all the criticism on here and yet Dr. Kaye gets away Scott free ?
    He was involved in the Imperial College study as well and he also co-authored the article in question, so how is he any different to Dr. McClure?

    I'm not defending McClure, just curious why she cops all of the flak. :worried:

    TGOP :confused:
     
  15. eric_s

    eric_s Senior Member

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    Probably because it was always Dr. McClure's name that was in the media.
     
  16. eric_s

    eric_s Senior Member

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    It's 9 months since the Science paper, one side says "it's there", one side says "it's not". It's ok to be wrong but in my opinion then you need to go back and check, best even before publishing a paper, if there is evidence that you might be wrong. If for such a long time you don't manage to figure out who is wrong and why or you don't even really try, then you should hear this (and at this point i can't tell for sure yet, who is wrong, but someone most certainly is)
    [​IMG]
     
  17. ukxmrv

    ukxmrv Senior Member

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    You are right of course, God of Pleasure. We should be commenting on Kaye as well.

    I think that it is because they were referred to McClure's team in the press. She's also so gobby with her "foot in mouth" quotes.
     
  18. muffin

    muffin Senior Member

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    How funny...

    Right after this stupid study was out, I emailed McClure and told her that she would be best served if she never dealt with the Weasel again. Her career and reputation would be further damaged and did she not note that all other researchers who had worked with him on other projects never worked with him again? What did that tell her?

    I'll bet McClure isn't going near CFIDS/ME/XMRV. She got enough emails and direct shots because of that quick and dirty piece of poor research -- Career damaging research "study".

    Who would be stupid enough to mess with Mrs. Whittemore? A wealthy, well placed and respected American woman who is confident and has a very sick child. Oh yea, I'm going to fight her, right after I swim the Atlantic in February.
     
  19. Wonko

    Wonko Senior Member

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    February? the atlantics quite big you know - used to take them several months to sail across it - so I'd allow a little more time lol
     
  20. SOC

    SOC Senior Member

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    :Sign Good one:

    As I understand it, McClure, Kaye and the rest of the lab crew do know how to find XMRV. They find it in prostate cancer samples. I think questioning their technical ability may not be in order.

    I still suspect that Wesseley took them for a ride -- fed them some "poor psychiatric patients being taken advantage of" story, and then gave them bum samples. They know they can find XMRV because they do it every day, so when they found nothing in the samples it seemed obvious to them that Wesseley was right. Then she gets ugly hate mail from ME/CFS patients which only reinforces her belief that we're a bunch of crazies. This is just a suspicion, so don't beat me up about it.... :worried:

    That said, McClure lost my sympathy when she started mouthing off before she had all the facts in hand. It would have been smarter to do some reading about ME/CFS before she got into a public spat. This latest published foolishness shows that McClure and Kaye clearly haven't bothered to read up on what's happening with XMRV/ME/CFS -- multicenter study, the Alter/Lo paper, etc.

    I also suspect that McClure, and others in her lab apparently, have pretty big egos. McClure, and maybe others, are probably having a very, very hard time accepting that they screwed up royally. They're trying to find a way to preserve their high opinion of their abilities. It has to be somebody else who screwed up, not them. They know there wasn't XMRV in those samples (and maybe they're right), so WPI has to be wrong. QED

    I sense quite a bit of back-pedalling in this latest article, along with a lot of wounded ego, and attempts at CYA. In general, I'd say this piece (the article, I mean) is more to our advantage than our disadvantage.

    In the long run, I think the Imperial College "study" and McClure's public statements about it since are going to be big black marks on her record and ultimately an obstacle in her career. Others, including Kaye, may get off more lightly (if it turns out they were taken in by Wesseley) because they haven't gotten into ill-informed public spats.
     

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