XMRV not found in Fibromyalgia Patients in Spain

Cort

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Another negative study. This appears to be a different group than the Clotet group that had the conference???

Emerg Infect Dis. 2011 Feb;17(2):314-5.
No Xenotropic Murine Leukemia Virus-related Virus Detected in Fibromyalgia Patients.

Luczkowiak J, Sierra O, Gonzalez-Martin JJ, Herrero-Beaumont G, Delgado R.
Hospital Universitario 12 de Octubre, Madrid, Spain (J. Luczkowiak, O. Sierra, R. Delgado); and IIS-Fundacion Jimenez Diaz, Madrid (J.J. Gonzalez-Martin, G. Herrero-Beaumont).
Abstract

To the Editor: Xenotropic murine leukemia virus-related virus (XMRV) is a recently described human retrovirus that has been associated with prostate cancer and chronic fatigue syndrome (CFS) (1,2). XMRV is similar to a classic murine endogenous leukemia retrovirus, murine leukemia virus (MLV), which infects strains of mice that do not express the specific viral receptor. XMRV is genetically close to, although differentiable from, MLV. The first evidence of its presence in humans was obtained by Urisman et al. in prostate cancer tissue (1). In 2009, Lombardi et al. (2) found XMRV sequences and specific antibody responses in 67% of a large group of patients with CFS in North America. This association was notable because XMRV sequences were found in only 4% of healthy controls. These results have generated controversy because several independent studies, mainly in Europe (3-5) but also in North America (6), have been unable to detect XMRV sequences in patients with CFS. Furthermore, a recent report from North America (7) appears to confirm the initial results by Lombardi et al. (2) in patients with CFS and expands the viral association to a wider variety of XMLV-related viruses that seem closer to polytropic mouse endogenous retroviruses.
 

free at last

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This is starting to become the norm now isnt it. Wonder what methods they use ? either methods are crucial, storage is crucial ( handling ect ) or something is so very odd. because there should be some detections you would have thought ? as xmrv was found in others in spain. where is the low healthy background detections. It just doesnt make sense none of it. ive been lost for some time. everytime a new negative study comes out, it just becomes more and more confusing. do we really consider the detection methods, handling and storage is the reason for so many non detections ? or is there another reason ?. Ive put a lot belief in this idea of retro viral immune dysfuntion. Its actually quite disheartening. to be offered a answer for years of illness, and mental confusion. then see such a confused state of detections.However much faith i have in the WPI, something just doesnt feel right. but i dont know what it is. when will a decent study find it ?
 

Cort

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The problem was explained to me as follows......All these groups are taking their hits at XMRV...most of them are a) using the same primers as the WPI study; that is - they are looking for the same general sequences plus they are broadening their search and including new sequences. (The WPI looked at just few sequences).

PCR - And they are focused on PCR; PCR is so powerful now that the research community seems unlikely to accept that that is not the right tool for XMRV. I was told they would have accepted that if the WPI had not found XMRV using PCR in the original study...if they had only found it using culture, for instance - they would have focused on culture - but PCR was the first finding in the paper. That was what the headlines were about - that was what got the researchers attention. PCR is what researchers use all over the world to search for viruses now.

The major differences occur in the reagents they use, the test tubes they use, the different types of storage - these are the things that have been really variable in the studies.

The problem with all these negative studies is as they take more and more approaches there are fewer and fewer options for XMRV. It seems like for XMRV to work it out it more and more has to have this special combination of factors.....which is not true for viruses in general. They don't require unique and special combinations of these various variables. The techniques researchers are using generally work for all viruses.

This is like a cascading effect - the more the negative studies pile up and the more things people try that don't work - it gets harder and harder to see how XMRV will work out - even if they never replicate the study.

I was told, however, that studies are coming out in which investigators are using the same reagents, test tubes as the original study -so we'll see true replications down, apparently, to the smallest details....
 

Esther12

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I really wish that 18 months ago some central organisation had sent the WPI blinded samples from 50 healthy controls, and 50 patients previously identified as XMRV+. Blood collected in exactly the same way, using whatever protocol the WPI wanted.

I can't believe it's been so long and we still don't know what's going on. I'm feeling more negative since the dubious BWG results. The lack of more positive news does make it seem less likely that XMRV is highly correlated with CFS. It didn't take the WPI this long to find it, and they were a small new lab just starting up.
 

Navid

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was told, however, that studies are coming out in which investigators are using the same reagents, test tubes as the original study -so we'll see true replications down, apparently, to the smallest details...


Did they mention if these true replications resulted in positives? hope so. this whole process is taking W AAAAAAA Y too long.

thanks.
 

Cort

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was told, however, that studies are coming out in which investigators are using the same reagents, test tubes as the original study -so we'll see true replications down, apparently, to the smallest details...

Did they mention if these true replications resulted in positives? hope so. this whole process is taking W AAAAAAA Y too long.

thanks.
Don't know the actual results...
 

free at last

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The pcr question is something that seems odd isnt it Cort, though we do know the WPI said sometimes multiple testting at different times of the day was needed to detect xmrv via pcr, somthing i doubt many studys are doing.

The monkey studys really did show a potentiall problem with pcr detection, as the virus appeared to be cleared from the blood shortly after infection, only to reapear after activation by the group. Do we assume the multiple times testing of the wpi, overcame this problem by slowly getting detections over time, again something most other ( or all ) studys will not be doing ?

The German xmrv study again showed something is clearly wrong either with the pcr method in bloodwork ? or something else, because after zero detections in blood via pcr, they then find it saliva via pcr. ( though its notable the cohort was defiantly immune compromised ) Possibly showing cohorts are actually crucial. proving eiither the method is flawed in some way ( note the pcr machine problem mentioned by i think Hanson ) and or possibly the the other potentiall pitfulls you mention. freezing the blood more than once is another possible big one isnt it. and the cohort quality indicater of the german contradiction studys ?

its a shame that data isnt being made available by these studys, the way the BWG has asked to clarify what the heck is going on with all this. of course in time we probably will get answers, as more studys doing serology and culture will be forthcoming. what those answers will be is anyones guess, but something is clearly wrong, and unless we figure out what it is, more of the same is likely to happen, thats something that is becoming painfully obviouse by now.

The science study. and uk study. just seems so compelling its hard to see how they are not really making xmrv detections. some of the cancer studys too ? especially sings gleason score correlation with xmrv detection. seems unlikely contamination would correlate with a gleason score ? very weird.

BTW where has sing gone, its like shes dropped of the science map, anyone know whats happening with her ? wondering if anyone could contact her, and ask if anything could be shared about her published studys actually seeing the light of day.

I do wonder whats going to happen if xmrv somehow falls as we go further down the road. how and what is going to be the WPIs response ? I stll think the monkey and german studys are giving us a clue Cort. I just cant seem to neatly figure out what it could be. Someone needs to prove xmrv intergration, and isolate the virus, so we can at least move on and figure whats going wrong with the detections, seems unlikey its geographic as the wpi had good success, after the second british study ( forget mclures cohort ) the Kerr study faild to find it.

Though ive noted before. although the anti body test seemed cross reactive, in the second kerr study. there was ( 4 i think ? ) that seemed to show a xmrv specific anti body response. which if true makes everything even more confusing then it already is. as they may infact have actually detected It ?

Only ME/CFS would have these problems, after its checkerd history and difficulty in finding a answer. Aint we the lucky ones. It seems ME/CFS doesnt want to give up its vague status just yet. when will that day come ?

I wonder if many of us will see the day before the illness takes us. I have so many health issues likely related to this disease, that i never really know whats going to happen next. like joint pains seem to be getting worse on my left side only, my right shoulder is now getting difficult to put my arm over things. and my left hip joints are doing the same funny how its just the left side ( as of yet ) my kneck is also getting slowly worse with stiff pain almost every morning taking hours to relax. and sometimes not at all. unexplained headachs ( often head pains not headachs ) that are occassionally connected to the kneck problem. muscle problems. vision problems. and the intermittent poisend symptoms that come and go like the wind. not sure how many more years ive got before these symptoms cripple me ? I want a answer. its just so unfair for all of us, to go round and round, like hamsters on a wheel. you see what we are doing Cort. its because science has for the most part failed us, turning us all into hamsters with a wheel agenda. Or are we slowly turning into mice with the extra Genes. Think someone should look for retro viruses in hamsters. as we surely are turning into them. Better to be a hamster i guess. than in the dark. at least this hamster, has more light than he did. ( or do i ? ) Rant over, Hope my points give food for thought. What food you may ask, erm what do hamsters eat ?
 
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Erm, these are fibromyalgia patients, are they not?

Next big news, XMRV has NOT been found in a group of diabetics. That's another negative study for CFS! Or not.
 

free at last

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Erm, these are fibromyalgia patients, are they not?

Next big news, XMRV has NOT been found in a group of diabetics. That's another negative study for CFS! Or not.
True Angela but two points, 1 whats happened to the 3.7% healthy controls infected ? and two Judy Mikovits has suspected many diseases could be xmrv linked, and this was one of them. Didnt know about the diabetes study. again no 4% of healthy infected people ?
 
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Why Isn't Anybody Taking Tissue Samples and Looking for XMRV

The monkey studys really did show a potentiall problem with pcr detection, as the virus appeared to be cleared from the blood shortly after infection, only to reapear after activation by the group. Do we assume the multiple times testing of the wpi, overcame this problem by slowly getting detections over time, again something most other ( or all ) studys will not be doing ?"

I think I remember from reading the monkey study they said they also "stressed" the monkeys and the virus reappeared in the blood. So if the virus comes back after reactivation or stress, could it be that a human would have to have significant stress in their lives or be sick with something else in order for the virus to re-enter the blood stream? Maybe this is the PCR problem with the studies .

What about those tissue resevoirs? Why isn't anybody taking tissue from XMRV positive patients and testing for the virus in the tissue (i.e. the bladder, uterus, ovaries, prostate, etc.) ? If it dissappears from the blood it has to be hiding somewhere. Perhaps it is like HPV and localized somewhere else in the body. I e-mailed the WPI today and asked them this question. I know they are busy and probably won't have time to get back to me. Has anyone heard of any studies where they are taking biopsies or tissue from XMRV positive patients and trying to detect XMRV?
 

eric_s

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I think this might be the Madrid group that has so far never been able to find XMRV. Nevertheless, for me too, with each negative study it gets harder and harder to think of an explanation why this might be happening.
But then i think that the WPI and Alter/Lo have been working on this for so long now and we haven't heard them say "Oops, sorry, we've made a mistake". So how could it be possible for them to create false positives over and over again at similar rates (i guess) without noticing the mistake? This seems as hard to explain as the discrepancy in results.
I'm looking forward to the webcast by Alter and Lo and other upcoming events like the workshop. But i agree with Esther, how can it be that the question has not been cleared after so long, when there would be a more or less easy way to achieve that? BWG phase III will do that, though.

Whatever happens we will have to fight to get to a solution and i'm convinced we can make it, if we put all we have (i'm not thinking of money exclusively here, not at all) in it. We will have to force it, one way or the other. You can't stop a million of people.
 

Sushi

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What about those tissue resevoirs? Why isn't anybody taking tissue from XMRV positive patients and testing for the virus in the tissue (i.e. the bladder, uterus, ovaries, prostate, etc.) ?
Hi Mya,

KDM is doing biopsies of the stomach looking for (and finding) XMRV there. He is doing this both on patients who have tested negative by culture and serology and also on some that have tested positive. While this isn't part of a study, he may be gathering data for a future study.

Sushi
 

asleep

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...most of them are a) using the same primers as the WPI study
Can you provide evidence that "most" groups used the same primers?

And even if some or most groups did, my understanding of PCR (as a non-scientist) is that there are many more factors involved than just primers. PCR is a complex chemical reaction and any number of variables can throw it off. Therefore, any PCR attempt must be empirically validated against know clinical positives, which is a step that none of the negative studies have done. And that is to say nothing of potential cohort, collection, storage, processing, tissue reservoir, replication cycle, etc issues.

PCR - And they are focused on PCR; PCR is so powerful now that the research community seems unlikely to accept that that is not the right tool for XMRV. I was told they would have accepted that if the WPI had not found XMRV using PCR in the original study...if they had only found it using culture, for instance - they would have focused on culture - but PCR was the first finding in the paper. That was what the headlines were about - that was what got the researchers attention. PCR is what researchers use all over the world to search for viruses now.
What matters is not how "powerful" a tool is, but how you use it. Humans have invented very powerful telescopes, but I can assure you that if they are pointed at the ground very little information about the cosmos will be obtained.

Regarding the WPI finding XMRV using PCR, you will recall that Mikovits was only able to find it in a small percentage of samples from a very tightly defined cohort and after testing them multiple times. The sum of these negative studies amount to very little beyond a lesson on how difficult it is to find XMRV using PCR. Remember, absence of evidence is not evidence of absence. Furthermore, this scientific truth is not conditional on the number of times you fail to find something: absence of evidence x 100000 is still not evidence of absence.

Also, the idea that PCR was central to either the findings or the publicity of the Science paper is pure fantasy.

The problem with all these negative studies is as they take more and more approaches there are fewer and fewer options for XMRV. It seems like for XMRV to work it out it more and more has to have this special combination of factors.....which is not true for viruses in general. They don't require unique and special combinations of these various variables. The techniques researchers are using generally work for all viruses.
But not all approaches are equal, especially if they are fundamentally inadequate or not performed correctly. You seem very fixated on what "generally" works for finding known viruses without any consideration for the possibility that we may be in the midst of discovering the limits of currently favored technology.

This is like a cascading effect - the more the negative studies pile up and the more things people try that don't work - it gets harder and harder to see how XMRV will work out - even if they never replicate the study.
This is an alarming and profoundly unscientific statement. You cannot bypass replication and declare something dis-proven by accumulating failures of different methods. To suggest otherwise is wholly misleading and logically unsound. The fact that you suggest and condone this idea is shocking. To me, this is nothing short of a public admission that you desire XMRV association to be decided politically instead of scientifically.
 

asleep

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Before being too disheartened by each new negative PCR study, I urge everyone to ponder these two questions:

  1. Why, after 15+ months, have we had 10+ negative PCR studies but not one single replication attempt?
  2. Why are people (e.g. Cort) obscuring the science by suggesting that, in aggregate, these negative studies prove something that is far from scientifically tenable?

Something very strange is going on in our hallowed halls of scientific inquiry. We are being presented with an illusion of science and being sold the idea that it is the real deal. Don't buy!

Until a true replication study is conducted, no number of negative PCR studies can disprove XMRV association. This is the only thing to remember here.
 

August59

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Why are all the negative studies getting published, but not a damn one that has any positive tone to it can get close to publication. I know we always hear soon and we have been hearing soon for a year.

There is a very strong peer bias scaring publishers away evidently. As usual science gets squashed due to politics. They can do all the studies they want but it doesn't do any good because if it is negative it gets published and if it's positive put it in the drawer.

If they published 10 positive studies today, 8 of them should have been published a year ago. These studies surely could have steered treatments that could have slowed down the needless and continuing suffering to very sick human beings.

XMRV will have to dig out of a very, very deep avalanche before it will even get a chance to breath. The whole thing is an injustice!
 

Esther12

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Perhaps positive researchers like the WPI hadn't realised how concerned journals would be about the possibility of contamination following these negative studies? These studies will have made editors more sceptical of positive studies, and insistent upon more stringent controls. Maybe the controls used for the WPI's work is not now enough to satisfy these new standards, so they're struggling to get published in prestigous journals?
 

asleep

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Perhaps positive researchers like the WPI hadn't realised how concerned journals would be about the possibility of contamination following these negative studies? These studies will have made editors more sceptical of positive studies, and insistent upon more stringent controls. Maybe the controls used for the WPI's work is not now enough to satisfy these new standards, so they're struggling to get published in prestigous journals?
To be honest, I don't think this reason can come close to legitimately explaining the publication impasse on positive studies.

It is very easy to rule out contamination: ensure that all case and control specimens are collected in the same manner and fully blinded before any processing and testing. If, under such conditions, the same positivity rates hold (~4% controls vs ~80%+ cases), then contamination is probabilistically ruled out.

Furthermore, if extreme caution on the part of journals were fully to blame, why have all of these negative studies been published without a single one of them showing that their assays can detect XMRV in a known clinical sample? Selective caution is just a re-branding of bias.