Putting it all together?

[Marco]

I've been following a few threads over past weeks and trying to get up to speed with the sheer range of information and to try and tie all this stuff together. Sometimes its hard to see the wood for the trees. This includes (off the top of my head and obviously not exhaustive) :

1.The range of symptoms that we all know and love. No need to repeat them.

2.Many findings over the years of organic disease process(es) including : evidence of various specific infections, immune system dysregulation and/or damage; low blood volume, orthostatic hypotension, brain hypoperfusion, lesions, loss of grey matter, mitochondrial disorders, leaky gut etc. Various contributory factors have been proposed including viruses, bacteria, physical or psychological stress, environmental toxins, vaccines etc. None of these findings have fully explained the illness and none have been universally accepted.

3.Working back from 1 and 2 above, some researchers have tried to speculate on what pathogen could lead to the observed findings and have suggested that either a retrovirus or enterovirus might fit.

4.Dr Kerr's gene expression studies, which show some 80 plus genes either up or down regulated in ME patients compared to controls, suggesting an identifiable acquired ME genotype. The functions of most of these genes are identified and appear a close fit with the observed symptoms and disease processes : Genomic analysis revealed some common (neurological, haematological, cancer) and some distinct (metabolic, endocrine,cardiovascular, immunological, inflammatory) disease associations among the subtypes. Dr Kerr also states : It is intriguing that within our 88 gene signature, there are several genes with links to various aetiological triggering factors. For example, virus infection (EIF4G1, EBI2) and organophosphate exposure.

5.The WPI findings suggesting that 67% (or 95% unpublished) of a well specified ME cohort tested positive for the XMRV retrovirus. Three European studies have failed to find XMRV in either CFS patients or controls leading to much debate on cohorts, methodology, the original WPI findings and even the nature of the virus itself which appears to be 'hard to find'.

6.The recent virologists' findings that when monkeys were infected with XMRV, the virus didn't appear in the blood but was largely limited to CD4+ T cells in lymphoid organs -- spleen, lymph nodes, and GI tract -- as well as in reproductive organs, including prostate, testes, ovaries, vagina, and cervix. Despite the infection the animals 'appeared not to be' ill. Again the locations where the virus clusters appears consistent with the symptoms and findings of organic disease.


While these are different approaches I don't see much evidence of incompatibility between them and indeed a lot of scope for a synthesis.

The monkey studies and the European studies suggest that XMRV may be hard to detect, even in infected patients and that biopsy material may be more useful. There are obviously logistical and ethical issues with using biopsy material.

One indirect route might be if Dr Kerr were to run his microassay tests on samples from the infected monkeys to see if the same gene expression patterns were seen. If positive, it would tie XMRV (or any other suggested pathogen) nicely to gene expression and the symptoms of ME. A negative result might suggest that there is no XMRV connection, or that something else is needed to make us and the monkeys ill.

As for the negative XMRV findings, the ability to select between the infected monkey samples and controls might help determine if their methodology can detect XMRV or if the problem lies with cohorts or the absence or presence of XMRV in Europe.

 

[Gerwyn]

I've been following a few threads over past weeks and trying to get up to speed with the sheer range of information and to try and tie all this stuff together. Sometimes its hard to see the wood for the trees. This includes (off the top of my head and obviously not exhaustive) :

1.The range of symptoms that we all know and love. No need to repeat them.

2.Many findings over the years of organic disease process(es) including : evidence of various specific infections, immune system dysregulation and/or damage; low blood volume, orthostatic hypotension, brain hypoperfusion, lesions, loss of grey matter, mitochondrial disorders, leaky gut etc. Various contributory factors have been proposed including viruses, bacteria, physical or psychological stress, environmental toxins, vaccines etc. None of these findings have fully explained the illness and none have been universally accepted.

3.Working back from 1 and 2 above, some researchers have tried to speculate on what pathogen could lead to the observed findings and have suggested that either a retrovirus or enterovirus might fit.

4.Dr Kerr's gene expression studies, which show some 80 plus genes either up or down regulated in ME patients compared to controls, suggesting an identifiable acquired ME genotype. The functions of most of these genes are identified and appear a close fit with the observed symptoms and disease processes : “Genomic analysis revealed some common (neurological, haematological, cancer) and some distinct (metabolic, endocrine,cardiovascular, immunological, inflammatory) disease associations among the subtypes”. Dr Kerr also states : “It is intriguing that within our 88 gene signature, there are several genes with links to various aetiological triggering factors. For example, virus infection (EIF4G1, EBI2) and organophosphate exposure”.

5.The WPI findings suggesting that 67% (or 95% unpublished) of a well specified ME cohort tested positive for the XMRV retrovirus. Three European studies have failed to find XMRV in either CFS patients or controls leading to much debate on cohorts, methodology, the original WPI findings and even the nature of the virus itself which appears to be 'hard to find'.

6.The recent virologists' findings that when monkeys were infected with XMRV, the virus didn't appear in the blood but was “largely limited to CD4+ T cells in lymphoid organs -- spleen, lymph nodes, and GI tract -- as well as in reproductive organs, including prostate, testes, ovaries, vagina, and cervix”. Despite the infection the animals 'appeared not to be' ill. Again the locations where the virus clusters appears consistent with the symptoms and findings of organic disease.


While these are different approaches I don't see much evidence of incompatibility between them and indeed a lot of scope for a synthesis.

The monkey studies and the European studies suggest that XMRV may be hard to detect, even in infected patients and that biopsy material may be more useful. There are obviously logistical and ethical issues with using biopsy material.

One indirect route might be if Dr Kerr were to run his microassay tests on samples from the infected monkeys to see if the same gene expression patterns were seen. If positive, it would tie XMRV (or any other suggested pathogen) nicely to gene expression and the symptoms of ME. A negative result might suggest that there is no XMRV connection, or that something else is needed to make us and the monkeys ill.

As for the negative XMRV findings, the ability to select between the infected monkey samples and controls might help determine if their methodology can detect XMRV or if the problem lies with cohorts or the absence or presence of XMRV in Europe.

very good idea

 

[Gemini]

Excellent idea, Marco. Paper #150 of the monkey studies noted "a wide dissemination of replicating virus even when the plasma viral load was undetectable."

 

[usedtobeperkytina]

That is why Mikovitz is saying "It makes sense. It explains everything."

I agree. If underlying viruses are reactivated at higher rate than healthy people, depending on what virus you have, throw in candida, then it has to be immune system. Ok, see immune system problems. Track back from there and you either have retrovirus attacking immune system cells or you have genetic weakness in immune system or CNS controlling it. That's one of three.

I have had vasovagal hypotension since I was five. When I was in young 30s, I had a fainting episode that led to seizure, after not having an episode since I was 18. I thought I should go get it checked out again to see if advances in scientific knowledge might could lead to medicine or better understanding of it. I went to neurologist. She said, "You don't have epilepsy." My response. "Ok, so why do I faint?" Her explanation: "Some people faint and some don't. Given enough pressure, everyone will faint. Your threshold is just lower." I am a news reporter. That wasn't good enough. "But what causes it?" Her answer, "We don't know." And then I asked, "Then why is it when I faint, I have seizures?" Her answer was, "Some who faint have seizures and some don't. We don't know."

Well, I went straight to library (pre-Internet days) and I learned about the HPA axis and communication with vagal nerves and vessels. And they don't know where the failure is in the system..

I knew then that it is likely a problem in my hypothalamus. Why? Because I have had acne problems continuously since I was 13. The hypothalamus (and pituitary) is involved in controlling sex hormones and the blood pressure.

You have to track things back up stream. If A is true, then what can cause A? And as they have done that with each abnormality, they are getting closer and closer to the cause. I predicted last year that within two years there would be a big announcement related to CFS.

Then, when 39, I got the virus that came and went for a year, with gradual CFS symptoms developing after it. And the CFS symptoms also relate to hypothalamus. Now, I am not saying cause is in hypothalamus. The hypothalamus also responds to signals from the body. But just keep following the water up stream and you will find the source.

Tina

 

[Anika]

You've pulled things together well, I think, Marco. Thanks.

Retroviral involvement has made sense for a long time as an elegant solution to the diverse symptoms, along with other infections that can affect the neuroimmune status.

I think transmission and host susceptibility and co-factors are big questions no matter what type of infectious agents are in play. Transmission, we've got outbreaks and sporadic, some familial but many or most not obviously so. Clearly not direct sexual transmission in many / most.

XMRV is interesting no matter what the level of involvement in CFS turns out to be - and I think it appears promising. With the advances in other areas like genomics, research into this area could take the understanding of many illnesses into a new dimension. The learning that was achieved with HIV / AIDS is invaluable but will have to be adapted. Great fun for retrovirologists! XMRV may take science to a new level.

I think it's also vitally important to keep the other research around CFS moving forward. Even if they can associate viral involvement such as XMRV with CFS, we will still need a good understanding of the effects and how they relate to symptoms and illness, and how thoroughly treatments can address those.

The macaque studies from the Retrovirus Conference were fascinating. Apart from the major trends in lymphatic and reproductive organs, there was some infection found in the brain stem and heart of the sole female (1 of the 5 total, and 1 of 3 tested for chronic infection), and the 2 chronically infected males (but not the female) showed some kidney involvement. One of 2 acutely infected males (and none of the 3 chronic total) showed an effect in bone marrow.

Admittedly, these are small samples. But understanding the differences, as well as the similarities, in their response to infection, is where medical research is trying to go.

 

[usedtobeperkytina]

You guys did see this, right: http://forums.aboutmecfs.org/showthread.php?3381-Positive-Studies

Tina

 

[Anika]

You guys did see this, right: http://forums.aboutmecfs.org/showthread.php?3381-Positive-Studies

Tina

Tina, I hadn't seen it before, but you make good points. I think the negative studies show what they show - and they do not "refute."

 

[natasa778]

The macaque studies from the Retrovirus Conference were fascinating. Apart from the major trends in lymphatic and reproductive organs, there was some infection found in the brain stem and heart of the sole female (1 of the 5 total, and 1 of 3 tested for chronic infection), and the 2 chronically infected males (but not the female) showed some kidney involvement. One of 2 acutely infected males (and none of the 3 chronic total) showed an effect in bone marrow.

Did they say how old the monkeys were when infected? Were they infant or adult monkeys?

 

[Anika]

Did they say how old the monkeys were when infected? Were they infant or adult monkeys?

I'd strongly recommend looking at the videos of the two talks. I printed out for myself one of the slides that showed locations of infected cells. I don't have the link to the talk handy.

Somewhere in those two talks and slides, the ages were shown - I think they ranged from somewhere in 4 -5 year range, to one around 20 - I don't know that much about science, but I think these would all be adults.

If you or others have some knowledge on these types of studies, it would be great to get your insights.

 

[Marco]

Many thanks for the responses.

While trying to 'put it all together', for my own benefit, I was also thinking of how to get out of this impasse between the psych and organic lobby and the positive and negative XMRV studies. I've been getting the feeling that these 'debates' could run on and on with no consensus being reached and ergo no cure!

I was very impressed with Kerr's gene expression work. Not too impressed with the sub-types idea but he appears to have identified a unique genetic marker that distinguished ME from healthy controls, those with depression and those with anxiety. At a stroke this cuts through any debates about ME being secondary to depression, vague diagnostic criteria, subjective reporting of symptoms etc. Plus I suspect that gene expression is pretty immune to laziness or illness beliefs.

Likewise, the macaque (apologies to them for calling them monkeys - I couldn't recall the species) studies cut through any methodological issues leading to false negatives or positives. We know the macaques have XMRV because they were infected with it and it was found in tissues during autopsy.

These two pieces of information are very powerful if used properly, potentially in conjunction.

 

[Gemini]

I agree, Marco. Kerr should go back and test CFS/ME patients from his genetic study for XMRV, and future XMRV animal studies should include genetic testing.

 

[ukxmrv]

It is possible that Kerr was testing the same patients as his gene expression studies. The patients provided by Kerr for the XMRV paper came from a set of hospitals and these hospitals are some of the same referred to in his gene expression paper. Banked samples was used and there is no reason why these could not have been banked for the gene expression paper. Just an idea.

 

[usedtobeperkytina]

I made my post about the positive findings related to XMRV because, with all the so-called "It isn't in CFS patients" studies, I wondered if researchers would still be interested. And then I thought of what has been discovered / proved. Much of that would still create researcher curiosity. So, XMRV study is not dead, even if researchers believed it wasn't linked to CFS, as purported by the European studies. XMRV is still exciting and cutting edge. Lots still to learn. It is there, it is infectious in humans and some properties have been proved.

So there is a lot to keep the research going.

Tina

 

[HopingSince88]

It seems to me that if a new study is done with macaques that they should be mostly female, and pre-pubescent; with the study extending through to adulthood to see what develops. This would better reflect the CFS population in terms of gender, and will test one of the triggers that we have seen here, the onset of puberty.

 

[usedtobeperkytina]

Also, infect the poor animals, some pre-pubescent and some after. Then watch them over time, testing them. Give them some body stressors. For example, inject them with other viruses, one at a time. Put them under emotional / circumstantial stress. Two different groups. Then have another group they do both other viruses and circumstantial stressors. See if they start showing CFS symptoms or any biological abnormalities. Of course, this would be very expensive, caring for so many over so many years. (I guess five to ten, maybe?)

Tina

 

[subtr4ct]

Just how much do macaques cost?

Also, infect the poor animals, some pre-pubescent and some after. Then watch them over time, testing them. Give them some body stressors. For example, inject them with other viruses, one at a time. Put them under emotional / circumstantial stress. Two different groups. Then have another group they do both other viruses and circumstantial stressors. See if they start showing CFS symptoms or any biological abnormalities. Of course, this would be very expensive, caring for so many over so many years. (I guess five to ten, maybe?)

In addition to introducing other viruses, try artificially boosting things that promote XMRV replication in vitro: androgens, hydrocortisone, etc. If CFS is XMRV + other stressors/circumstances, then maybe it would not take years to create CFS in macaques? If CFS is XMRV + genetic susceptibility, things would obviously be more tricky. It seems, however, that this type of direct experimentation could possibly rapidly sort out causality regarding XMRV and CFS, bypassing all of the messy details of causal inference using observational data (XMRV detection methods; sample collection and storage; HERV confounders; blood versus tissue; replicating vs. not; cohort issues).