• Welcome to Phoenix Rising!

    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

    To become a member, simply click the Register button at the top right.

A biomarker in low NK cell activity...

Jonathan Edwards

"Gibberish"
Messages
5,256
I can't remember where I saw the figure, but the publication of null findings in this field is notably higher than other fields.

Most of the publication bias in this field arises from singular positive studies with no attempted replication, or replication studies that failed and were not finished (and therefore not published).

If the effect size is not strong (As I mentioned due to the lack of sensitivity/specificity vs CFS criteria) and such studies are underpowered, it is quite possible for there to be such studies even if there is a true effect.

But on this specific issue - three unpublished studies, it seems to me there is an opportunity for such researchers to combine these studies into one paper and do an additional meta-analysis on the NK activity findings in other papers along with analysis of publication bias, eg funnel plots and the like. Such a paper would no doubt be welcome in the newer open access journals committed to combating publication bias.

I think the reason why there is a higher rate of null findings in ME/CFS papers is that there is nothing to find in the places people are looking. Moreover, in other conditions where things have already been found people move away from areas where nothing much is to be found and focus on the areas where you are guaranteed to find something.

Very often what happens with clinical studies is not that they are not finished but that as the study progresses it becomes clear that some things are not showing much but others are - so you end up with a study that started out looking at one thing but publishes on something else without mentioning that the first thing showed nothing much.

I think you need to consider the motivation that is behind publication. It is almost entirely financial - wanting to get another grant, which increasingly means another pay packet for the author. Publishing negative replication of previous findings does not bring in grants. Moreover, it is quite likely to annoy the referees sitting on your grant boards - enough to ensure you are never invited to sit on the boards yourself. This is a dog eat dog life, I am afraid.

So in most research fields the accepted practice is not to publish non-replications but simply to ignore the area and move on to something that gives positive data. In ME/CFS research we have the problem that there are virtually no positive data at hand. So people do not necessarily move on. Yet there is no consensus on what has really been found. The only solution to this is to set up big collaborative confirmation studies that involve everyone (so nobody gets blamed for a negative result) with a predefined agenda. The motivation to publish is then the kudos of being part of a well organised programme with lots of famous names on it.

It is certainly true that small differences may be missed but the problem we have here is that those who are convinced of an NK cell function defect seem to suggest that more or less every ME/CFS patient has a very low level. It cannot be both ways. What worries me is that if low NK cell function is actually being used as a way to distinguish 'real ME' then we have a circular argument - patients with ME are bound to have low levels because that is how they are defined. WE need to make sure we are not falling into that trap.
 

heapsreal

iherb 10% discount code OPA989,
Messages
10,089
Location
australia (brisbane)
It is certainly true that small differences may be missed but the problem we have here is that those who are convinced of an NK cell function defect seem to suggest that more or less every ME/CFS patient has a very low level. It cannot be both ways. What worries me is that if low NK cell function is actually being used as a way to distinguish 'real ME' then we have a circular argument - patients with ME are bound to have low levels because that is how they are defined. WE need to make sure we are not falling into that trap.

No one is saying low nk function is an absolute to getting an mecfs diagnosis but it is a common finding which for some reason you have this, put your head in the sand attitude .

Using nk testing along with the CCC will help diagnose cfsme alot better than without. Especially when some drs compare cfs to how they had to wake up early to drive to the airport or something and call it ME1 or 2 or whatever. Shows great understanding, not. Relying on the average dr to make a diagnosis off symptoms alone on an illness they arent familiar is bound to have multiple misdiagnosis , which is probably happening. The more biomarkers the better the chance of avoiding misdiagnosis.

For some reason you prefer to ignore all the previous research showing cfsme having a high prevalence of low nk function, even though these drs/researchers are far more experienced in this field than yourself with decades of actually treating and testing thousands of cfsme patients. Maybe like many drs that dont get it or dont understand , your dismissive attitude seems very similar to the way Simon wessely dismisses nk testing. Probably because it doesn't fit his theory either.

Maybe you could benefit by reading the research done by klimas, peterson and sonya marshall and when you dont understand you could try to email them to clarify what it is you dont understand . Greys anatomy has a section on what natural killer cells do. They seem rather important .
 

Jonathan Edwards

"Gibberish"
Messages
5,256
How would low NK function help make a diagnosis of ME if, as the IOM report says: It is present as well in healthy individuals who are older, smokers, psychologically stressed, depressed, physically deconditioned, or sleep deprived.

You do not seem to see, heapsreal, that you are advocating precisely the circular argument I was wary of - you use low NK function to diagnose ME and then find hey presto that people with ME have low NK function. I presume Dr Marshall Gradisnik does not use low NK function to diagnose ME. If she had then showing that her patients had low NK function would be self-fulfilling.

If I was dismissive of NK studies why would I be involved in a large collaborative effort to replicate them?

I appreciate that it is reasonable to query other people's expertise but it is unhelpful to completely misinterpret their position. The original query was why NK cell function was not getting more attention. I have given what I think are the likely reasons having met with and talked to many of the researchers you quote.
 

lansbergen

Senior Member
Messages
2,512
cbi.nlm.nih.gov/pmc/articles/PMC3280992/

In most transmissible spongiform encephalopathies prions accumulate in the lymphoreticular system (LRS) long before they are detectable in the central nervous system. While a considerable body of evidence showed that B lymphocytes and follicular dendritic cells play a major role in prion colonization of lymphoid organs, the contribution of various other cell types, including antigen-presenting cells, to the accumulation and the spread of prions in the LRS are not well understood. A comprehensive study to compare prion titers of candidate cell types has not been performed to date, mainly due to limitations in the scope of animal bioassays where prohibitively large numbers of mice would be required to obtain sufficiently accurate data. By taking advantage of quantitative in vitro prion determination and magnetic-activated cell sorting, we studied the kinetics of prion accumulation in various splenic cell types at early stages of prion infection. Robust estimates for infectious titers were obtained by statistical modelling using a generalized linear model. Whilst prions were detectable in B and T lymphocytes and in antigen-presenting cells like dendritic cells and macrophages, highest infectious titers were determined in two cell types that have previously not been associated with prion pathogenesis, plasmacytoid dendritic (pDC) and natural killer (NK) cells. At 30 days after infection, NK cells were more than twice, and pDCs about seven-fold, as infectious as lymphocytes respectively. This result was unexpected since, in accordance to previous reports prion protein, an obligate requirement for prion replication, was undetectable in pDCs. This underscores the importance of prion sequestration and dissemination by antigen-presenting cells which are among the first cells of the immune system to encounter pathogens. We furthermore report the first evidence for a release of prions from lymphocytes and DCs of scrapie-infected mice ex vivo, a process that is associated with a release of exosome-like membrane vesicles.
 

heapsreal

iherb 10% discount code OPA989,
Messages
10,089
Location
australia (brisbane)
How would low NK function help make a diagnosis of ME if, as the IOM report says: It is present as well in healthy individuals who are older, smokers, psychologically stressed, depressed, physically deconditioned, or sleep deprived.

You do not seem to see, heapsreal, that you are advocating precisely the circular argument I was wary of - you use low NK function to diagnose ME and then find hey presto that people with ME have low NK function. I presume Dr Marshall Gradisnik does not use low NK function to diagnose ME. If she had then showing that her patients had low NK function would be self-fulfilling.

If I was dismissive of NK studies why would I be involved in a large collaborative effort to replicate them?

I appreciate that it is reasonable to query other people's expertise but it is unhelpful to completely misinterpret their position. The original query was why NK cell function was not getting more attention. I have given what I think are the likely reasons having met with and talked to many of the researchers you quote.


Yours is the circular argument .

Most biomarkers arent 100% accurate and require other symptoms and other tests to make a diagnosis , so i dont understand your point.

I didnt say Dr Sonya Marshall uses nk function to diagnose cfsme. At no time have i said anything about it being sole factor in a diagnosis but used in combination with the CCC and other potential biomarkers or 2 day exercise test . Even some research showing low cd8 t cell function.

Why isnt more attention not given to natural killer cells? Like everything in cfsme, lack of funding just like any other test, treatment etc for cfsme. Psychobabblers dont want a physiological biomarker as it goes against their illness beliefs theory and they have been trying to keep a lid on physiological abnormalities in cfsme to protect their own agenda. You should be asking why do dr klimas, dr peterson , kdm and other good cfs doctors use this test when they can.

Read your first paragraph , why would you bother being involved in nk testing then when u say its found in smokers , sleep deprived, stressed and dont seem to place much importance on it ? All those groups that have an increased risk of cancer and other co-morbities, oh maybe its poor nk function ? ???? Have they studied nk bright cell function in many other illnesses??

I just dont get it. You say your involved in an nk study but yet have said many times before that you dont think they are of importance ????
 
Messages
15,786
@Jonathan Edwards - I don't think people's concern about deliberate null results can be summarily dismissed. I've definitely seen at least a couple biomedical papers from the psychobabblers which were shockingly under-powered, yet confidently proclaimed that their results proved there was no correlation. There were some measurements with pretty big differences - just not enough patients to show statistical significance for pretty much any result.

A low-dose hydrocortisone trial did show statistically significant improvement in CFS patients, despite the small number of patients. The authors still concluded that it should never be used in patients, though didn't seem to have much basis for that conclusion, nor any interest in followup studies. In one meta-review of treatment trials, one or more authors of that trial even managed to trash it as being unreliable due to being poorly conducted.

Of course, that doesn't mean that the trial(s) being discussed in this thread are similarly self-sabotaged. But it certainly would not be unheard of in CFS research.
 
Last edited:

A.B.

Senior Member
Messages
3,780
When Lipkin and Horning published their cytokine immune signature study last year, White published a review on cytokines in CFS shortly afterwards.

Chronic fatigue syndrome and circulating cytokines: A systematic review.

I found this suspicious for the following reasons:

- Timing: it looked like a response to Lipkin's study.
- While it looked like a response to Lipkin's study, it ignored the main finding that cytokine abnormalities only become apparent if patients are divided into short and long term groups.
- The authors are all psychiatrists, except one immunologist from Barts (which is where White works). Why are psychiatrists suddenly interested in cytokines?

Of course it didn't come to the conclusions made by Lipkin. This looked like a deliberate effort to arrive at a result that is compatible with their psychogenic models of CFS.
 
Last edited:

Jonathan Edwards

"Gibberish"
Messages
5,256
@Jonathan Edwards - I don't think people's concern about deliberate null results can be summarily dismissed. I've definitely seen at least a couple biomedical papers from the psychobabblers which were shockingly under-powered, yet confidently proclaimed that their results proved there was no correlation. There were some measurements with pretty big differences - just not enough patients to show statistical significance for pretty much any result.

A low-dose hydrocortisone trial did show statistically significant improvement in CFS patients, despite the small number of patients. The authors still concluded that it should never be used in patients, though didn't seem to have much basis for that conclusion, nor any interest in followup studies. In one meta-review of treatment trials, one or more authors of that trial even managed to trash it as being unreliable due to being poorly conducted.

Of course, that doesn't mean that the trial(s) being discussed in this thread are similarly self-sabotaged. But it certainly would not be unheard of in CFS research.

Was anyone dismissing deliberate null results? I certainly did not mention anything from the psychiatry based teams. There may be underpowered results around but in this context of NK cell function it does not seem as if there are - at least not more than one or two. I am not sure where this fits in to the discussion. The experience with lymphocyte subsets across a number of groups has been that there really doesn't look to be anything much to find. And that looks to apply to a lot of other things - including cytokines. By and large there is not even a hint of a signal. And I don't think it can be a matter of subsets because there ought to be clearly non-Gaussian distributions if there are discrete subpopulations. The absence of scatter plots is a problem but where we have scatter plot data there do not seem to be obvious bimodalities.
 

jimells

Senior Member
Messages
2,009
Location
northern Maine
- The authors are all psychiatrists, except one immunologist from Barts (which is where White works). Why are psychiatrists suddenly interested in cytokines?

Why indeed. And why did UK psychiatrists start researching ME, a physiological illness, in the first place, at about the same time CDC decided to bury the illness?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
When Lipkin and Horning published their cytokine immune signature study last year, White published a review on cytokines in CFS shortly afterwards.

Chronic fatigue syndrome and circulating cytokines: A systematic review.

I found this suspicious for the following reasons:

- Timing: it looked like a response to Lipkin's study.
- While it looked like a response to Lipkin's study, it ignored the main finding that cytokine abnormalities only become apparent if patients are divided into short and long term groups.
- The authors are all psychiatrists, except one immunologist from Barts (which is where White works). Why are psychiatrists suddenly interested in cytokines?

Of course it didn't come to the conclusions made by Lipkin. This looked like a deliberate effort to arrive at a result that is compatible with their psychogenic models of CFS.

I think this interpretation must be wrong A.B. If it is the review that was presented in Bristol, which I think it must be, it was done before Hornig and Lipkin published. It seemed to be a literature review carried out by a young colleague, probably an early grade trainee and maybe not in psychiatry. The presentation in Bristol was very well done and I thought the review was very useful. If came to the right conclusion that up to that point most cytokines should not consistent difference. What was particularly interesting was that it picked up TGF beta as the one cytokine that did seem to come up consistently with a signal when it was looked at. It was presented as a positive observation, not just as a blanket negative.

I have no time for the PACE trial but that does not mean that this study is no good. Everything has to be looked at on its own merits. The psychiatrists have been interested in finding cytokine signatures for their diseases for a long time. I see nothing out of place here. Remember that their motto is biopsychosocial. Stress jiggers up cytokines. I see nothing particularly peculiar about this review appearing when it did.
 

funkyqueen

Senior Member
Messages
123
Location
South of France
My NK cell function done at OMI was 5 and six months later was 6. Have not tested it again and still not sure how it relates.

It was done at OMI via Quest Labs in July and then in Dec 2014. I do not remember the range but I will find out for you. ETA: My NK cell count was completely normal but NK cell functioning was very low and that is the number I am speaking about.

I was similar , normal numbers but low nk function as well as nk bright cell function . Bright cells is a further break down on nk cells into bright and dim cells.



My NK function was tested too at OMI, and was very low too ( 6 )




The study was done to look at developing a test or biomarker for cfsme. There was no indication about certain treatments or even trying to increase nk function . Most of the cfs gurus like klimas, peterson etc try to increase nk function.

What would be interesting would be if those cfs drs who test nk function , if they could show results of their patients who have improved with a variety of treatments and see how it correlates with nk function but also (...)

Im interested to see the rituximab research once its all done to see if they have done before and after nk function testing?

Peterson has had pts on ampligen improve and correlates with increase nk function.

?


+1 !
 

Strawberry

Senior Member
Messages
2,107
Location
Seattle, WA USA
My NK function was tested too at OMI, and was very low too ( 6 )

OMI also said my NK function is low, although I am at 8. The reference range for normal is 7-125, so 8 is very low in the normal range. I need to look into ampligen, and see if I could trial that.

EDIT: Eww, possibly not. I guess it is described as an immune system modulator. Isn't that what damaged @Gingergrrl ? Is ampligen similar to valcyte?
 

JollyRoger

Senior Member
Messages
138
I'm bedridden and unable to walk.
I used to speak five languages fluently and now I have problems to write simple sentences.

But my Nk cell function is 55.
If it would be the criteria for me/cfs I would be healthy.

@heapsreal
@Strawberry
Ampligen made an increase of 100% or to 100%??
Because 100% for you would be a nk cell function of 16.
Maybe a reason that ampligen would not be my wonder drug (if nk cell function is the reason for the remission in so many cases)
 
Last edited:

heapsreal

iherb 10% discount code OPA989,
Messages
10,089
Location
australia (brisbane)
I'm bedridden and unable to walk.
I used to speak five languages fluently and now I have problems to write simple sentences.

But my Nk cell function is 55.
If it would be the criteria for me/cfs I would be healthy.

@heapsreal
@Strawberry
Ampligen made an increase of 100% or to 100%??
Because 100% for you would be a nk cell function of 16.
Maybe a reason that ampligen would not be my wonder drug (if nk cell function is the reason for the remission in so many cases)

Different lab values from different labs so not always easy to compare. The nk research done in australia further divided nk cells into bright and dim cells. They found that nk bright cells are what they found more significantly abnormal in cfsme. So its possible your bright cell function could be very low. The other finding is that they found some with normal nk function had low cd8 t cells, not sure where else you could get these tested or the actual benefit for a diagnosis other than showing you had an abnormal immune system.
 

JollyRoger

Senior Member
Messages
138
Ebv igm negative
Ebv igg 98 ebna 110
Cmv Igm and igg negative
Herpes 1/2 igm negative and igg positive (ratio 3.99)
Lymphocytes 1.5x10^3
Neutrophils 2.16x10^3