Chronic fatigue syndrome and circulating cytokines: a systematic review

[SOC]

They did include the Hornig 2015 study but if I understand their table correctly they just extracted data for the whole group of 298 participants which, as we know, is very misleading since the cytokine pattern in that study changed over time.

Once again it appears that they cherry-picked and manipulated the data to get the pre-determined conclusion they want instead of looking at all the data in all its detail and drawing a conclusion based on the data itself. Either that or they are really bad at doing systematic review and/or reading and understanding the papers they are using in their review. No matter how I look at this, I can't find a way to see this as solid scientific research. At worst it's deliberately deceptive non-science. At best it's very sloppy poor science.

 

[JaimeS]

At worst it's deliberately deceptive non-science. At best it's very sloppy poor science.

There's so much of that going around. I was recently hired to write a CAP (critical analysis paper). In that case I genuinely believe that their hearts were in the right place, but their statistical analysis was significantly flawed (in a way even a statistics novice like me could spot/understand with minimal research) and for their qualitative analysis, they were only able to recruit 7 of their 100+ quantitative survey volunteers. They published anyway, and cited a flu outbreak at the time as to why they did not have more data.



-J

 

[sarah darwins]

@JaimeS — the superscript characters from the original site seem to have transmogrified themselves into extra letters after the names at the top of your first post (not that those guys will mind having more letters after their names).

Question for anyone who's managed to read the actual paper: when they say "There were no overall differences in cytokine concentrations after exercise" do they specify what they mean by "after exercise" (ie. how long after)? And how did Lipkin approach that? It feels sort of important, given the delay in onset of PEM in many patients.

 

[Cheshire]

Once again it appears that they cherry-picked and manipulated the data to get the pre-determined conclusion they want instead of looking at all the data in all its detail and drawing a conclusion based on the data itself.

Do they only know how to do otherwise?

That's what they've always done with psych studies: create a theory, then arrange the data so as to it looks to support the preconceived theory.

They have no idea of what science is, just know how to masquerade it and make something grossly look like science.

 

[Marco]

I would just add that TGF-β is often sky-high in CFS patients who've had it measured by certain "mold doctors" who have taken some heat here recently.

Chicken or egg though? Chronically activated microglia could make any mildly noxious stimulus a significant 'stressor'.

 

[Sidereal]

Chicken or egg though? Chronically activated microglia could make any mildly noxious stimulus a significant 'stressor'.

Exactly. I suspect it's just ME/CFS that happens to be particularly reactive to mold as an immune trigger and thus finds its way to a doctor who believes mold is causing the illness.

 

[Sidereal]

Question for anyone who's managed to read the actual paper: when they say "There were no overall differences in cytokine concentrations after exercise" do they specify what they mean by "after exercise" (ie. how long after)? And how did Lipkin approach that? It feels sort of important, given the delay in onset of PEM in many patients.

Lipkin didn't do an exercise study. Only a small number of studies in this review had an "after exercise" condition. I don't see any discussion of what exercise they did or when samples were collected after exercise.

 

[sarah darwins]

Thanks for the clarification re Lipkin.

Only a small number of studies in this review had an "after exercise" condition. I don't see any discussion of what exercise they did or when samples were collected after exercise.

Makes you wonder why it's a "highlight" of this systematic review, really.

 

[A.B.]

I assumed that the people involved would be psychiatrists and not people immunologists or other specialties who work with cytokines on a regular basis. The authors and their institutions:

S. Blundell and P.D. White: Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom.

K. K. Ray: East London Foundation NHS Trust, London, UK (Social and Community Psychiatry Unit).

M. Buckland: Barts Health Trust, London, UK.

Buckland is the odd one out at first glance, but I haven't been able to find more information about him, so he could still be involved in psychiatry.

So the question I have is whether it's normal for psychiatrists to do reviews on immunological stuff?

 

[Snow Leopard]

White may have inadvertently done us a favour in highlighting TGF-β

Agreed.

The only study (in the systematic review) finding no difference in TGF-β compared to controls worth worrying about is the Hornig study... (which also found that TGF-β was different between the short and long groups...)

Also, the increase in TGF-β was not found in cultured cells, suggesting it is not due to say, viral infection of those cells or SNPs.

TGF-β is interesting, for it is associated with abnormal (central) fatigue in an animal model:
http://www.ncbi.nlm.nih.gov/pubmed/10556630

There are also additional studies suggesting abnormal mRNA expression levels:
http://www.ncbi.nlm.nih.gov/pubmed/22118314

TGF-β is associated with increased fatty acid oxidation during exercise.

Also, more interesting to me I guess is the relationship between ROS and TGF-β activation, along with TGF-β being activated by CD-36 when complexed to TSP-1. CD-36 is a scavenger receptor that also plays a key role in fatty acid metabolism and if its function is altered in some way, then this provides a plausible hypothesis. CD-36 inhibition would also potentially explain the endothelial dysfunction hypothesised by Fluge & Mella.

There are some interesting feedback loops involved...
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072772
http://www.ncbi.nlm.nih.gov/pubmed/10625669
http://www.sciencedirect.com/science/article/pii/S0925443912001366
TGF-β and B cell regulation (both with and without T cells producing TGF-β)
http://www.jimmunol.org/content/180/12/8153.full

What I am particularly interested in is the ratios between the active and inactive isoforms and their relationship to CD-36 activity and gene expression (of CD-36 and TGF-β. Oh and TSP-1 for that matter).
I think this is something worth looking into @znahle @Jonathan Edwards @charles shepherd

It may also be interesting to watch any clinical trials of SB-431542 which is an inhibitor of TGFβR1 (and a few other tyrosine kinases) and whether it induces severe fatigue or not.

Lastly, in terms of specificity, the association with depression is unclear. In the three studies I have found so far, one found elevated TGF-β in patients with depression admitted to hospital, http://www.ncbi.nlm.nih.gov/pubmed/17433516
One found no differences before treatment, but TGF-β increased after treatment http://www.ncbi.nlm.nih.gov/pubmed/16782542/
One found lower TGF-β than controls. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248234/

TGF-β is also generally found to be decreased in MS patients (some evidence both CSF and blood).

 

[MeSci]

They did include the Hornig 2015 study but if I understand their table correctly they just extracted data for the whole group of 298 participants which, as we know, is very misleading since the cytokine pattern in that study changed over time.

Have you seen the full text then?

 

[Sidereal]

Have you seen the full text then?

Yep.

 

[sarah darwins]

M. Buckland: Barts Health Trust, London, UK.

Buckland is the odd one out at first glance, but I haven't been able to find more information about him, so he could still be involved in psychiatry.

He would seem to be an immunologist. I take it this is him:

https://uk.linkedin.com/pub/matthew-buckland/5/402/7b4

I am a Consultant Immunologist. My specialist interests are Behcet's (working within the London Centre for Excellence) and Primary Immunodeficiency (PID). I lead the UK registry for PID and am medical chair of the leading national patient support organisation PIDUK. My research is in the common themes of immune regulation in PID and Behcet's

 

[MeSci]

I assumed that the people involved would be psychiatrists and not people immunologists or other specialties who work with cytokines on a regular basis. The authors and their institutions:

S. Blundell and P.D. White: Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University of London, United Kingdom.

K. K. Ray: East London Foundation NHS Trust, London, UK (Social and Community Psychiatry Unit).

M. Buckland: Barts Health Trust, London, UK.

Buckland is the odd one out at first glance, but I haven't been able to find more information about him, so he could still be involved in psychiatry.

So the question I have is whether it's normal for psychiatrists to do reviews on immunological stuff?

A quick internet search for M Buckland Barts found this. So he's a consultant immunologist.

 

[MeSci]

He would seem to be an immunologist. I take it this is him:

https://uk.linkedin.com/pub/matthew-buckland/5/402/7b4

You just beat me to it!

 

[Scarecrow]

They did include the Hornig 2015 study but if I understand their table correctly they just extracted data for the whole group of 298 participants which, as we know, is very misleading since the cytokine pattern in that study changed over time.

I wasn't sure - I can't get through the paywall - but I thought it would be tight.

 

[Marco]

@Snow Leopard

Genetic variants in TGF-β expression are also associated with schizophrenia :

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824289/

and in susceptibility to chemotherapy induced fatigue :

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385032/

and a personal interest of mine - affecting sensory gating :

http://www.jneurosci.org/content/30/17/6025.full

 

[Snow Leopard]

@Snow Leopard

Genetic variants in TGF-β expression are also associated with schizophrenia :

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824289/

and in susceptibility to chemotherapy induced fatigue :

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385032/

and a personal interest of mine - affecting sensory gating :

http://www.jneurosci.org/content/30/17/6025.full

The association between chemo induced fatigue and TGF-β is interesting. They also found an inverse relationship between levels of TGF-β and reported fatigue, which suggests that the relationship isn't so simple (I don't believe the TGF-β is the mediating factor itself). The relevancy of the other papers is not clear. TGF-β is involved with a lot of things, but we need to know the specific patterns of expression and activity of TGF-β and its isoforms before we can make specific hypotheses.

 

[Marco]

The association between chemo induced fatigue and TGF-β is interesting. They also found an inverse relationship between levels of TGF-β and reported fatigue, which suggests that the relationship isn't so simple (I don't believe the TGF-β is the mediating factor itself). The relevancy of the other papers is not clear. TGF-β is involved with a lot of things, but we need to know the specific patterns of expression and activity of TGF-β and its isoforms before we can make specific hypotheses.

Agreed and it's a little hypocritical to accuse the review of cherry picking when we're cherry picking what we see as the interesting findings ourselves. Schizophrenia/sensory gating is relevant to me because I see the central problem as being one of disordered sensory processing.

At the very least the review does support the notion that any immune disruption is unlikely to involve what we traditionally consider as peripheral inflammation - it appears to be much more subtle than that with an important CNS contribution.

 

[snowathlete]

This review is a waste of time. It is flawed both its design and conception. It adds nothing of value toward figuring the disease out. So you have to question the motives of the authors. I try to read papers first, then look at who authored it; imagine my surprise...