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Cytokine responses to exercise and activity in patients with chronic fatigue syndrome: Case control

MeSci

ME/CFS since 1995; activity level 6?
Messages
8,231
Location
Cornwall, UK
Predictable...?

Date: August 5, 2017
URL: http://onlinelibrary.wiley.com/doi/10.1111/cei.13023/abstract

Cytokine responses to exercise and activity in patients with
chronic fatigue syndrome: Case control study
----------------------------------------------------------
L.V. Clark(1), M. Buckland(2,*), G. Murphy(2), N. Taylor(2),
V. Vleck(3), C. Mein(4), E. Wozniak(4), M. Smuk(1), P.D. White(1)
1 Centre for Psychiatry, Wolfson Institute of Preventive Medicine,
Queen Mary's School of Medicine and Dentistry, London, EC1M 6BQ.
2 UCL Centre for Immunodeficiency, Royal Free London NHS
Foundation Trust, London, WC1E 6BT.
3 CIPER, Faculty of Human Kinetics, University of Lisbon, Estrada
da Costa, Cruz Quebrada- Dafundo, 1499-002 Lisbon, Portugal.
4 Genome Centre, Barts and the London School of Medicine and
Dentistry, Queen Mary University of London, Charterhouse Square,
London EC1M 6BQ.
* Corresponding author: Dr Matthew Buckland.
E-mail: mbuckland@nhs.net

Summary

Chronic fatigue syndrome (CFS) is characterized by fatigue after
exertion. A systematic review suggested that transforming growth factor
beta (TGF-beta) concentrations are often elevated in cases of CFS when
compared to healthy controls. This study attempted to replicate this
finding, and investigate whether post-exertional symptoms were
associated with altered cytokine protein concentrations and their RNA in
CFS patients.

Twenty-four patients fulfilling Centers for Disease Control criteria for
CFS, but with no comorbid psychiatric disorders, were recruited from two
CFS clinics in London, UK. Twenty-one healthy, sedentary controls were
matched by gender, age, and other variables. Circulating proteins and
RNA were measured for TGF-beta, TNF, IL-8, IL-6 and IL-1beta. We
measured six further cytokine protein concentrations (IL-2, IL-4, IL-5,
IL-10, IL-12p70, and IFN-gamma). Measures were taken at rest, and before
and after both commuting and aerobic exercise.

CFS cases had higher TGF-beta protein levels compared to controls at
rest (median (quartiles) = 43.9 (19.2, 61.8) versus 18.9 (16.1, 30.0)
ng/ml) (p = 0.003), and consistently so over a nine-day period. However,
this was a spurious finding due to variation between different assay
batches.

There were no differences between groups in changes to TGF-beta protein
concentrations after either commuting or exercise. All other cytokine
protein and RNA levels were similar between cases and controls.
Post-exertional symptoms and perceived effort were not associated with
any increased cytokines.

We were unable to replicate previously found elevations in circulating
cytokine concentrations, suggesting that elevated circulating cytokines
are not important in the pathophysiology of CFS.

--------
(c) 2017 John Wiley & Sons, Inc.
 

lilpink

Senior Member
Messages
988
Location
UK
PDW really will stop at nothing to deny the biomedical basis of ME.


This contradicts his own earlier findings (and indeed, a shed load of others’ findings of altered cytokines):


Immunological changes after both exercise and activity in chronic fatigue syndrome: a pilot study. White PD, KE Nye, AJ Pinching et al. JCFS 2004:12 (2):51-66:


“Immunological abnormalities are commonly observed in CFS…Concentrations of plasma transforming growth factor-beta (TGF-b) (anti-inflammatory) and tumour necrosis factor-alpha (TNF-a) (pro-inflammatory) have both been shown to be raised….Abnormal regulation of cytokines may both reflect and cause altered function across a broad range of cell types…..Altered cytokine levels, whatever their origin, could modify muscle and or neuronal function.

Concentrations of TGF-b1 were significantly elevated in CFS patients at all times before and after exercise testing.


“We found that exercise induced a sustained elevation in the concentration of TNF-a which was still present three days later, and this only occurred in the CFS patients.


TGF-b was grossly elevated when compared to controls before exercise (and) showed an increase in response to the exercise entailed in getting to the study centre.


“These data replicate three out of four previous studies finding elevated TGF-b in subjects with CFS.


“The pro-inflammatory cytokine TNF-a is known to be a cause of acute sickness behaviour, characterised by reduced activity related to ‘weakness, malaise, listlessness and inability to concentrate’, symptoms also notable in CFS.


“These preliminary data suggest that ‘ordinary’ activity (ie. that involved in getting up and travelling some distance) may induce anti-inflammatory cytokine release (TGFb), whereas more intense exercise may induce pro-inflammatory cytokine release (TNF-a) in patients with CFS”.
 

A.B.

Senior Member
Messages
3,780
What does that mean?
How do they determine it was spurious I wonder?

They wrote

In contrast, our data showed a significant elevation in circulating TGF-β at rest at rest and afterwards over the nine days of testing in patients compared to controls. Further analysis showed a clear bimodal distribution to TGF- β, particularly in cases. This was found to be an artefact, explained by a laboratory anomaly, with technician 1 finding consistently higher values for TGF-β in both cases and controls, compared to technician 2. Since there were 13 (54%) cases and only 2 (10%) controls assayed by technician 1, it therefore appeared as though cases were more likely to have elevated concentrations when analysed by summarised group. Changes in TGF- β protein levels due to commuting or exercise were similar in patients and controls.
 

Cheshire

Senior Member
Messages
1,129
What does that mean?
How do they determine it was spurious I wonder?


On deeper analysis of confounders, we examined TGF-β values by both values by both assay batches and by the two laboratory technicians who ran the assays. We show these data for one of the times where there was a significant difference between groups (table 7). This shows that batch one TGF- concentrations (both for cases and controls) were significantly higher than the concentrations for batches 2 and 3. Comparing the results of the two technicians shows that technician 1 found significantly higher concentrations than technician 2 (patient versus patient p <0.001).
 

msf

Senior Member
Messages
3,650
I´m not normally a conspiracy person, but if you weren´t a complete moron (which the study´s authors may well be) and felt you needed to defend your career at any cost, wouldn´t you pick people who you suspected wouldn´t have been selected for studies such as Montoya´s for your own study? People with CFS rather than ME?
 

Sidereal

Senior Member
Messages
4,856
I´m not normally a conspiracy person, but if you weren´t a complete moron (which the study´s authors may well be) and felt you needed to defend your career at any cost, wouldn´t you pick people who you suspected wouldn´t have been selected for studies such as Montoya´s for your own study? People with CFS rather than ME?

Or cytokines have nothing to do with ME symptoms and people need to move on from this and look elsewhere.
 

msf

Senior Member
Messages
3,650
To adapt something Christopher Hitchens once said: which is more likely, that Montoya´s, Lipkin´s and De Meirleir´s studies are wrong, or that White lied (or is a moron)?
 
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msf

Senior Member
Messages
3,650
Just wait for Hanson´s latest research, mentioned in Cort´s latest blog: ´Maureen Hanson, PhD - talk about an exciting project: last seen examining the effect exercise has on the immune system and metabolomics.´

Basically, you´ve got all the smart people on one side, and all the dumb/amoral people on the other. Which side would you back? (I am talking about the ME field, and nothing else!)
 

Murph

:)
Messages
1,799
This had the potential to be good science. I really like the way they took blood even before people got out of bed in the morning, just in case commuting to the hospital was the cause of higher cytokines. It could have validated the earlier cytokine finding, and kudos to these psychs for exploring a physical explanation.

However, the principle of good scientific method is holding things constant and it seems they effed that up. The data are so wonky they can only assume one of their lab techs ran the centrifuge wrong. :(

It's interesting to me that they still publish the study even after that. Good on the journal for accepting a null result I guess. I suppose it can serve as a warning on just how hard it is to do science well.

Interestingly they even admit that the process error might have screwed up their initial TGF finding they were trying to replicate.

"We cannot know whether the same laboratory variation explains the previous case control findings for TGF-, but case control studies can start subject recruitment with cases, in order to ascertain accurate matching of controls, so any inter-batch assay variation might explain why it appeared that cases had different concentrations from controls. We were unable to ascertain the differences in laboratory processing that led to the differences between batches, but assume that the difference was due to using different centrifuge times, which might affect TGF-release from platelets, leading to differences in TGF-concentrations."
 
Messages
15,786
This was found to be an artefact, explained by a laboratory anomaly, with technician 1 finding consistently higher values for TGF-β in both cases and controls, compared to technician 2. Since there were 13 (54%) cases and only 2 (10%) controls assayed by technician 1, it therefore appeared as though cases were more likely to have elevated concentrations when analysed by summarised group.
This sounds like suspicion of an artefact, with the source of the artefact not having been found. They imply human error, but give no details.

I´m not normally a conspiracy person, but if you weren´t a complete moron (which the study´s authors may well be) and felt you needed to defend your career at any cost, wouldn´t you pick people who you suspected wouldn´t have been selected for studies such as Montoya´s for your own study? People with CFS rather than ME?
They came from CFS clinics, which are generally avoided by ME patients and primarily recruit with Oxford. So I'd suspect they're on the lighter side of Fukuda, with no PEM being mandatory.

Or cytokines have nothing to do with ME symptoms and people need to move on from this and look elsewhere.
TGF-B results seem pretty consistent thus far, which makes it a bit suspect that it was the positive result from this paper, and which they have then declared to be a false positive.
 
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Gijs

Senior Member
Messages
690
This had the potential to be good science. I really like the way they took blood even before people got out of bed in the morning, just in case commuting to the hospital was the cause of higher cytokines. It could have validated the earlier cytokine finding, and kudos to these psychs for exploring a physical explanation.

However, the principle of good scientific method is holding things constant and it seems they effed that up. The data are so wonky they can only assume one of their lab techs ran the centrifuge wrong. :(

It's interesting to me that they still publish the study even after that. Good on the journal for accepting a null result I guess. I suppose it can serve as a warning on just how hard it is to do science well.

Interestingly they even admit that the process error might have screwed up their initial TGF finding they were trying to replicate.

"We cannot know whether the same laboratory variation explains the previous case control findings for TGF-, but case control studies can start subject recruitment with cases, in order to ascertain accurate matching of controls, so any inter-batch assay variation might explain why it appeared that cases had different concentrations from controls. We were unable to ascertain the differences in laboratory processing that led to the differences between batches, but assume that the difference was due to using different centrifuge times, which might affect TGF-release from platelets, leading to differences in TGF-concentrations."

Again an example of sloppy science. Using different centrifuges and blame it for inconsistenty makes this study useless. TGF B have been found many times before in CFS/ME patiënts. It could be an important finding. So, i like to see replication by other groups before we take any conclusion.