The Role of Cytokines in Muscle Fatigue in Patients with Chronic Fatigue Syndrome

[msf]

Thanks for the explanation, I guess it's a good thing that different ME researchers are focusing on different pieces of the puzzle, I just hope that all this research can be drawn together into a theory of the disease that is backed by solid evidence, so people no longer dare to refer to Wessely's half-baked ideas.

 

[Dr Speedy]

You can have a sedentary lifestyle (as much of the UK population now does) but this does not automatically equate to what scientific opinion would regard as being deconditioned

DECONDITIONING is:
"Deconditioning can be defined as the multiple, potentially reversible changes in body systems brought about by physical inactivity and disuse. Such changes often have significant functional and clinical consequences in older people. Deconditioning commonly occurs in two situations: (1) a sedentary lifestyle, which is common in older people even in the absence of significant disease or disability and may result in a slow, chronic decline in physical fitness; and (2) bed or chair rest during an acute illness, which can lead to disastrously rapid physical decline."

You can have a sedentary lifestyle (as much of the UK population now does) but this does not automatically equate to what scientific opinion would regard as being deconditioned

DECONDITIONING is:
"Deconditioning can be defined as the multiple, potentially reversible changes in body systems brought about by physical inactivity and disuse. Such changes often have significant functional and clinical consequences in older people. Deconditioning commonly occurs in two situations: (1) a sedentary lifestyle, which is common in older people even in the absence of significant disease or disability and may result in a slow, chronic decline in physical fitness; and (2) bed or chair rest during an acute illness, which can lead to disastrously rapid physical decline."

 

[charles shepherd]

Read what I said!

,,,,a sedentary lifestyle does not automatically equate to what scientific opinion would regard as being deconditioned

There are various ways of defining deconditioned - from deconditioned light to deconditioned heavy

In relation to deconditioned individuals being used as controls in ME/CFS research I would want to use people who had physiological evidence of deconditioning (as set out below) rather than the 'couch potatoes' reconditioning.

After experiencing an injury or with any chronic disease, it is common to experience deconditioning, a physical and/or psychological decline in function. Prolonged bed rest and inactivity can affect nearly all systems of the body. Some of these effects include:

-Cardiovascular (heart): decrease in cardiac output, faster heart rates at rest and with activity, decreased blood pressure in upright positions (orthostatic hypotension), decreased ability to exercise.

-Pulmonary (lungs): mild lung collapse, pneumonia, decreased oxygen to the organs (hypoxemia), increased difficulty breathing with activity and at rest.

-Muscles and bones: decreased muscle size, increased weakness (atrophy), osteoporosis, contractures, osteoarthritis, loss of flexibility.

-Digestive (gastrointestinal and bowel): loss of appetite, constipation.

-Urinary: loss of bladder control (incontinence), bladder infection, electrolyte imbalance.

-Blood: tendency to develop blood clots (thromboembolism), blood thickening (increased blood viscosity).

-Endocrine: impaired response to insulin, high blood sugar (hyperglycemia), nausea.

-Skin: pressure ulcers or wounds.

-Functional: decrease performance in Activities of Daily Living (ADL) and activity endurance, impaired balance and coordination.

-Psychological: confusion, disorientation, anxiety, depression.

 

[Dr Speedy]

Read what I said!

,,,,a sedentary lifestyle does not automatically equate to what scientific opinion would regard as being deconditioned

There are various ways of defining deconditioned - from deconditioned light to deconditioned heavy

In relation to deconditioned individuals being used as controls in ME/CFS research I would want to use people who had physiological evidence of deconditioning (as set out below) rather than the 'couch potatoes' reconditioning.

After experiencing an injury or with any chronic disease, it is common to experience deconditioning, a physical and/or psychological decline in function. Prolonged bed rest and inactivity can affect nearly all systems of the body. Some of these effects include:

-Cardiovascular (heart): decrease in cardiac output, faster heart rates at rest and with activity, decreased blood pressure in upright positions (orthostatic hypotension), decreased ability to exercise.

-Pulmonary (lungs): mild lung collapse, pneumonia, decreased oxygen to the organs (hypoxemia), increased difficulty breathing with activity and at rest.

-Muscles and bones: decreased muscle size, increased weakness (atrophy), osteoporosis, contractures, osteoarthritis, loss of flexibility.

-Digestive (gastrointestinal and bowel): loss of appetite, constipation.

-Urinary: loss of bladder control (incontinence), bladder infection, electrolyte imbalance.

-Blood: tendency to develop blood clots (thromboembolism), blood thickening (increased blood viscosity).

-Endocrine: impaired response to insulin, high blood sugar (hyperglycemia), nausea.

-Skin: pressure ulcers or wounds.

-Functional: decrease performance in Activities of Daily Living (ADL) and activity endurance, impaired balance and coordination.

-Psychological: confusion, disorientation, anxiety, depression.

The basis of the deconditioning theory in ME is that we are lazy, there is nothing wrong with us and we are simply deconditioned because we don't do anything. So you need to compare us with healthy sedentary controls who are deconditioned because they don't do anything.

The people you mention all suffer from an illness so they can never be healthy controls.

 

[charles shepherd]

The basis of the deconditioning theory in ME is that we are lazy, there is nothing wrong with us and we are simply deconditioned because we don't do anything. So you need to compare us with healthy sedentary controls who are deconditioned because they don't do anything.

The people you mention all suffer from an illness so they can never be healthy controls.

Whilst I strongly disagree with the deconditioning theory, I don't know anyone who is involved in researching or promoting GET as a treatment who believes that people with ME/CFS are 'lazy'

If you are going to challenge clinicians and researchers who believe the deconditioning model there's no point in misrepresenting what the other side believe - this is counter-productive

Put very simply, the deconditioning model is based on a model of illness whereby a person contracts a viral infection, does not recover, and because activity exacerbates symptoms they then avoid activity and enter a vicious circle of fear of activity and progressive inactivity, which leads to leads to progressive deconditioning

My view remains that you have to use people who have physiological evidence of reconditioning - but it all depends what you mean by sedentary

Interesting to look back at the memorable CIBA Symposium on ME/CFS that was held in London >> discussion involving Edwards, McCluskey (pro deconditioning) and Behan (against deconditioning) on page 118

https://books.google.co.uk/books?id...what is a deconditioned control group&f=false

 

[daisybell]

Interesting to look back at the memorable CIBA Symposium on ME/CFS that was held in London >> discussion involving Edwards, McCluskey (pro deconditioning) and Behan (against deconditioning) on page 118

https://books.google.co.uk/books?id=uXISpTK0mHMC&pg=PA118&lpg=PA118&dq=what is a deconditioned control group&source=bl&ots=rFK6s2CUsO&sig=PsCeFhQ6Zf6fMiDy-AIhgVsf2MA&hl=en&sa=X&ei=a1UgVebhB8iRsAGNpYPQBA&ved=0CFkQ6AEwCQ#v=onepage&q=what is a deconditioned control group&f=false[/QUOTE]

That makes for some pretty depressing reading!

 

[Bob]

In case anyone is not aware of it yet, the pace team have now debunked and rejected their own deconditioning theory:
http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(15)00054-1/fulltext

 

[adreno]

The PACE trial is to our knowledge the largest investigation of CBT and GET for chronic fatigue syndrome to date. The deconditioning hypothesis was not supported, and the fear-avoidance hypothesis was not supported by the trial's objective outcomes. These factors, along with the disappointing self-report clinical response rates for CBT and GET in an open-label trial, cast substantial doubt over the validity of the fear-avoidance and deconditioning hypothesis for chronic fatigue syndrome.

Wow.

 

[Bob]

Wow.

Just so there's no misunderstanding, that wasn't written by the PACE authors. Unfortunately. But it was published in the Lancet Psychiatry.

 

[Dr Speedy]

Whilst I strongly disagree with the deconditioning theory, I don't know anyone who is involved in researching or promoting GET as a treatment who believes that people with ME/CFS are 'lazy'

If you are going to challenge clinicians and researchers who believe the deconditioning model there's no point in misrepresenting what the other side believe - this is counter-productive

Put very simply, the deconditioning model is based on a model of illness whereby a person contracts a viral infection, does not recover, and because activity exacerbates symptoms they then avoid activity and enter a vicious circle of fear of activity and progressive inactivity, which leads to leads to progressive deconditioning

My view remains that you have to use people who have physiological evidence of reconditioning - but it all depends what you mean by sedentary

Interesting to look back at the memorable CIBA Symposium on ME/CFS that was held in London >> discussion involving Edwards, McCluskey (pro deconditioning) and Behan (against deconditioning) on page 118

https://books.google.co.uk/books?id...what is a deconditioned control group&f=false

The basis of the deconditioning idea about ME is that there is physically nothing wrong with us but it's about anxiety fear of exercise avoidance behaviour etc. So you need to compare us to people who also don't do any exercise but who are healthy if u want to prove or disprove deconditioning. Hence the sedentary controls. If you start using patients who have heart, long or other diseases then you are actually comparing diseases. That way you can never prove or disprove deconditioning in ME.

You yourself posted this study from the denial doctors from nijmegen. Their conclusion is:
"CONCLUSIONS:
Physical deconditioning does not seem a perpetuating factor in CFS."

And which two groups did they use?
"Twenty CFS patients and 20 matched neighbourhood controls performed a maximal exercise test with incremental load.".

They obviously used healthy controls.

http://www.ncbi.nlm.nih.gov/pubmed/11200949

 

[srmny]

I just read the Author's reply to Robert Courtney's
Doubts over the validity of the PACE hypothesis

Author’s reply

We did a randomised controlled trial (n=640) and found two rehabilitative treatments, graded exercise therapy (GET) and cognitive behaviour therapy (CBT), added to specialist medical care to be superior to adaptive pacing therapy added to specialist medical care and specialist medical care alone in improving fatigue and physical functioning for patients with chronic fatigue syndrome.1 These findings were robust irrespective of how we defined the illness.1 In a mediational analysis2 we examined how the effective treatments worked. We noted that fear avoidance beliefs mediated both GET and CBT.2 This result was pertinent for both physical functioning and self-reported fatigue. It is also consistent with a review3 of the role of beliefs in chronic fatigue syndrome and fibromyalgia, which suggested that fear and avoidance of movement were associated with poorer outcomes.

http://www.thelancet.com/pdfs/journals/lanpsy/PIIS2215-0366(15)00054-1.pdf

 

[Sean]

The lack of a link with deconditioning renders the whole psycho-behavioural model of ME/CFS fundamentally untenable. No way around that.

Time that was acknowledged by it's authors and proponents, and any claims based on that model explicitly withdrawn and discarded.

 

[srmny]

This is a link to

http://www.bmj.com/content/350/bmj.h227

This is a link to a rapid response
Tackling fears about exercise is important for ME treatment, analysis
I would like to draw your attention to an error in the rapid response from Chalder et al (1), most of whom were also authors of the original PACE Trial paper. They wrongly stated that PACE was a “randomised, controlled trial”.

The title of the PACE Trial, “Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial” clearly and correctly describes it as just a “randomised trial” not as a "randomised, controlled trial" (2)

This is reiterated under “Method, study design” where it states “PACE was a parallel, four group, multicentre, randomised trial”(2).

As has been explained here in several of the rapid responses, in common with most cognitive behavioural therapy research, the PACE trial failed methodologically to attain the gold standard of a randomised, controlled trial (3-5).

For example, Robert Courtney points out:
“Although it was a large and expensive government-funded trial, the PACE trial, as with most cognitive-behavioural research, was open-label and failed to control for placebo effects and biases such as response bias [24,25]. CBT and GET changed the way that a minority of patients interpreted their illness and responded to self-report questionnaires, as demonstrated by the 11-15% self-report clinical response rate to CBT/GET, but as placebo effects and response bias were not controlled for in this open-label study, it is possible that the self-reported effects could be explained by weaknesses of the trial methodology [24-28].” (3)

May I suggest this significant error is corrected to ensure accuracy and avoid further confusion.

30 January 2015
Margaret Williams
Retired from clinical post in the NHS

The good news is that most people have begun to realize that the PACE Trial authors can not be trusted.

 

[Bob]

I just read the Author's reply to Robert Courtney's
Doubts over the validity of the PACE hypothesis

Author’s reply

We did a randomised controlled trial (n=640) and found two rehabilitative treatments, graded exercise therapy (GET) and cognitive behaviour therapy (CBT), added to specialist medical care to be superior to adaptive pacing therapy added to specialist medical care and specialist medical care alone in improving fatigue and physical functioning for patients with chronic fatigue syndrome.1 These findings were robust irrespective of how we defined the illness.1 In a mediational analysis2 we examined how the effective treatments worked. We noted that fear avoidance beliefs mediated both GET and CBT.2 This result was pertinent for both physical functioning and self-reported fatigue. It is also consistent with a review3 of the role of beliefs in chronic fatigue syndrome and fibromyalgia, which suggested that fear and avoidance of movement were associated with poorer outcomes.

http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(15)00114-5/fulltext

We noted that fear avoidance beliefs mediated both GET and CBT.

Except, the authors fabricated their conclusion, and fear-avoidance didn't actually mediate GET or CBT (or, to be precise, their analysis failed to demonstrate a meditation effect):
http://forums.phoenixrising.me/inde...e-response-from-pace.36651/page-2#post-581772

 

[MeSci]

Physical deconditioning in ME/CFS - from the dim and distant past

Finally, it was found that more CFS patients than controls did not achieve a physiological limitation at maximal exercise.

What does the above sentence mean?

 

[MeSci]

Although exercise intervention is the logical treatment for patients showing acidosis, any trial must exclude subjects who do not initiate exercise as they will not benefit. This potentially explains previous mixed results in CFS exercise trials.

I've seen that one before, and have been unable to understand what they mean by

any trial must exclude subjects who do not initiate exercise as they will not benefit.

Do they mean patients who do not initiate exercise in their everyday life or in the research? Surely it could mean patients who cannot tolerate exercise and/or patients who are simply lazy? Maybe it's just poor wording and the full text makes it clearer.

Also, is exercise really

the logical treatment for patients showing acidosis

? Are there not a number of conditions for which this is not the case?

 

[MeSci]

I've started a thread on this paper here: http://forums.phoenixrising.me/inde...-cultured-skeletal-muscle-cells-in-cfs.36689/

That one doesn't seem to work - maybe it's been merged with the one Charles started here.

 

[John Mac]

They appear to have changed the title of this as yet unpublished study with an intriguing reference to polyphenols.

From:
Determination of mitochondrial function and cytokine production in skeletal muscle of patients with CFS.
https://www.mrc.ac.uk/documents/pdf/cfsme-current-projects/

To:
Modulation of aberrant mitochondrial function and cytokine production in skeletal muscle of patients with CFS by supplementary polyphenols
http://gtr.rcuk.ac.uk/projects?ref=MR/J002895/1


It's definitely the same study

Original
MR/J002895/1
PI: Professor Anne McArdle, University of Liverpool
Title: Determination of mitochondrial function and cytokine production in skeletal muscle of patients with CFS.
Start Date: 01/05/2012
End Date: 30/04/2015
Award Amount: £252,030.40

Latest
Funded Value: £252,030
Funded Period: Sep 12 - Aug 15
Funder: MRC
Project Status: Closed
Project Category: Research Grant
Project Reference: MR/J002895/1
Principal Investigator: Anne McArdle


Is it normal for a study title to change? Is it an indication that they've found something.

I can't find any reference to polyphenols in the original study protocol.

 

[Dolphin]

http://www.fasebj.org/content/29/1_Supplement/913.2.short

The Impact of a Polyphenol Treatment on TNF-α-Induced Cytokine Release from C2C12 Myotubes

1. Kate Earl1,
2. Adam Lightfoot1 and
3. Anne McArdle1

+ Author Affiliations

1. 1Musculoskeletal Biology University of Liverpool United Kingdom

Abstract

Tumour necrosis factor –alpha (TNF-α) promotes skeletal muscle dysfunction and the effects of systemic increases in cytokines can be exacerbated by further local production of pro-inflammatory cytokines.

Increased levels of dietary polyphenols including resveratrol, Epigallocatechin gallate (EGCG) and curcumin are associated with a reduction in systemic inflammation and may therefore alleviate symptoms of muscle dysfunction.

We hypothesised that treatment of C2C12 myotubes with TNF-α would result in increased production of cytokines by muscle and that prior treatment of myotubes with physiological levels of dietary polyphenols would protect against this. C2C12 myotubes were pre-treated with 1µM or 10 µM of resveratrol, EGCG or curcumin for 24 hours followed by 5ng/ml or 25ng/ml TNF-α for 24 hours, with appropriate controls.

Release of pro-inflammatory cytokines IL-6, MCP-1/CCL2, RANTES/CCL5 and Keratinocyte Chemoattractant (KC) from C2C12 muscle cells was significantly increased in response to 5 and 25ng/ml TNF-α (p<0.05) compared with untreated cells.

Pre-treatment with 1µM resveratrol significantly reduced the TNF-α-induced release of IL-6, MCP-1, RANTES/CCL5 and KC from C2C12 cells (p<0.5).

These data suggest that resveratrol may be a potent anti-inflammatory treatment to reduce the local effects of increased systemic TNF-α in muscle.

Funded by BBSRC and the ME Association.

 

[Dolphin]

They appear to have changed the title of this as yet unpublished study with an intriguing reference to polyphenols.

From:
Determination of mitochondrial function and cytokine production in skeletal muscle of patients with CFS.
https://www.mrc.ac.uk/documents/pdf/cfsme-current-projects/

To:
Modulation of aberrant mitochondrial function and cytokine production in skeletal muscle of patients with CFS by supplementary polyphenols
http://gtr.rcuk.ac.uk/projects?ref=MR/J002895/1


It's definitely the same study

Original
MR/J002895/1
PI: Professor Anne McArdle, University of Liverpool
Title: Determination of mitochondrial function and cytokine production in skeletal muscle of patients with CFS.
Start Date: 01/05/2012
End Date: 30/04/2015
Award Amount: £252,030.40

Latest
Funded Value: £252,030
Funded Period: Sep 12 - Aug 15
Funder: MRC
Project Status: Closed
Project Category: Research Grant
Project Reference: MR/J002895/1
Principal Investigator: Anne McArdle


Is it normal for a study title to change? Is it an indication that they've found something.

I can't find any reference to polyphenols in the original study protocol.

From 2011

http://www.meassociation.org.uk/201...announces-mecfs-research-projects-worth-1-6m/

Modulation of aberrant mitochondrial function and cytokine production in skeletal muscle of patients with CFS by supplementary polyphenols Principal investigator: Professor Anne McArdle

Institution: University of Liverpool (joint with the University of Leeds )

Summary: Scientists will use a newly-developed technique to study the energy-generating components of muscle cells (mitochondria). Some studies have suggested that mitochondria may be dysfunctional in CFS/ME, leading to an energy deficit. The scientists hope this will help them learn more about how CFS/ME develops and becomes a chronic condition.