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Old but interesting CFS Research papers

Simon

Senior Member
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Monmouth, UK
I hope it's OK if I put this thread in 'Latest Research' as there are many interesting, important or just plain shocking papers published well before this forum was born that might be worth discussing here. Moderators/other posters please comment/take action if you think this is inappropriate.

As an example, here's a paper from 1998 that was well ahead of the game in using stress/challenge testing to reveal diffrences between CFS patients and healthy controls:

Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression, Blackwood 1998 (free full text)

Abstract:

Patients with chronic fatigue syndrome complain of physical and mental fatigue that is worsened by exertion. It was predicted that the cognitive and motor responses to vigorous exercise in patients with chronic fatigue syndrome would differ from those in depressed and healthy controls.

METHODS Ten patients with chronic fatigue syndrome, 10 with depressive illness, and 10 healthy controls completed cognitive and muscle strength testing before and after a treadmill exercise test...

RESULTS ...During the treadmill test, patients with chronic fatigue syndrome had higher ratings of perceived effort and fatigue than both control groups.... After exertion, patients with chronic fatigue syndrome showed a greater decrease than healthy controls on everyday tests of focused (p=0.02) and sustained (p=0.001) attention, [performance on the exercise test itself was normal, except for CFS patients showing higher levels of perceived exertion]

CONCLUSIONS Patients with chronic fatigue syndrome show a specific sensitivity to the effects of exertion on effortful cognitive functioning. This occurs despite subjective and objective evidence of effort allocation in chronic fatigue syndrome, suggesting that patients have reduced working memory capacity, or a greater demand to monitor cognitive processes, or both. Further insight into the pathophysiology of the core complaints in chronic fatigue syndrome is likely to be realised by studying the effects of exercise on other aspects of everyday functioning.
This study is very small (n=10) and doesn't appear to have been replicated (or refuted) in the years since, which is a shame given the potential importance of the findings. In the last couple of years, measuring CFS function after a challenge finally seems to be taking off, eg the Lights' study of gene expression of sensory receptors following moderate exercise.
 

Simon

Senior Member
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3,789
Location
Monmouth, UK
Tired of being inactive: a systematic literature review of physical activity, physiological exercise capacity and muscle strength in patients with chronic fatigue syndrome. Nijs 2010

Apologies if this had its own thread but I couldn't find one for it

I was surprised by some of the statements in this study we appear remarkably patient-friendly, particularly as I 'd thought Jo Nijs was part of the Dutch/Belgium biosychosocial school.

from the introduction
...Once CFS is established, post-exertional
malaise is a major characteristic of the illness.
Symptoms are typically made worse after modest
amounts of exercise [3], after increased daily physical
activity [4] and after a maximal exercise stress test
[5,6]. A delayed recovery from exercise typically
occurs in patients with CFS [7]. Hence, resting and
activity avoidance could be a way to cope with the
illness and its post-exertional malaise [8]....

from the Discussion
Kinesiophobia, a specific
kind of fear-avoidance behavior, is defined as ‘an
excessive, irrational, and debilitating fear of physical
movement and activity resulting from a feeling of
vulnerability to painful injury or reinjury’ [37]. In
patients with CFS, kinesiophobia represents a
common feature [at least one study disputes this] that was found to be of clinical
importance (i.e. related to disability), but did not
appear to be a determinant of physiological exercise
capacity [38–40].

It has been shown that too vigorous exercise
[12,13,42] or even a 30% increase in activity [34]
frequently triggers a relapse, which may consequently
explain at least part of the physical inactivity
seen in patients with CFS. This post-exertional
malaise has been linked to acute immune changes
following physical activity that exceeds a CFS
patient’s physical capabilities [43–45]. It is concluded
that fatigue and other CFS characteristics like
post-exertional malaise make it difficult, if not
impossible, to be physically active. Anyone who has
worked with CFS patients can confirm that they do
not choose to be physically inactive. On the contrary,
patients with CFS are tired of being inactive.

There was plenty in the paper I'd disagree with, but it seemed to go well beyond striking a patient-friendly posture. Maybe others know different.
 

WillowJ

คภภเє ɠรค๓թєl
Messages
4,940
Location
WA, USA
Nijs is pretty much a mystery to me. Can't predict what he'll be saying next.

Chronic fatigue syndrome: lack of association between pain-related fear of movement and exercise capacity and disability.
Nijs J, Vanherberghen K, Duquet W, De Meirleir K.
Phys Ther. 2004 Aug;84(8):696-705

Still, there is currently no evidence that having “high fear” has any functional relevance in patients with CFS, especially given that fear of movement has not been shown to be related to either disability (as measured by the CFS-APQ) or exercise capacity in the types of patients we studied.

Conclusion: In a subgroup of patients with CFS, namely those who were experiencing widespread pain as defined by the 1990 American College of Rheumatology criteria for fibromyalgia,26 measurements of pain-related fear of movement were neither correlated with exercise capacity data nor correlated with data obtained for activity limitations and participation restrictions. Future studies regarding these associations are needed in different subgroups of people with CFS or in a sample that is more likely to reflect people with CFS in general.

cf with:

Exercise performance and chronic pain in chronic fatigue syndrome: the role of pain catastrophizing.
Nijs J, Van de Putte K, Louckx F, Truijen S, De Meirleir K.
Pain Med. 2008 Nov;9(8):1164-72. Epub 2007 Oct 3.

CONCLUSIONS: These data provide evidence favoring a significant association between pain catastrophizing, bodily pain, exercise performance, and self-reported disability in female patients with CFS who experience widespread pain. Further prospective longitudinal studying of these variables is required.

How to explain central sensitization to patients with 'unexplained' chronic musculoskeletal pain: practice guidelines.
Nijs J, Paul van Wilgen C, Van Oosterwijck J, van Ittersum M, Meeus M.
Man Ther. 2011 Oct;16(5):413-8. Epub 2011 May 31.
Central sensitization provides an evidence-based explanation for many cases of 'unexplained' chronic musculoskeletal pain. Prior to commencing rehabilitation in such cases, it is crucial to change maladaptive illness perceptions, to alter maladaptive pain cognitions and to reconceptualise pain.

This can be accomplished by patient education about central sensitization and its role in chronic pain, a strategy known as pain physiology education. Pain physiology education is indicated when: 1) the clinical picture is characterized and dominated by central sensitization; and 2) maladaptive illness perceptions are present. Both are prerequisites for commencing pain physiology education.

Face-to-face sessions of pain physiology education, in conjunction with written educational material, are effective for changing pain cognitions and improving health status in patients with various chronic musculoskeletal pain disorders. These include patients with chronic low back pain, chronic whiplash, fibromyalgia and chronic fatigue syndrome.

cf with:

Intracellular immune dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: state of the art and therapeutic implications.
Nijs J, Frémont M.
Expert Opin Ther Targets. 2008 Mar;12(3):281-9. Review.

RESULTS/CONCLUSION: From the scientific literature it is concluded that proteolytic cleavage of the native RNase L enzyme is characteristic of the dysregulation of intracellular immunity in people with ME/CFS, but the origin of the dysregulation is speculative. There is increasing evidence for immune cell apoptosis and upregulation of various aspects of the 2'-5' oligoadenylate (2-5A) synthetase/RNase L pathway in ME/CFS. This review provides the theoretical rationale for conducting studies examining the effectiveness of direct or indirect drug targeting of the 2-5A synthetase/RNase L pathway in ME/CFS patients.

Disability evaluation in chronic fatigue syndrome: associations between exercise capacity and activity limitations/participation restrictions.
Nijs J, De Meirleir K, Wolfs S, Duquet W.
Clin Rehabil. 2004 Mar;18(2):139-48.

RESULTS: A statistically significant correlation between the score obtained with the CFS-APQ and the body weight-adjusted peak oxygen uptake (Spearman rho = -0.32; p = 0.005), functional aerobic impairment (rho = 0.33; p = 0.004), workload/body weight (rho = -0.30; p = 0.009), exercise duration (rho = -0.30; p = 0.008), and the percentage of target heart rate achieved (rho = -0.33; p = 0.004) was observed. The correlations between the remaining exercise capacity parameters and the scores obtained with the CFS-APQ all indicated a trend towards association (0.01 <p<0.05).

CONCLUSIONS: These results suggest a moderate association between exercise capacity and activity limitations/participation restrictions in patients with CFS. The observed correlations lack strength to predict activity limitations/ participation restriction based on exercise capacity parameters. Disability evaluation in CFS should therefore encompass both exercise capacity testing and measurements at the activity/participation dimension.

cf with "How to Exercise People with Chronic Fatigue Syndrome"

Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue?
Meeus M, Mistiaen W, Lambrecht L, Nijs J.
Anticancer Res. 2009 Nov;29(11):4717-26. Review.

Besides fatigue, certain aspects of immune dysfunctions appear to be present in both illnesses. In this regard, a literature review of overlapping immune dysfunctions in CFS and cancer is provided. Special emphasis is given to the relationship between immune dysfunctions and fatigue.

example para with annoying bits:
The cause may yet not be clear, but fatigue is the hallmark of CFS. Several hypotheses as to the cause of the fatigue have been proposed in the literature. Most rely on a biopsychosocial model with possible contributing factors such as neuroendocrine abnormalities, neuropsychological dysfunctions, autonomic dysregulations, environmental factors, psychological processes and personality traits, abnormal exercise response, overactive or passive lifestyle, infections and immune dysfunctions. Many reviews are available on these possible contributing or predisposing factors. But then again, CFS, with the hallmark fatigue, can only be diagnosed in the absence of a clear medical cause for the fatigue.

some interesting bits from the full text
CFS patients. One of the major intracellular immune dysfunctions in CFS is the dysregulation of the RNase L antiviral pathway. .... By regulating viral and cellular RNA expression, RNase L plays an important role in the antiviral and antiproliferative activities of IFN and contributes to innate immunity and cell metabolism.

In consequence [of some cell biology stuff it discussed], the LMW RNase L fragments in CFS patients are responsible for the uncontrolled degradation of ribosomal and mitochondrial RNA, leading to apoptosis. Apoptosis triggers the production of elastase and calpain (37), which are, in turn, considered to be responsible for the proteolytic cleavage of a number of structurally and functionally vital proteins, including the authentic RNase L (35), leading to an apoptopic vicious circle (37). In addition, the LMW RNase L may disturb proper ion flux through cell membranes by binding to the ion channels. The subsequent channelopathy causes inefficient ion transport, possibly leading to several of the CFS symptoms (38).

Cancer patients. Besides antiviral activity, RNase L has been suggested to function as a tumour suppressor based on its roles in mediating apoptosis and antiproliferative activity of IFN (40).
[which interferon?]

The R462Q variant of RNASEL, having about 3-fold reduced catalytic activity in vitro, is the most prevalent genetic marker for prostate cancer.

It remains to be seen if mutated RNASEL predisposes to any other forms of cancer. Bartsch and colleagues (46) showed that the RNASEL R462Q variant might be associated with an increased risk for sporadic pancreas cancer and with more aggressive tumours in familial pancreatic cancer. Furthermore, the occurrence of elevated levels of RNase L seems to be an early event in colorectal tumourigenesis, suggesting that control of RNA turnover is an important step in tumour progression (47).

CFS patients. NF-κB, as well as inducible nitric oxide synthetase and NO have been shown to be increased in CFS (50-52). The production of NF-κB is significantly correlated to the severity of illness and symptoms, such as fatigue and pain. These correlations suggest that the symptoms of CFS, such as fatigue, pain, muscular tension and depressive symptoms reflect a genuine inflammatory response in those patients (50).
The produced NO, in turn, has an immunological function: it is cytotoxic by inhibiting the mitochondrial electron transport and the DNA synthesis and by influencing iron metabolism (important for the proliferation of viruses) (49, 53). Excessive or persistent NO production as reported in CFS (52), is, however, detrimental for physiological functions, as explained in earlier studies on intracellular immune dysfunctions in CFS (34, 54, 55).

Cancer patients. Aberrant activation of NF-κB has been observed in many cancer types (56-58).
...
Based on the evidence describing the role of NF-κB, it is evident that NF-κB plays a pivotal role in suppression of apoptosis, promotion of cell proliferation and inflammation, and is closely associated with cancer development (61).

Curiously, the low NK syndrome itself is characterized by an uncomfortable chronic fatigue, malaise and reduced interest in physical or mental activities. In addition, long-lasting low-grade fever is often reported and most of the sufferers are disabled or even bedridden. These symptoms are almost identical to those associated with CFS (66). Observations suggest that individuals with chronically low NK activity may be genetically predisposed to the development of CFS (65).

Cancer patients. Natural cytotoxic receptors (e.g. NKp46, NKp44, NKp30) are displayed on the surface of NK cells and trigger NK cytotoxicity against tumour cells (67). Tumour cells appear continuously, but in healthy people they are cleared by NK cells. This is accomplished by perforins, stored in the cytoplasm of NK cells and capable of destroying the cell membrane of tumour cells (67). Alternatively, activated NK cells produce tumour necrosis factor α, which in turn initiates tumour cell apoptosis (68).

In general, the level of NK activity is a stable individual trait, which fluctuates within a low, middle, or high normal range characteristic for each individual. Therefore it is not surprising that both CFS and cancer often occur in the same family (65).

Physical activity (i.e. aerobic exercise) is known to have positive effects on the number and cytotoxicity of natural killer cells in healthy humans (78-80), but this interaction is currently unexplored in people with cancer or CFS.

Finally, increased oxidative stress, apparent in CFS patients (as reviewed in 81) and also in cancer survivors due to the aftercare (82), can reduce NK cytotoxicity (reviewed in 83) and cause fatigue (82).

These authors hypothesize that the fatigue [of CFS] may be the consequence of a chronic inflammatory response due to reduced NK activity.
including chanellopathy, mitochondrial dysfunction, etc.

It is proposed that cancer-related symptom clusters, which include fatigue, share common cytokine-based neuroimmunological mechanisms. The review of Lee et al. (90) provides evidence for a correlation between the altered cytokine profile and cancer-related symptoms. The expression of coexisting symptoms such as fatigue could thus be linked to the dysregulated activity of NF-κB.
As presented in Figure 1, there is already evidence for the relation between immune dysfunctions and fatigue in CFS, but in cancer this relation is far less understood.

characteristic solution proposed:
Since, for example, RNase L and NK cells may play a role in both the disabling fatigue and the protection of cancer patients against cancer reoccurrence, it would be important to target treatment approaches at improving functioning of these immune aspects.

Several pharmacological therapies could offer a solution, but rehabilitation might also be beneficial. Given the fact that appropriate amounts of physical activity have positive effects on the number and cytotoxicity of NK cells in both healthy humans (72) and cancer patients (91), sufficient physical activity could be an important item in rehabilitation, especially since both CFS and cancer patients seems to be rather passive (92-96). A lack of physical activity might not only predispose cancer patients to experience severe fatigue, it might even decrease NK cell functioning and hence make them prone to cancer reoccurrence (97, 98). In addition, in CFS patients, light physical activity is associated with better well-being (unpublished data).
hahahahaha, being better is associated with being better! imagine that #tautology
In consequence, exercise is currently recommended as a conservative intervention for both fatigued cancer patients and CFS patients. However, with regard to these immunological abnormalities, prudence is called concerning exercise during the rehabilitation of these patients. Based on literature findings and our own results, we know that intracellular immune dysfunctions restrict exercise capacity, but also that too vigorous exercise may further worsen the immune system (99, 100) and the complaints in CFS patients (1). The exercise response to intensive activity in cancer patients is less understood. Several conditions during cancer treatment and recovery can preclude any physical activity,...
rather thin discussion on the risks of exercise in ME or CFS, but immunology is acknowledged
 

jimells

Senior Member
Messages
2,009
Location
northern Maine
willow, thanks for your impressive post. Obviously a lot of work to put it together.

The similarity between cancer-induced fatigue and what we experience strikes me as very significant. I have a friend who recently went through the cancer sugery/chemo-poison treatment. I thought it was a strange coincidence that he described what we would call PEM. Maybe not a coincidence at all?

So is there a treatment to improve NK cell function? (Besides GET, of course!)
 
Messages
759
Location
Israel
....The similarity between cancer-induced fatigue and what we experience strikes me as very significant. I have a friend who recently went through the cancer sugery/chemo-poison treatment. I thought it was a strange coincidence that he described what we would call PEM. Maybe not a coincidence at all?

So is there a treatment to improve NK cell function? (Besides GET, of course!)

I once tried to get a rather disgusting doctor to test my NK cell function. He refused of course. He said that even if you have low NK cell function, the treatment for it is vitamin C supplementation.

I take high vitamin C supplements every day. They don't get rid of my M.E or exhaustion but I have problems digesting and constipation as some of my symptoms and it helps with that.
 
Messages
759
Location
Israel
There is a website that lists "grey area" research in M.E from past years that just got ignored. I don't know much about the organisation or the website it is on. I'm too brain fogged to read and understand much. It's too much info even for a healthy person.
The website is here:
http://www.meactionuk.org.uk/Grey-information-on-ME-CFS.htm
http://www.meactionuk.org.uk/Grey-Info-Part-3.htm

I found it by accident. while looking for 2 long lost doctors on the web.
It's a strange story. Back in 1994, not long after I got ill, I was living in Sheffield and I heard that in a Leeds hospital there was a partnership of 2 doctors who had discovered something in M.E. They were called Dr Swinburne and Dr Coyle. Years later I found their paper in the link below. When I went to see them they were continuing in further research on metabolism or some such... I can't remember. They were the first proper M.E doctors I ever saw and I wish I had stuck with them but I was seduced by Dr Myhill and went to her. After getting worse on Dr Myhill's treatment I strangely stopped getting appointments from them. I tried to contact them and was told that Dr Coyle had comitted suicide and Dr Swinborne had left. I asked why Dr Coyle had comitted suicide, he seemed such a nice man and did not look unhappy. They said it was "personal reasons". I never heard of them or their research again until I found this on the web now. It looks like a pretty serious bit of research that has been completely forgotton:
http://www.meactionuk.org.uk/Grey-Info-Part-3.htm
(You have to scroll down.)
"Dr Layinka Swinburne from Leeds confirmed that the distinct symptom of ME is fatigability of muscle after minimal exercise, with slow recovery before muscle power is restored, and said that Dr Melvin Ramsay called this phenomenon the ‘sheet anchor of diagnosis’. She presented evidence that the basis of the fatiguability is a defect in the regeneration of high energy phosphates, especially ATP, and that such an impairment would generate changes in membrane bound transport and ion movement, leading to chronic intracellular ion depletion (phosphate, potassium and magnesium), with further impairment of mitochondrial function; physical activity would produce greater depletion, leading to interference with many other functions such as immune reactions, hepatic detoxification, gut motility, neurotransmitter function, maintenance of red cell shape and tissue respiration.

Dr Sean Coyle, an associate of Dr Swinburne, noted that serum potassium and phosphate levels have been shown to be decreased in ME and that renal tubular handling of phosphate was low, suggesting an inappropriate loss of phosphate in patients with ME. He noted that low phosphate levels could affect every cell in the body and may cause bone factures, weakness, fatigue, abnormal pulmonary function, low blood pressure and depressed cardiac stroke volume, as well as cognitive dysfunction."

I remember Dr Coyle of the partneship was a nice shy Irish man with an accent and endearing eccentricity. He was a pathologist IIRC. I'm don't think anything sinister happened. It could easily have been bad luck in Dr Coyle dying.
 

Seven7

Seven
Messages
3,444
Location
USA
So is there a treatment to improve NK cell function? (Besides GET, of course!)

I am on prescription for imunovir to increase NK. Inosine is as effective.
Supplements: AHCC, also some research on Maitake Mushroom supplement.

To Eat: Maitake and Shaitake Mushroom.
 

Seven7

Seven
Messages
3,444
Location
USA
I could definitely use some Mushroom Therapy :alien:

Where do I get a prescription??
The mushroom (AHCC and Maitake Supplements) are online, you buy it anywhere. To eat, they sell them here in any supermarket just check the name on the pack. The maitake sometimes I only find on the health store.

The prescription of imunorvir I got from Dr Rey. Inosine I heard people get it from Drs, And if I am not wrong is over the counter in Europe?!?
 

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
Nijs is pretty much a mystery to me. Can't predict what he'll be saying next.

Chronic fatigue syndrome: lack of association between pain-related fear of movement and exercise capacity and disability.
Nijs J, Vanherberghen K, Duquet W, De Meirleir K.
Phys Ther. 2004 Aug;84(8):696-705

cf with:

Exercise performance and chronic pain in chronic fatigue syndrome: the role of pain catastrophizing.
Nijs J, Van de Putte K, Louckx F, Truijen S, De Meirleir K.
Pain Med. 2008 Nov;9(8):1164-72. Epub 2007 Oct 3.

How to explain central sensitization to patients with 'unexplained' chronic musculoskeletal pain: practice guidelines.
Nijs J, Paul van Wilgen C, Van Oosterwijck J, van Ittersum M, Meeus M.
Man Ther. 2011 Oct;16(5):413-8. Epub 2011 May 31.

cf with:

Intracellular immune dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: state of the art and therapeutic implications.
Nijs J, Frémont M.
Expert Opin Ther Targets. 2008 Mar;12(3):281-9. Review.

Disability evaluation in chronic fatigue syndrome: associations between exercise capacity and activity limitations/participation restrictions.
Nijs J, De Meirleir K, Wolfs S, Duquet W.
Clin Rehabil. 2004 Mar;18(2):139-48.

cf with "How to Exercise People with Chronic Fatigue Syndrome"

Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue?
Meeus M, Mistiaen W, Lambrecht L, Nijs J.
Anticancer Res. 2009 Nov;29(11):4717-26. Review.

example para with annoying bits:

some interesting bits from the full text

including chanellopathy, mitochondrial dysfunction, etc.

characteristic solution proposed:

hahahahaha, being better is associated with being better! imagine that #tautology

rather thin discussion on the risks of exercise in ME or CFS, but immunology is acknowledged
Hi Willow

That was quite a tour de force, thank you. I see what you mean about Jo Nijs having a pretty wide range of opinions on the same subject. I think he actually overstated some of the evidence for some of the immunological changes, particular for RNA-ase L, which I think has failed to stand up to robust replication. Similarly, I think the
case for Central sensitisation is also overstated, he presents it almost as fact. But then I'd probably say the same thing about his reviews of the evidence for physical inactivity being the answer to CFS.

Still, I suppose at least it shows he is willing to embrace the possibility of biological factors playing an important role.
 

halcyon

Senior Member
Messages
2,482
Dr Sean Coyle, an associate of Dr Swinburne, noted that serum potassium and phosphate levels have been shown to be decreased in ME and that renal tubular handling of phosphate was low, suggesting an inappropriate loss of phosphate in patients with ME. He noted that low phosphate levels could affect every cell in the body and may cause bone factures, weakness, fatigue, abnormal pulmonary function, low blood pressure and depressed cardiac stroke volume, as well as cognitive dysfunction."
Interesting to come across this. I just had a metabolic panel done several weeks ago that for the first time included a serum phosphate determination and mine came back low. It was repeated again several days later and again was low. The renal loss of phosphate is interesting as well as I've had a severe increase in kidney stones since becoming ill with ME.