Seriously?

Dear Jo Nijs,

I have a question regarding one of your results.

You state that:
"From the available literature, it is concluded that musculoskeletal factors are unlikely to account for pain from CFS."

My question originates from the 2009 study "Light AR, White AT, Hughen RW, Light KC. Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects." that you cite in your paper.

I was under the impression that the data by the author Alan Light actually suggest that it are the sensory nerve endings on the muscles that sense increased fatigue (and in extension pain) in CFS (and Fibromyalgia).

E.g. as Alan Light says here in a lecture (at minute 4:11):
http://www.youtube.com/watch?v=x3Hylumohfo&t=4m11s

I would like to ask what suggest that the increased expression of sensory genes in peripheral blood cells is a phenomenon occurring centrally, and what makes you think that changes in peripheral blood are a central phenomenon and therefore "unlikely" to originate from musculoskeletal factors.

Kindest regards

I really had to watch my language with such fine research from such fine researchers.

Cytotoxic lymphocyte microRNAs as prospective biomarkers for CFS/ME

Cytotoxic lymphocyte microRNAs as prospective biomarkers for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.
Brenu EW, Ashton KJ, van Driel M, Staines DR, Peterson D, Atkinson GM, Marshall-Gradisnik SM.

Faculty of Health Science and Medicine, Bond University, Australia.

Abstract

BACKGROUND:
Immune dysfunction associated with a disease often has a molecular basis.

A novel group of molecules known as microRNAs (miRNAs) have been associated with suppression of translational processes involved in cellular development and proliferation, protein secretion, apoptosis, immune function and inflammatory processes.

MicroRNAs may be implicated in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), where immune function is impaired.

The objective of this study was to determine the association between miRNAs in cytotoxic cells and CFS/ME.

METHODS:
Natural Killer (NK) and CD8(+)T cells were preferentially isolated from peripheral blood mononuclear cells from all participants (CFS/ME, n=28; mean age=41.8±9.6years and controls, n=28; mean age=45.3±11.7years), via negative cell enrichment.

Following total RNA extraction and subsequent synthesis of cDNA, reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to determine the expression levels of nineteen miRNAs.

RESULTS:
There was a significant reduction in the expression levels of miR-21, in both the NK and CD8(+)T cells in the CFS/ME sufferers.

Additionally, the expression of miR-17-5p, miR-10a, miR-103, miR-152, miR-146a, miR-106, miR-223 and miR-191 was significantly decreased in NK cells of CFS/ME patients in comparison to the non-fatigued controls.

LIMITATIONS:
The results from these investigations are not yet transferable into the clinical setting, further validatory studies are now required.

CONCLUSIONS:
Collectively these miRNAs have been associated with apoptosis, cell cycle, development and immune function.

Changes in miRNAs in cytotoxic cells may reduce the functional capacity of these cells and disrupt effective cytotoxic activity along with other immune functions in CFS/ME patients.

Via CO-CURE

iPOP (integrative personal omics profile) – tracking proteins, metabolites, metabolism, microRNAs, cytokines, antibodies, and gene transcripts in one person

Michael Snyder tracks his health status with iPOP and finds a virus causing his Type 2 Diabetes (T2DM)?

Snyder had a cold at the first blood draw, which allowed the researchers to track how a rhinovirus infection alters the human body in perhaps more detail than ever before. The initial sequencing of his genome had also showed that he had an increased risk for type 2 diabetes, but he initially paid that little heed because he did not know anyone in his family who had had the disease and he himself was not overweight. Still he and his team decided to closely monitor biomarkers associated with the diabetes, including insulin and glucose pathways. The scientist later became infected with respiratory syncytial virus, and his group saw that a sharp rise in glucose levels followed almost immediately. "We weren't expecting that," Snyder says. "I went to get a very fancy glucose metabolism test at Stanford and the woman looked at me and said, 'There's no way you have diabetes.' I said, 'I know that's true, but my genome says something funny here.' "

So much for "These people eat too much."

Topol writes in an e-mail, "this type of 'pan-ar-omic' study of individuals is now not only feasible but in select individuals with medical conditions, particularly useful clinically."

We'll have to wait until this will be used more often in research, and then it will take some considerable time, but it will reach clinical use some time, maybe in the next decade.

Read it all.

[Update] Here's another blog post about this.

"At least two subgroups of patients with CFS can be identified by gene expression changes following exercise"

A follow up to their previous studies by "The Lights".

Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome.
Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, Light KC.

Department of Anesthesiology The Brain Institute Department of Neurobiology and Anatomy Department of Exercise and Sport Science, University of Utah, Salt Lake City, UT 84132, USA.

Abstract

OBJECTIVES:

To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise.

DESIGN:

Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate).

Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise.

Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen.

Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise.

Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments.

RESULTS:

No gene expression changes occurred following exercise in controls.

In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor's and one cytokine gene's transcription for 48 h.

These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic α-2A receptor's transcription was decreased at all time-points after exercise; other genes were not altered.

History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup.

FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls.

CONCLUSIONS:

At least two subgroups of patients with CFS can be identified by gene expression changes following exercise.

The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine.

The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for α-2A.

FM-only patients can be identified by baseline increases in three genes.

Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups.

Alan Light 2011 Lecture: Gene Expression Biomarkers for Chronic Fatigue & Fibromyalgia Syndromes

As a follow-up to the last post, here is his 2011 lecture (about 1 hour) by Alan Light for OFFER Utah about his very excellent ME/CFS gene-expression study.

This is objective data that there is biological reason for the symptoms [in ME/CFS and Fibromyalgia].

You may want to switch to 1080p HD to best view the slides.
(Part 1 Part 2 Part 3 Part 4 Part 5)

My take-home messages:

1. 70% of ME/CFS patients have Fibromyalgia (FMS) symptoms. And Fibromyalgia gets worse after exercise, even if the definition for FMS does not specify for it. And a majority of FMS patients (but not all) have ME/CFS symptoms.

2. TRPV1 contributes to the body's temperature set point.

3. Alan Light found a sensory definition of fatigue (The nerves at the muscle tell the brain "You are tired") in ME/CFS that contributes to the desire to use the muscles less. It is related to "actual" muscle fatigue ("The muscle is about to fail"), but it is not the same.

4. In both ME/CFS and FMS there is a 40% subgroup, that has a Ad2A (vasoconstriction) decrease. That gene is responsible for preventing orthostatic intolerance (OI / POTS). 70% patients with this gene expression profile have orthostatic intolerance, and 20% without have POTS (it might depend when and how you measure POTS).

5. FMS without CFS patients look like controls after execercise, but have different baseline levels. P2X4, TRPV1 and IL10 are expressed higher at baseline.

6. Gene expression as biomarker for ME/CFS and Fibromyalgia? Specificity 94% (6% of false negatives) and sensitivity of 65% (35% of false positives), good but not excellent biomarker, could be improved. Might be clinically available within 2 to 3 years.

7. The orthostatic subgroup should be treated differently.

8. Pregabalin or Gabapentin decrease the level of pain and of mental fatigue - maybe.

9. The cause could be increase of sensitivity of fatigue and pain, or dysfunction of the sympathetic nervous system.
(My comment, this the only flaw of Alan Light's work I can think of. He is leaving out one possibility: Of course it could be that there is an actual increase of fatigue and pain due to a pathologically increased muscle exhaustion in ME/CFS and FMS patients. If the nerves are sensing something, it could actually be there – doh!)

10. This is objective data that there is biological reason for the symptoms.
(Translated to English: "The psychosomatic school can go and f*ck themselves.")

As an addendum:
Don't miss Christopher Snell's 2012 lecture, which ties in nicely!