TGI Friday! Our weekly round-up of recently published research abstracts | 27 May 2016

May 27, 2016

From Arthritis Care and Research (Hoboken), January 2016.

Gene Expression Factor Analysis to Differentiate Pathways Linked to Fibromyalgia, Chronic Fatigue Syndrome, and Depression in a Diverse Patient Sample.

Iacob E, Light AR, Donaldson GW, Okifuji A, Hughen RW, White AT, Light KC.
University of Utah, Salt Lake City



To determine if independent candidate genes can be grouped into meaningful biologic factors, and whether these factors are associated with the diagnosis of chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS), while controlling for comorbid depression, sex, and age.


We included leukocyte messenger RNA gene expression from a total of 261 individuals, including healthy controls (n = 61), patients with FMS only (n = 15), with CFS only (n = 33), with comorbid CFS and FMS (n = 79), and with medication-resistant (n = 42) or medication-responsive (n = 31) depression. We used exploratory factor analysis (EFA) on 34 candidate genes to determine factor scores and regression analysis to examine whether these factors were associated with specific diagnoses.


EFA resulted in 4 independent factors with minimal overlap of genes between factors, explaining 51% of the variance. We labeled these factors by function as 1) purinergic and cellular modulators, 2) neuronal growth and immune function, 3) nociception and stress mediators, and 4) energy and mitochondrial function. Regression analysis predicting these biologic factors using FMS, CFS, depression severity, age, and sex revealed that greater expression in factors 1 and 3 was positively associated with CFS and negatively associated with depression severity (Quick Inventory for Depression Symptomatology score), but not associated with FMS.


Expression of candidate genes can be grouped into meaningful clusters, and CFS and depression are associated with the same 2 clusters, but in opposite directions, when controlling for comorbid FMS. Given high comorbid disease and interrelationships between biomarkers, EFA may help determine patient subgroups in this population based on gene expression.

From Medicine and Science in Sports & Exercise, published online 16 May 2016.

Fatigue Exacerbation by Interval or Continuous Exercise in Chronic Fatigue Syndrome.

Sandler, Carolina X.; Lloyd, Andrew R.; Barry, Benjamin K.



To determine if the typical exacerbation of symptoms in patients with chronic fatigue syndrome (CFS) following a bout of exercise differs between high-intensity interval training (HIIT) or continuous (CONT) aerobic exercise of the same duration and mechanical work.


Participants with specialist-diagnosed CFS performed two 20-minute bouts of cycling in a randomised crossover study. The bouts were either moderate-intensity-continuous (70% age predicted heart rate max (APHRM)) or high-intensity-interval exercise, separated by at least 2 weeks. Self-report questionnaires capturing fatigue and related symptoms, and actigraphy were collected across 2 days before and 4 days following the exercise. Comparisons between exercise bouts were made using paired sample t-tests.


Fourteen moderately affected participants who were unable to work, but not bed bound, completed the study (9 female, 32 +/- 10 years, 67 +/- 11 kg). Mechanical work was matched successfully between the exercise bouts (HIIT 83,037 vs CONT 83,348 J, p=0.84). Mean heart rate (HIIT 76 +/- 5 vs CONT 73 +/- 6 %APHRM, p<0.05) and RPE (6-20) in the legs (HIIT 15.4 +/- 1.4 vs CONT 13.2 +/- 1.2, p<0.001) were higher for the interval compared to continuous exercise. Mean fatigue scores (0-10) were similar before each exercise challenge (HIIT 4.5 +/- 1.8 vs CONT 4.1 +/- 1.7, p=0.43). Participants reported an increase in fatigue scores following both challenges (Mean difference: HIIT 1.0 +/- 1.3, p<0.01; CONT 1.5 +/- 0.7, p<0.001), but these exacerbations in fatigue were not statistically or clinically different (p=0.20).CONCLUSIONSHigh-intensity interval exercise did not exacerbate fatigue any more than continuous exercise of comparable workload. This finding supports evaluation of HIIT in graded exercise therapy interventions for patients with CFS.

From the American Journal of Case Reports, 11 May 2016.

Reversal of Refractory Ulcerative Colitis and Severe Chronic Fatigue Syndrome Symptoms Arising from Immune Disturbance in an HLA-DR/DQ Genetically Susceptible Individual with Multiple Biotoxin Exposures.

Gunn SR(1), Gunn GG(1), Mueller FW(2).
1) Department of Genomic Pathology, Targeted Genomics, San Antonio, TX, USA.
2) Family Practice, Huebner Family Medicine, San Antonio, TX, USA.



Patients with multisymptom chronic conditions, such as refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS), present diagnostic and management challenges for clinicians, as well as the opportunity to recognize and treat emerging disease entities. In the current case we report reversal of co-existing RUC and CFS symptoms arising from biotoxin exposures in a genetically susceptible individual.


A 25-year-old previously healthy male with new-onset refractory ulcerative colitis (RUC) and chronic fatigue syndrome (CFS) tested negative for autoimmune disease biomarkers. However, urine mycotoxin panel testing was positive for trichothecene group and air filter testing from the patient's water-damaged rental house identified the toxic mold Stachybotrys chartarum. HLA-DR/DQ testing revealed a multisusceptible haplotype for development of chronic inflammation, and serum chronic inflammatory response syndrome (CIRS) biomarker testing was positive for highly elevated TGF-beta and a clinically undetectable level of vasoactive intestinal peptide (VIP). Following elimination of biotoxin exposures, VIP replacement therapy, dental extractions, and implementation of a mind body intervention-relaxation response (MBI-RR) program, the patient's symptoms resolved. He is off medications, back to work, and resuming normal exercise.


This constellation of RUC and CFS symptoms in an HLA-DR/DQ genetically susceptible individual with biotoxin exposures is consistent with the recently described CIRS disease pathophysiology. Chronic immune disturbance (turbatio immuno) can be identified with clinically available CIRS biomarkers and may represent a treatable underlying disease etiology in a subset of genetically susceptible patients with RUC, CFS, and other immune disorders.

From the Journal of Psychosomatic Research, June 2016.

Why patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis improve or deteriorate with graded exercise therapy

A. Cheshire, D. Ridge, L. Clark, P. White



Graded exercise therapy, GET, (along with cognitive behaviour therapy, CBT) is one of only two treatments recommended by the 2007 National Institute of Health Care Excellence (NICE) CFS/ME guidelines as having an evidence-base. NICE describes GET as an “approach to CFS/ME that involves physical assessment, mutually negotiated goal-setting and education”. However, lay surveys show that GET is considered unacceptable or harmful by many patients. Further investigation is needed to understand why some people seem to benefit from GET, and not others.


The study aimed to answer the question, “What are the differences and similarities in treatment perceptions and experiences of GET, among participants who improved and got worse in a pragmatic randomised controlled trial of Guided graded Exercise Self-help (GETSET).”?


This qualitative, one-to-one interview study was situated within the GETSET Trial. A sub-sample of patients were stratified into improved and deteriorated and recruited: 9 were better, 10 were worse (according to Clinical Global Impression (CGI) scale). Interviews were semi-structured to ensure all participants discussed all relevant topics to the study. Interviews were transcribed in full and a thematic, “constant comparison” approach was used in the analysis, using NVivo software to ensure all relevant data were analysed.


Participants generally found GET challenging, especially during initiation, as participants had to wait considerable time for any benefit. The deteriorated group reported experiencing more barriers to GET, including a worse exacerbation of symptoms in response to GET, which interfered with their life commitments (e.g. work, caring duties). They also reported greater interference with GET from comorbid conditions and other things happening in their lives. Additionally, they had had CFS for considerably longer than the improved group. The improved group on the other hand reported more facilitators to doing GET (e.g. using other therapies), and were more likely to report exceptionally high levels of motivation. Paradoxically, GET engagement could be supported by having worse levels of CFS/ME, as participants felt too ill to do activities that could distract them from GET.


Our findings flesh out the deeper meanings behind polarized experiences of GET, pointing to the specific conditions under which GET is most likely to work, and how health professionals could assist patients to benefit from GET.

From Biological Psychology, published online 17 May 2016.

A potential biomarker for fatigue: oxidative stress and anti-oxidative activity

Sanae Fukuda(a,b,c),Junzo Nojima(d), Yukari Motoki(d), Kouzi Yamaguti(c,e), Yasuhito Nakatomi(c,e), Naoko Okawa(a), Kazumi Fujiwara(a), Yasuyoshi Watanabe(b,c), Hirohiko Kuratsune(a,b,c,e).
a) University of Kansai Welfare Sciences, Kashiwara, Osaka 582-0026, Japan
b) RIKEN Center for Life Science Technologies, Kobe, Hyogo 650-0047, Japan
c) Department of Physiology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
d) Department of Laboratory Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, 755-8505, Japan
e) Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan


• Fatigue is a frequent symptom in both healthy individuals and patients, therefore, biomarkers indicating several differential levels of fatigue would be needed for evaluating fatigue and its improvement.
• Following the hard work term, the mean values of oxidative stress increased; however, anti-oxidative activity did not decrease, except only one case.
• Measured of oxidative stress (d-ROMS) and anti-oxidative activity (BAP) might be useful for discriminating acute, sub-acute, and resting fatigue in healthy people from patients with CFS, or for evaluating fatigue levels in healthy people.


We sought to determine whether oxidative stress and anti-oxidative activity could act as biomarkers that discriminate patients with chronic fatigue syndrome (CFS) from healthy volunteers at acute and sub-acute fatigue and resting conditions.

We calculated the oxidative stress index (OSI) from reactive oxygen metabolites-derived compounds (d-ROMs) and the biological antioxidant potential (BAP). We determined changes in d-ROMs, BAP, and OSI in acute and sub-acute fatigue in two healthy groups, and compared their values at rest between patients with CFS (diagnosed by Fukuda 1994 criteria) and another group of healthy controls.

Following acute fatigue in healthy controls, d-ROMs and OSI increased, and BAP decreased. Although d-ROMs and OSI were significantly higher after sub-acute fatigue, BAP did not decrease.

Resting condition yielded higher d-ROMs, higher OSI, and lower BAP in patients with CFS than in healthy volunteers, but lower d-ROMs and OSI when compared with sub-acute controls.

BAP values did not significantly differ between patients with CFS and controls in the sub-acute condition. However, values were significantly higher than in the resting condition for controls.

Thus, measured of oxidative stress (d-ROMS) and anti-oxidative activity (BAP) might be useful for discriminating acute, sub-acute, and resting fatigue in healthy people from patients with CFS, or for evaluating fatigue levels in healthy people.

From Neuroscience and Biobehavioural Reviews, 18 May 2016

Dysregulated stress signal sensitivity and inflammatory disinhibition as a pathophysiological mechanism of stress-related chronic fatigue

Jana Strahler (a), Nadine Skoluda (a), Nicolas Rohleder(b), Urs M Nater(a)
a) Clinical Biopsychology, University of Marburg, Gutenbergstrasse 18, Marburg, 35037, Germany
b) Health Psychology, Friedrich-Alexander-University Erlangen-Nuremberg, Nägelsbachstrasse 49a, Erlangen 91052, Germany


• We review stress signal sensitivity of immune cells in chronic stress and fatigue.
• Chronic stress seems to result in resistance of immune cells to stress signals.
• Findings on stress signal sensitivity under acute stress were inconclusive.
• Pathological consequences (self-maintaining inflammation, fatigue) are discussed.


Chronic stress and its subsequent effects on biological stress systems have long been recognized as predisposing and perpetuating factors in chronic fatigue, although the exact mechanisms are far from being completely understood.

In this review, we propose that sensitivity of immune cells to glucocorticoids (GCs) and catecholamines (CATs) may be the missing link in elucidating how stress turns into chronic fatigue.

We searched for in vitro studies investigating the impact of GCs or CATs on mitogen-stimulated immune cells in chronically stressed or fatigued populations, with 34 original studies fulfilling our inclusion criteria. Besides mixed cross-sectional findings for stress- and fatigue-related changes of GC sensitivity under basal conditions or acute stress, longitudinal studies indicate a decrease with ongoing stress.

Research on CATs is still scarce, but initial findings point towards a reduction of CAT sensitivity under chronic stress. In the long run, resistance of immune cells to stress signals under conditions of chronic stress might translate into self-maintaining inflammation and inflammatory disinhibition under acute stress, which in turn lead to fatigue.

Shopping Basket