TGI Friday! Our weekly round-up of recently published research abstracts and related items | 26 September 2014

September 26, 2014

From PLoSONE, 19 September 2014.

High-Throughput Sequencing of Plasma MicroRNA in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Ekua W. Brenu(1,2,*), Kevin J. Ashton(3), Jana Batovska(3), Donald R. Staines(2, 4), Sonya M. Marshall-Gradisnik (1, 2)
1) School of Medical Science, Griffith Health Centre, Griffith University, Gold Coast, Queensland, Australia
2) The National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, Queensland, Australia
3) Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia
4) Queensland Health, Gold Coast Public Health Unit, Robina, Gold Coast, Queensland, Australia
*) Corresponding Author Email:



MicroRNAs (miRNAs) are known to regulate many biological processes and their dysregulation has been associated with a variety of diseases including Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The recent discovery of stable and reproducible miRNA in plasma has raised the possibility that circulating miRNAs may serve as novel diagnostic markers. The objective of this study was to determine the role of plasma miRNA in


Using Illumina high-throughput sequencing we identified 19 miRNAs that were differentially expressed in the plasma of CFS/ME patients in comparison to non-fatigued controls. Following RT-qPCR analysis, we were able to confirm the significant up-regulation of three miRNAs (hsa-miR-127-3p, hsa-miR-142-5p and hsa-miR-143-3p) in the CFS/ME patients.


Our study is the first to identify circulating miRNAs from CFS/ME patients and also to confirm three differentially expressed circulating miRNAs in CFS/ME patients, providing a basis for further study to find useful CFS/ME biomarkers.

From Clinical Pathology, 19 September 2014 (first published online).

Use of single-nucleotide polymorphisms (SNPs) to distinguish gene expression subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

Nana Shimosako(1), Jonathan R Kerr(1,2)
1) CFS Group, Department of Cellular & Molecular Medicine, St George's University of London, London, UK
2) Escuela de Medicina y Ciencias de Salud, Universidad del Rosario, Bogota, Colombia



We have reported gene expression changes in patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and the fact that such gene expression data can be used to identify subtypes of CFS/ME with distinct clinical phenotypes. Due to the difficulties in using a comparative gene expression method as an aid to CFS/ME disease and subtype-specific diagnosis, we have attempted to develop such a method based on single-nucleotide polymorphism (SNP) analysis.


To identify SNP allele associations with CFS/ME and CFS/ME subtypes, we tested genomic DNA of patients with CFS/ME (n=108), patients with endogenous depression (n=17) and normal blood donors (n=68) for 504 human SNP alleles located within 88 CFS-associated human genes using the SNP Genotyping GoldenGate Assay (Illumina, San Diego, California, USA). 360 ancestry informative markers (AIM) were also examined.


21 SNPs were significantly associated with CFS/ME compared with depression and normal groups. 148 SNP alleles had a significant association with one or more CFS/ME subtypes. For each subtype, associated SNPs tended to be grouped together within particular genes.

AIM SNPs indicated that 4 subjects were of Asian origin while the remainder were Caucasian. Hierarchical clustering of AIM data revealed
the relatedness between 2 couples of patients with CFS only and confirmed the overall heterogeneity of all subjects.


This study provides evidence that human SNPs located within CFS/ME associated genes are associated with particular genomic subtypes of CFS/ME. Further work is required to develop this into a clinically useful subtype-specific diagnostic test.

From Cytokine, published online on 16 September 2014.

The role of cytokines in the cerebrospinal fluids of patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)

Sonya Marshall-Gradisnik(1), Gunnar Gottschalk(2), Sandra Ramos(1), Ekua Brenu(1), Don Staines(1), Dan Peterson(2)
1) Griffith University, Parklands, QLD, Australia
2) Simmaron Research, Incline Village, NV, USA



Previous research has provided evidence for a dysregulation in cytokine levels in the periphery of patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). To date few studies have examined cytokines in the cerebrospinal fluid. The purpose of this research is to examine the role of cytokines in the symptom presentation of CFS/ME patients.


Cerebrospinal fluid (CSF) was collected from 18 CFS/ME patients and 5 healthy controls. The CSF samples were examined for the expression of 27 cytokines [interleukin (IL)-1ββ, IL-1ra, IL-2, IL-4, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17, basic FGF, eotaxin, G-CSF, GM-CSF, IFN-γγ, IP-10, MCP-1 (MCAF), MIP-1αα, MIP-1ββ, PDGF-BB, RANTES, TNF-αα and VEGF] using the bio-plex human cytokine 27-plex assay.


Of the cytokines examined, only four were significantlY reduced in the CFS/ME patients in comparison to the controls.


The results show a decrease in pro-inflammatory cytokines in the CSF of CFS/ME patients and this may contribute to the clinical disease progression.

From Microbial Ecology in Health & Disease, 19 September 2014.


Intestinal staphylococcal small colony variants: a cause of medically unexplained physical symptoms?

Irritable bowel syndrome (IBS) is often associated with food intolerances, fibromyalgia, and chronic fatigue (1), a symptom cluster commonly denoted as medically unexplained physical symptoms. We here present three cases which may give new thoughts concerning the etiology of the condition.

Case 1:

A male veterinarian, age 57. At age 38, he was treated with several long-lasting courses of antibiotics due to epididymitis. He thereafter developed IBS and subsequently musculoskeletal pain and chronic fatigue. Following an open knee injury complicated with chronic infection with antibiotic-resistant Staphylococcus epidermidis at age 55, his systemic complaints deteriorated, forcing him to restrict his veterinary practice considerably. He himself had discovered similar bacterial growth from swabs of his own rectal mucosa as from the mucinous secretion of his injured knee.


Fig. 1. Swabs from rectal mucosa plated directly on mannitol-salt agar. The samples are from two different patients with irritable bowel syndrome, chronic fatigue and fibromyalgia. Normal coagulase-negative staphylococci (CNS) is seen in mixed population with small colony variants (SCV). The bacteria to the right are mannitol fermenting.

Case 2:

A male physician, age 60. At age 21, he got severe IBS following several courses of antibiotics due to recurrent airways infections. Subsequently, he gradually developed musculoskeletal pain and chronic fatigue which forced him to reduce his workload to less than the half. Some hearing loss and a slight aortic valve insufficiency were also diagnosed.

Case 3:

A female physician, age 55. At age 35, she developed mild IBS following multiple courses of antibiotics for nasal sinusitis. Subsequently, she gradually developed mild mental fatigue and facial rosacea. At age 54, following an episode of acute gastroenteritis combined with stress related to the death of a near family member, she developed severe IBS. Simultaneously, she experienced worsening of her mental fatigue and the rosacea as well as having additional symptoms (such as joint stiffness). With considerable efforts, she maintains full job.

Common to all three cases is a normal routine physical and laboratory examination and no apparent cause of their abdominal and systemic complaints which also included food intolerances. Upper endoscopy was unremarkable. However, duodenal biopsies showed increased (but within normal limits) counts of intraepithelial lymphocytes (IELs), and the patients had all growth of numerous pin-point clear staphylococcal small colony variants (SCVs) in virtually pure culture, when brush samples from the duodenum were plated directly on mannitol salt agar. In a supplementary investigation, we examined 50 patients with similar symptomatology with brush samples from deep in the nasal cavity and from the rectal mucosa 3–4 cm above the anal sphincter. From these locations, all patients had growth of coagulase-negative staphylococci (CNS) in a mixed population with SCVs (Fig. 1).

CNS species are considered normal commensals on skin and mucosal membranes and therefore often ignored by clinicians. However, in both humans and animals, CNS is now a growing concern due to persistent infections at several body sites (2). By switching to a SCV phenotype, metabolism is slowed down, enabling intracellular growth and escape from antibiotics and immunological attacks (3). In fact, formation of SCVs may be a consequence of antibiotic therapy (4), as might be the case in the present cases. Extensive growth of CNS in the gastrointestinal tract of patients with IBS is therefore a potentially important finding. Some earlier studies with a staphylococcal vaccine suggested that staphylococcal infections may be involved in the pathogenesis of fibromyalgia and chronic fatigue (5), but we were unable to find reports on any relationship between staphylococcal infections and IBS. The present cases remind us that intestinal CNS, and maybe staphylococcal SCVs in particular, should not be neglected as a possible cause of IBS and associated conditions (1). The disease mechanisms may involve activation of innate immunity (note increased numbers of duodenal IELs), which in turn will modify tryptophan metabolism with a range of consequences including impaired brain and gut functions as outlined earlier (6).

Arnold Berstad
Unger-Vetlesen’s Institute
Lovisenberg Diakonale Hospital, Oslo, Norway

Olav Hauso
Unger-Vetlesen’s Institute
Lovisenberg Diakonale Hospital, Oslo, Norway

Jørgen Valeur
Unger-Vetlesen’s Institute
Lovisenberg Diakonale Hospital, Oslo, Norway


1. Berstad A, Undseth R, Lind R, Valeur J. Functional bowel symptoms, fibromyalgia and fatigue: a food-related triad? Scand J Gastroenterol 2012; 47: 914–19.
2. Proctor RA, von Eiff C, Kahl BC, Becker K, McNamara P, Herrmann M, et al. Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat Rev Microbiol 2006; 4: 295–305.
3. Baddour LM, Simpson WA, Weems JJ, Jr, Hill MM, Christensen GD. Phenotypic selection of small-colony variant forms of Staphylococcus epidermidis in the rat model of endocarditis. J Infect Dis 1988; 157: 757–63.
4. Proctor RA, Kahl B, von Eiff C, Vaudaux PE, Lew DP, Peters G. Staphyl
5. Zachrisson O, Colque-Navarro P, Gottfries CG, Regland B, Mollby R. Immune modulation with a staphylococcal preparation in fibromyalgia/chronic fatigue syndrome: relation between antibody levels and clinical improvement. Eur J Clin Microbiol Infect Dis 2004; 23: 98–105.
6. Berstad A, Raa J, Valeur J. Tryptophan: ‘essential’ for the pathogenesis of irritable bowel syndrome? Scand J Gastroenterol 2014: 1–6. doi: 10.3109/00365521.2014.936034. Publisher Full Text

From Biology (Basel), 22 September 2014.

Discerning Primary and Secondary Factors Responsible for Clinical Fatigue in Multisystem Diseases.

Maughan D(1), Toth M(2).
1) Department of Molecular Physiology & Biophysics, University of Vermont, Burlington, VT 05405, USA.
2) Department of Molecular Physiology & Biophysics, University of Vermont, Burlington, VT 05405, USA.


Fatigue is a common symptom of numerous acute and chronic diseases, including myalgic encephalomyelitis/chronic fatigue syndrome, multiple sclerosis, heart failure, cancer, and many others. In these multi-system diseases the physiological determinants of enhanced fatigue encompass a combination of metabolic, neurological, and myofibrillar adaptations.

Previous research studies have focused on adaptations specific to skeletal muscle and their role in fatigue. However, most have neglected the contribution of physical inactivity in assessing disease syndromes, which, through deconditioning, likely contributes to symptomatic fatigue.

In this commentary, we briefly review disease-related muscle phenotypes in the context of whether they relate to the primary disease or whether they develop secondary to reduced physical activity. Knowledge of the etiology of the skeletal muscle adaptations in these conditions and their contribution
to fatigue symptoms is important for understanding the utility of exercise rehabilitation as an intervention to alleviate the physiological precipitants of fatigue.

From Frontiers in Neurology, 19 September 2014.


Clinical features associated with Macrophagic Myofasciitis

Muriel Rigolet(2), Jessie Aouizerat(2,3), Maryline Couette(3), Nilusha Thangarajah(1,2), Mehdi Aoun-Sebaita(3), Romain K. Gherardi(1,2,3), Josette Cadusseau(1,2) and Francois Jerome Authier(1,2,3*)
1) Paris Est-Creteil University, France
2) U955-Team 10, INSERM, France
3) Henri Mondor University Hospital, APHP, France


Macrophagic myofasciitis (MMF) is an emerging condition characterized by specific muscle lesions assessing abnormal long-term persistence of aluminium hydroxide within macrophages at the site of previous immunization.

Affected patients usually are middle-aged adults, mainly presenting with diffuse arthromyalgias, chronic fatigue, and marked cognitive deficits, not related to pain, fatigue or depression. Clinical features usually correspond to that observed in chronic fatigue syndrome/myalgic encephalomyelitis.

Representative features of MMF-associated cognitive dysfunction include dysexecutive syndrome, visual memory impairment and left ear extinction at dichotic listening test. Most patients fulfil criteria for non-amnestic/dysexecutive mild cognitive impairment, even if some cognitive deficits appear unusually severe.

Cognitive dysfunction seems stable over time despite marked fluctuations. Evoked potentials may show abnormalities in keeping with central nervous system involvement, with a neurophysiological pattern suggestive of demyelination.

Brain perfusion SPECT shows a pattern of diffuse cortical and subcortical abnormalities, with hypoperfusions correlating with cognitive deficiencies. The combination of musculoskeletal pain, chronic fatigue and cognitive disturbance generates chronic disability with possible social exclusion. Classical therapeutic approaches are usually unsatisfactory making patient care difficult.

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