TGI-Plus1 Friday | Our weekly round-up of recently published research abstracts | 18 March 2016

From PLoS One, 11 March 2016. Open access.

MicroRNAs hsa-miR-99b, hsa-miR-330, hsa-miR-126 and hsa-miR-30c: Potential Diagnostic Biomarkers in Natural Killer (NK) Cells of Patients with Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME).

Robert D. Petty(1,2), Neil E. McCarthy(3), Rifca Le Dieu(2), Jonathan R. Kerr(1,4)
1) CFS Group, St George´s University of London, Cranmer Terrace, London, United Kingdom.
2) Centre for Haemato-Oncology, Bart's Cancer Institute, Queen Mary University of London, London, United Kingdom.
3) Centre for Immunobiology, The Blizzard institute, Queen Mary University of London, London, United Kingdom.
4) Grupo de Salud Publica, Escuela de Medicine y Ciencias de la Salud, Universidad del Rosario, Quinta de Mutis, Bogotá 111221,
Colombia.

Abstract

BACKGROUND

Chronic Fatigue Syndrome (CFS/ME) is a complex multisystem disease of unknown aetiology which causes debilitating symptoms in up to 1% of the global population.

Although a large cohort of genes have been shown to exhibit altered expression in CFS/ME patients, it is currently unknown whether microRNA (miRNA) molecules which regulate gene translation contribute to disease pathogenesis.

We hypothesized that changes in microRNA expression in patient leukocytes contribute to CFS/ME pathology, and may therefore represent useful diagnostic biomarkers that
can be detected in the peripheral blood of CFS/ME patients.

METHODS

miRNA expression in peripheral blood mononuclear cells (PBMC) from CFS/ME patients and healthy controls was analysed using the Ambion Bioarray V1. miRNA demonstrating differential expression were validated by qRT-PCR and then replicated in fractionated blood leukocyte subsets from an independent patient cohort.

The CFS/ME associated miRNA identified by these experiments were then transfected into primary NK cells and gene expression analyses conducted to identify their gene
targets.

RESULTS

Microarray analysis identified differential expression of 34 miRNA, all of which were up-regulated. Four of the 34 miRNA had confirmed expression changes by qRT-PCR.

Fractionating PBMC samples by cell type from an independent patient cohort identified changes in miRNA expression in NK-cells, B-cells and monocytes with the most significant abnormalities occurring in NK cells. Transfecting primary NK cells with hsa-miR-99b or hsa-miR-330-3p, resulted in gene expression changes consistent with NK cell activation but diminished cytotoxicity, suggesting that defective NK cell function contributes to CFS/ME
pathology.

CONCLUSION

This study demonstrates altered microRNA expression in the peripheral blood mononuclear cells of CFS/ME patients, which are potential diagnostic biomarkers. The greatest degree of miRNA deregulation was identified in NK cells with targets consistent with cellular activation and altered effector function.

From NeuroRegulation, 9 March 2016 (full text available).

Functional Neural Network Connectivity in Myalgic Encephalomyelitis

Marcie L. Zinn, Mark A. Zinn, Leonard A. Jason
Center for Community Research, DePaul University, Illinois, USA.

Abstract

Myalgic Encephalomyelitis (ME) is a chronic illness with debilitating neurocognitive impairment that remains poorly understood. Previous studies have characterized cognitive deficits as a process by which brain abnormalities are inferred from pre-established testing paradigms using neuroimaging with low temporal resolution. Unfortunately, this approach has been shown to provide limited predictive power, rendering it inadequate for the study of neuronal communication between synchronized regions.

More recent developments have highlighted the importance of modeling spatiotemporal dynamic interactions within and between large-scale and small-scale neural networks on a millisecond time scale. Here, we focus on recent emergent principles of complex cortical systems, suggesting how subtle disruptions of network properties could be related to significant disruptions in cognition and behavior found in ME.

This review, therefore, discusses how electrical neuroimaging methods with time-dependent metrics (e.g., coherence, phase, cross-frequency coupling) can be a useful approach for the understanding of the cognitive symptoms in ME. By providing a platform for utilizing real-time alterations of the perpetual signals as an outcome, the disruptions to higher-level cognition typically seen in ME can be readily identified, creating new opportunities for better diagnosis and targeted treatments.

From Population Health Metrics, 12 March 2016 (open access).

Methods of applying the 1994 case definition of chronic fatigue syndrome –impact on classification and observed illness characteristics

E. R. Unger, J.-M. S. Lin , H. Tian, B. M. Gurbaxani, R. S. Boneva, J. F. Jones

Abstract

BACKGROUND

Multiple case definitions are in use to identify chronic fatigue syndrome (CFS). Even when using the same definition, methods used to apply definitional criteria may affect results. The Centers for Disease Control and Prevention (CDC) conducted two population-based studies estimating CFS prevalence using the 1994 case definition; one relied on direct questions for criteria of fatigue, functional impairment and symptoms (1997 Wichita; Method 1), and the other used subscale score thresholds of standardized questionnaires for criteria (2004 Georgia; Method 2). Compared to previous reports the 2004 CFS prevalence estimate was higher, raising questions about whether changes in the method of operationalizing affected this and illness characteristics.

METHODS

The follow-up of the Georgia cohort allowed direct comparison of both methods of applying the 1994 case definition. Of 1961 participants (53 % of eligible) who completed the detailed telephone interview, 919 (47 %) were eligible for and 751 (81 %) underwent clinical evaluation including medical/psychiatric evaluations. Data from the 499 individuals with complete data and without exclusionary conditions was available for this analysis.

RESULTS

A total of 86 participants were classified as CFS by one or both methods; 44 cases identified by both methods, 15 only identified by Method 1, and 27 only identified by Method 2 (Kappa 0.63; 95 % confidence interval [CI]: 0.53, 0.73 and concordance 91.59 %). The CFS group identified by both methods were more fatigued, had worse functioning, and more symptoms than those identified by only one method. Moderate to severe depression was noted in only one individual who was classified as CFS by both methods. When comparing the CFS groups identified by only one method, those only identified by Method 2 were either similar to or more severely affected in fatigue, function, and symptoms than those only identified by Method 1.

CONCLUSIONS

The two methods demonstrated substantial concordance. While Method 2 classified more participants as CFS, there was no indication that they were less severely ill or more depressed. The classification differences do not fully explain the prevalence increase noted in the 2004 Georgia study. Use of standardized instruments for the major CFS domains provides advantages for disease stratification and comparing CFS patients to other illnesses.

From the Journal of the American Academy of Physician Assistants, published online on 10 March 2016 (open access).

Recognizing postural orthostatic tachycardia syndrome.

Pavlik, Daniel MSPAS, PA-C; Agnew, Donna MSPAS, PA-C, DFAAPA; Stiles, Lauren JD; Ditoro, Rachel MSPAS, PA-C
Daniel Pavlik is an assistant professor in the Department of Medical Science at Arcadia University in Glenside, Pa., and practices in the ED at Our Lady of Lourdes Medical Center in Camden, N.J.
Donna Agnew is an associate professor and director of the PA program at Salus University in Elkins Park, Pa., and practices internal medicine at Fountainville (Pa.) Medical Specialists.
Lauren Stiles is the co-founder of Dysautonomia International, a nonprofit focused on advancing research on POTS and other autonomic disorders.
Rachel Ditoro is an assistant professor in Arcadia University’s Department of Medical Science.

Abstract

This article describes the pathophysiology, clinical presentation, differential diagnosis, diagnosis, and management of postural orthostatic tachycardia syndrome (POTS), a potentially debilitating autonomic disorder that can have many causes and presentations. POTS can be mistaken for panic disorder, inappropriate sinus tachycardia, and chronic fatigue syndrome. Clinician suspicion for the syndrome is key to prompt patient diagnosis and treatment.

From Mayo Clinic Proceedings, published online 11 March 2016.

Opioid Use in Fibromyalgia: A Cautionary Tale

Don L. Goldenberg, MD, Daniel J. Clauw, MD, Roy E. Palmer, DPhil, Andrew G. Clair, PhD

Abstract

Multiple pharmacotherapies are available for the treatment of fibromyalgia (FM), including opioid analgesics. We postulate that the mechanism of action of traditional opioids predicts their lack of efficacy in FM.

Literature searches of the MEDLINE and Cochrane Library databases were conducted using the search term opioid AND fibromyalgia to identify relevant articles, with no date limitations set. Citation lists in returned articles and personal archives of references were also examined for additional relevant items, and articles were selected based on the expert opinions of the authors.

We found no evidence from clinical trials that opioids are effective for the treatment of FM. Observational studies have found that patients with FM receiving opioids have poorer outcomes than patients receiving nonopioids, and FM guidelines recommend against the use of opioid analgesics. Despite this, and despite the availability of alternative Food and Drug Administration–approved pharmacotherapies and the efficacy of nonpharmacologic therapies, opioids are commonly used in the treatment of FM.

Factors associated with opioid use include female sex; geographic variation; psychological factors; a history of opioid use, misuse, or abuse; and patient or physician preference.

The long-term use of opioid analgesics is of particular concern in the United States given the ongoing public health emergency relating to excess prescription opioid consumption. The continued use of opioids to treat FM despite a proven lack of efficacy, lack of support from treatment guidelines, and the availability of approved pharmacotherapy options provides a cautionary tale for their use in other chronic pain conditions.

And the ME Association's new research assistant, SOPHIE LOUP, considers the implications of another recently published research study:

Shukla SK, et al. (2015) Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). PLoS ONE 10(12): e0145453. Available at: dx.doi.org/10.1371%2Fjournal.pone.0145453.

LAY SUMMARY

The worsening of symptoms experienced by ME/CFS patients after exercise is a useful way to uncover potential differences between patients and controls that might not be apparent at rest.

Unhealthy changes in the flora of the intestines and systemic responses to gut microorganisms may play a role in the symptoms of ME/CFS. This paper hypothesises that post-exertional malaise could be due to bacteria leaving the intestine to go into the blood circulation.

To test this, the authors collected symptom reports and blood and stool samples from ten ME/CFS patients meeting the Fukuda criteria and ten healthy controls matched on age, gender, BMI, and self-reported general activity patterns. The samples were collected before and 15 minutes, 48 hours, and 72 hours after a maximal exercise challenge. The exercise challenge consisted in pedalling on a stationary bike at an increasing rate of difficulty, until the patient could no longer maintain a specified rhythm.

Following maximal exercise challenge, there was an increase in relative abundance of 6 of the 9 major bacterial groups in the stool of ME/CFS patients from the first sample collection to 72 hours post-exercise, compared to only 2 of the 9 groups in controls. In the stool of controls, the relative abundance of most major bacterial groups decreased at 72h. Furthermore, there was an increase in a type of bacteria in the blood of ME/CFS patients at 48h hours but not in the blood of controls.

The study suggests that the intestinal flora and the translocation of bacteria from the intestine to the blood may be altered following exercise in ME/CFS patients, and this may account for the post-exertional malaise they experience. This means treatments aimed at preventing these alterations, such as probiotics, dietary fibres or others, could be tested in the future with a better understanding of their mechanism of action.

Caution is still in order however, as the sample size was very small. This means the researchers cannot assert that their results were not due solely to chance. They were also unable to assess the direct association between changes in symptoms and changes to the gut flora and bacteria in the blood.