Support for the microgenderome invites enquiry into sex differences

Abstract:

The microgenderome defines the interaction between microbiota, sex hormones and the immune system. Our recent research inferred support for the microgenderome by showing sex differences in microbiota-symptom associations in a clinical sample of patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

This addendum expands upon the sex-specific pattern of associations that were observed. Interpretations are hypothesized in relation to genera versus species-level analyses and D-lactate theory. Evidence of sex-differences invites future research to consider sex comparisons in microbial function even when microbial abundance is statistically similar. Pairing assessment of clinical symptoms with microbial culture, DNA sequencing and metabolomics methods will help advance our current understandings of the role of the microbiome in health and disease.

 

Source: Wallis A, Butt H, Ball M, Lewis DP, Bruck D. Support for the microgenderome invites enquiry into sex differences. Gut Microbes. 2017 Jan 2;8(1):46-52. doi: 10.1080/19490976.2016.1256524. Epub 2016 Nov 3. https://www.ncbi.nlm.nih.gov/pubmed/27808584

 

‘PACE-Gate’: When clinical trial evidence meets open data access

Abstract:

Science is not always plain sailing and sometimes the voyage is across an angry sea. A recent clinical trial of treatments for chronic fatigue syndrome (the PACE trial) has whipped up a storm of controversy. Patients claim the lead authors overstated the effectiveness of cognitive behavioural therapy and graded exercise therapy by lowering the thresholds they used to determine improvement. In this extraordinary case, patients discovered that the treatments tested had much lower efficacy after an information tribunal ordered the release of data from the PACE trial to a patient who had requested access using a freedom of information request.

© The Author(s) 2016.

 

Source: Geraghty KJ. ‘PACE-Gate’: When clinical trial evidence meets open data access. J Health Psychol. 2016 Nov 1. pii: 1359105316675213. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27807258

 

Psychological wellbeing and quality-of-life among siblings of paediatric CFS/ME patients: A mixed-methods study

Abstract:

Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a disabling condition known to have a negative impact on all aspects of a child’s life. However, little is understood about the impact of CFS/ME on siblings.

A total of 34 siblings completed questionnaires measuring depression (Hospital Anxiety and Depression Scale (HADS)), anxiety (HADS and Spence Children’s Anxiety Scale (SCAS)) and European Quality-of-life-Youth (EQ-5D-Y). These scores were compared with scores from normative samples. Siblings had higher levels of anxiety on the SCAS than adolescents of the same age recruited from a normative sample; however, depression and quality-of-life were similar. Interviews were undertaken with nine siblings of children with CFS/ME who returned questionnaires. Interview data were analysed using a framework approach to thematic analysis.

Siblings identified restrictions on family life, ‘not knowing’ and lack of communication as negative impacts on their family, and change of role/focus, emotional reactions and social stigma as negative impacts on themselves. They also described positive communication, social support and extra activities as protective factors.

Paediatric services should be aware of the impact of CFS/ME on the siblings of children with CFS/ME, understand the importance of assessing paediatric CFS/ME patients within the context of their family and consider providing information for siblings about CFS/ME.

© The Author(s) 2015.

 

Source: Velleman S, Collin SM, Beasant L, Crawley E. Psychological wellbeing and quality-of-life among siblings of paediatric CFS/ME patients: A mixed-methods study. Clin Child Psychol Psychiatry. 2016 Oct;21(4):618-633. Epub 2015 Sep 22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094299/ (Full article)

 

Metagenomic Investigation of Plasma in Individuals with ME/CFS Highlights the Importance of Technical Controls to Elucidate Contamination and Batch Effects

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating disease causing indefinite fatigue. ME/CFS has long been hypothesised to have an infectious cause; however, no specific infectious agent has been identified.

We used metagenomics to analyse the RNA from plasma samples from 25 individuals with ME/CFS and compare their microbial content to technical controls as well as three control groups: individuals with alternatively diagnosed chronic Lyme syndrome (N = 13), systemic lupus erythematosus (N = 11), and healthy controls (N = 25).

We found that the majority of sequencing reads were removed during host subtraction, thus there was very low microbial RNA content in the plasma. The effects of sample batching and contamination during sample processing proved to outweigh the effects of study group on microbial RNA content, as the few differences in bacterial or viral RNA abundance we did observe between study groups were most likely caused by contamination and batch effects.

Our results highlight the importance of including negative controls in all metagenomic analyses, since there was considerable overlap between bacterial content identified in study samples and control samples. For example, Proteobacteria, Firmicutes, Actinobacteria, and Bacteriodes were found in both study samples and plasma-free negative controls. Many of the taxonomic groups we saw in our plasma-free negative control samples have previously been associated with diseases, including ME/CFS, demonstrating how incorrect conclusions may arise if controls are not used and batch effects not accounted for.

 

Source: Miller RR, Uyaguari-Diaz M, McCabe MN, Montoya V, Gardy JL, Parker S, Steiner T, Hsiao W, Nesbitt MJ, Tang P, Patrick DM; CCD Study Group. Metagenomic Investigation of Plasma in Individuals with ME/CFS Highlights the Importance of Technical Controls to Elucidate Contamination and Batch Effects. PLoS One. 2016 Nov 2;11(11):e0165691. doi: 10.1371/journal.pone.0165691. ECollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091812/ (Full article)

 

Binocular Vision in Chronic Fatigue Syndrome

Abstract:

INTRODUCTION AND PURPOSE: To compare binocular vision measurements between Chronic Fatigue Syndrome (CFS) patients and healthy controls.

METHODS: Forty-one CFS patients referred by the Reference Centre for Chronic Fatigue Syndrome of the Antwerp University Hospital and forty-one healthy volunteers, matched for age and gender, underwent a complete orthoptic examination. Data of visual acuity, eye position, fusion amplitude, stereopsis, ocular motility, convergence, and accommodation were compared between both groups.

RESULTS: Patients with CFS showed highly significant smaller fusion amplitudes (P < 0.001), reduced convergence capacity (P < 0.001), and a smaller accommodation range (P < 0.001) compared to the control group.

CONCLUSION: In patients with CFS binocular vision, convergence and accommodation should be routinely examined. CFS patients will benefit from reading glasses either with or without prism correction in an earlier stage compared to their healthy peers. Convergence exercises may be beneficial for CFS patients, despite the fact that they might be very tiring. Further research will be necessary to draw conclusions about the efficacy of treatment, especially regarding convergence exercises. To our knowledge, this is the first prospective study evaluating binocular vision in CFS patients.

© 2016 Board of regents of the University of Wisconsin System, American Orthoptic Journal, Volume 66, 2016, ISSN 0065-955X, E-ISSN 1553-4448.

 

Source: Godts D, Moorkens G, Mathysen DG. Binocular Vision in Chronic Fatigue Syndrome. Am Orthopt J. 2016 Jan;66(1):92-97. https://www.ncbi.nlm.nih.gov/pubmed/27799582

 

Investigation of the effects of vanilloids in chronic fatigue syndrome

Abstract:

AIM OF THE STUDY: To assess the effectiveness of TRPV1 modulators in animal model of Chronic fatigue syndrome (CFS). To assess central and peripheral behavioral activity of TRPV1 modulators.

MATERIAL AND METHODS: CFS was induced by forcing the rats to swim for 10min for 21 consecutive days. The rats were treated with capsaicin (TRPV1 agonist, 2.5mg/kg) and n-tert-butylcyclohexanol (TRPV1 antagonist, 10mg/kg) for 21days 30min before the exposure to stress procedure. The behavioral consequence of CFS was measured in terms of immobility time, grip strength, locomotor activity, and anxiety level using Rota rod, Actophotometer, and Elevated plus maze model respectively. The other parameters include Plasma corticosterone, adrenal gland and spleen weight, complete blood count, blood urea niterogen (BUN), Lactate dehydrogenase (LDH), Lipid peroxidation, catalase and reduced glutathione (GSH).

RESULTS AND DISCUSSION: TRPV1 modulators reversed (p<0.05) the increase in immobility period, anxiety, spleen weight, BUN and LDH levels, and MDA levels along with decrease in grip strength, locomotor activity, plasma corticosterone, adrenal gland weight, catalase, and GSH. There was also significant increase in total WBC count when compared with the disease control group. The reversal was attributed to modulation of HPA axis, oxidative stress, anaerobic respiration product, muscle degradation product.

CONCLUSION: The present study reveals the effectiveness of n-tert-butylcyclohexanol and capsaicin against chronic fatigue syndrome. The mechanism of action can be attributed to inhibition of TRPV1 channel and thereby modulating pain perception, neuroendocrine function, oxidative stress and immune function.

Copyright © 2016 Elsevier Inc. All rights reserved.

 

Source: Sarvaiya K, Goswami S. Investigation of the effects of vanilloids in chronic fatigue syndrome. Brain Res Bull. 2016 Oct;127:187-194. doi: 10.1016/j.brainresbull.2016.09.015. Epub 2016 Sep 28. https://www.ncbi.nlm.nih.gov/pubmed/27693335

 

Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways

Abstract:

There is evidence that immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways play a role in the pathophysiology of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS). There is also evidence that these neuroimmune diseases are accompanied by hypothalamic-pituitary-adrenal (HPA) axis hypoactivity as indicated by lowered baseline glucocorticoid levels.

This paper aims to review the bidirectional communications between immune-inflammatory and O&NS pathways and HPA axis hypoactivity in ME/CFS, considering two possibilities: (a) Activation of immune-inflammatory pathways is secondary to HPA axis hypofunction via attenuated negative feedback mechanisms, or (b) chronic activated immune-inflammatory and O&NS pathways play a causative role in HPA axis hypoactivity.

Electronic databases, i.e., PUBMED, Scopus, and Google Scholar, were used as sources for this narrative review by using keywords CFS, ME, cortisol, ACTH, CRH, HPA axis, glucocorticoid receptor, cytokines, immune, immunity, inflammation, and O&NS.

Findings show that activation of immune-inflammatory and O&NS pathways in ME/CFS are probably not secondary to HPA axis hypoactivity and that activation of these pathways may underpin HPA axis hypofunction in ME/CFS. Mechanistic explanations comprise increased levels of tumor necrosis factor-α, T regulatory responses with elevated levels of interleukin-10 and transforming growth factor-β, elevated levels of nitric oxide, and viral/bacterial-mediated mechanisms.

HPA axis hypoactivity in ME/CFS is most likely a consequence and not a cause of a wide variety of activated immune-inflammatory and O&NS pathways in that illness.

 

Source: Morris G, Anderson G, Maes M. Hypothalamic-Pituitary-Adrenal Hypofunction in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) as a Consequence of Activated Immune-Inflammatory and Oxidative and Nitrosative Pathways. Mol Neurobiol. 2016 Oct 20. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27766535

 

Elevated Energy Production in Chronic Fatigue Syndrome Patients

Abstract:

Chronic Fatigue Syndrome (CFS) is a debilitating disease characterized by physical and mental exhaustion. The underlying pathogenesis is unknown, but impairments in certain mitochondrial functions have been found in some CFS patients. To thoroughly reveal mitochondrial deficiencies in CFS patients, here we examine the key aspects of mitochondrial function in blood cells from a paired CFS patient-control series. Surprisingly, we discover that in patients the ATP levels are higher and mitochondrial cristae are more condensed compared to their paired controls, while the mitochondrial crista length, mitochondrial size, shape, density, membrane potential, and enzymatic activities of the complexes in the electron transport chain remain intact. We further show that the increased ATP largely comes from non-mitochondrial sources. Our results indicate that the fatigue symptom in this cohort of patients is unlikely caused by lack of ATP and severe mitochondrial malfunction. On the contrary, it might be linked to a pathological mechanism by which more ATP is produced by non-mitochondrial sources.

 

Source: Lawson N, Hsieh CH, March D, Wang X. Elevated Energy Production in Chronic Fatigue Syndrome Patients. J Nat Sci. 2016;2(10). pii: e221. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065105/ (Full article)

 

‘It’s personal to me’: A qualitative study of depression in young people with CFS/ME

Abstract:

BACKGROUND: Paediatric chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has a prevalence of 0.4-2.4% and is defined as ‘generalised disabling fatigue persisting after routine tests and investigations have failed to identify an obvious underlying cause’. One-third of young people with CFS/ME have probable depression. Little is known about why depression develops, the relationship between depression and CFS/ME, or what treatment might be helpful.

METHODS: We conducted nine semi-structured interviews with young people with CFS/ME (aged 13-17 years, 8/9 female) and probable depression, covering perceived causes of depression, the relationship between CFS/ME and depression, and treatment strategies.

RESULTS: Most thought CFS/ME caused depression. Many discussed a cyclical relationship: low mood made CFS/ME worse. A sense of loss was common. CFS/ME restricted activities participants valued and changed systemic structures, causing depression. There was no single helpful treatment approach. Individualised approaches using combinations of cognitive behavioural therapy (CBT), medication, activity management and other strategies were described.

CONCLUSION: This study suggests that depression may be secondary to CFS/ME in young people because of the impact of CFS/ME on quality of life. Clinicians treating young people with CFS/ME need to consider strategies to prevent development of depression, and research is needed into approaches that are effective in treating CFS/ME with co-morbid depression.

© The Author(s) 2016.

 

Source: Taylor AK, Loades M, Brigden AL, Collin SM, Crawley E. ‘It’s personal to me’: A qualitative study of depression in young people with CFS/ME. Clin Child Psychol Psychiatry. 2016 Oct 14. pii: 1359104516672507. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27742756

 

Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels

Abstract:

Transient receptor potential melastatin subfamily 3 (TRPM3) ion channels play a role in calcium (Ca2+ ) cell signalling. Reduced TRPM3 protein expression has been identified in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) patients. However, the significance of TRPM3 and association with intracellular Ca2+ mobilization has yet to be determined.

Fifteen CFS/ME patients (mean age 48·82 ± 9·83 years) and 25 healthy controls (mean age 39·2 ± 12·12 years) were examined. Isolated natural killer (NK) cells were labelled with fluorescent antibodies to determine TRPM3, CD107a and CD69 receptors on CD56dim CD16+ NK cells and CD56bright CD16dim/- NK cells. Ca2+ flux and NK cytotoxicity activity was measured under various stimulants, including pregnenolone sulphate (PregS), thapsigargin (TG), 2-aminoethoxydiphenyl borate (2APB) and ionomycin.

Unstimulated CD56bright CD16dim/- NK cells showed significantly reduced TRPM3 receptors in CFS/ME compared with healthy controls (HC). Ca2+ flux showed no significant difference between groups. Moreover, PregS-stimulated CD56bright CD16dim/- NK cells showed a significant increase in Ca2+ flux in CFS/ME patients compared with HC. By comparison, unstimulated CD56dim CD16+ NK cells showed no significant difference in both Ca2+ flux and TRPM3 expression. PregS-stimulated CD56dim CD16+ NK cells increased TRPM3 expression significantly in CFS/ME, but this was not associated with a significant increase in Ca2+ flux.

Furthermore, TG-stimulated CD56dim CD16+ NK cells increased K562 cell lysis prior to PregS stimulation in CFS/ME patients compared with HC. Differential expression of TRPM3 and Ca2+ flux between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in CFS/ME.

© 2016 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.

 

Source: Nguyen T, Johnston S, Clarke L, Smith P, Staines D, Marshall-Gradisnik S. Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels. Clin Exp Immunol. 2017 Feb;187(2):284-293. doi: 10.1111/cei.12882. Epub 2016 Nov 23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217865/ (Full article)