​Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia
January 23, 2018
New research published in Fatigue: Biomedicine, Health & Behavior found ventricular lactate (lactate present in cerebrospinal fluid) might serve as a biological marker of underlying brain dysfunction for patients with chronic fatigue syndrome (CFS), fibromyalgia (FM), and those with a dual diagnosis. The study, titled “Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia”, also found evidence for a unitary hypothesis of the pathophysiology of CFS and FM – that is, they are different presentations of the same condition.
The study was authored by Dr. Natelson, of the Pain & Fatigue Study Center at Beth Israel Medical Center, in conjunction with pain specialists, clinicians, and quantitative experts. The team used neuroimaging to measure ventricular lactate in subjects across three diagnostic groups – FM only, CFS only, or CFS plus FM – and compared to healthy controls. A modified version of the 1994 Fukuda (CDC) criteria was used to select CFS patients.
The group found that, relative to healthy controls, ventricular lactate was higher in all illness groups included in the study. Elevations in ventricular lactate suggests a shift to anaerobic processes and a problem with brain-related mitochondrial metabolism across the CFS-FM spectrum. The authors conclude that, while there is evidence that ventricular lactate measured by neuroimaging can be used as a biomarker of syndromes characterized by medically unexplained pain or fatigue, this result does not indicate it can be used to differentiate CFS from FM.
Previous work from 2008 considering the relationship between ventricular lactate and ME/CFS also used a condition with symptomatic overlap as a study comparison group. The researchers looked at ventricular lactate levels in individuals with CFS (diagnosed with the 1994 guidelines) and Generalized Anxiety Disorder (GAD) – a condition that includes fatigue with an unknown origin as a hallmark symptom. However, this study found an abnormal increase in ventricular lactate in CFS relative to the comparison group (GAD). Unlike the connection between FM and CFS supported by Dr. Natelson’s study, this finding suggests distinct neurobiological differences between CFS and GAD.
CFS and FM were found to have statistically indistinguishable levels of lactate in the recent finding detailed in Fatigue, but we don’t have proof this reflects the same underlying cause. Nonetheless, ventricular lactate is indicated as a viable biomarker of underlying brain dysfunction for some patients with either or both diagnoses. The authors note that further research will be needed to further address if CFS and FM are different illnesses or variations of the same condition.
New Therapies in Irritable Bowel Syndrome: What Works and WhenOrla Craig
Curr Opin Gastroenterol. 2018;34(1):50-56. 

Abstract and IntroductionPurpose of review. The purpose of this review is to examine the evidence supporting the use of recently developed pharmacological treatments for IBS together with new evidence supporting more traditional therapies in order to understand where the new agents are best used in the treatment pathway.
Recent findings. There is evidence to support the use of traditional treatments such as antispasmodics, antidepressants and dietary alteration in IBS. New therapeutic agents such as Linaclotide, Lubiprostone, Plecanatide, Rifaxamin and Eluxadoline are all more effective than placebo in treating symptoms of IBS with Tenapanor being a promising new agent. The majority of patients, however, treated with these medications remain symptomatic and they are not suitable for use in all patients.
Summary. Traditional treatments such as antispasmodics, antidepressants, dietary and lifestyle modifications retain their importance in the treatment of IBS with the newer agents to be considered wherever these treatments are ineffective or poorly tolerated.

 
Stigma in Myalgic Encephalomyelitis and its association with functioning
Don M. Baken, Shane T. Harvey, David L. Bimler & Kirsty J. Ross
Pages 30-40 | Received 20 Oct 2016, Accepted 17 Dec 2017, Published online: 04 Jan 2018
https://doi.org/10.1080/21641846.2018.1419553
 
ABSTRACT
Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is categorised by the World Health Organisation as a neurological condition. It is poorly understood and people with ME/CFS report experiencing stigma. Research suggests that stigma might be linked to functional ability.
Purpose: This study investigated the relationship of stigma to factors associated with functional ability. Additionally, the use of standardised measures allowed for comparison of stigma severity in ME/CFS to other neurological conditions.
Method: A convenience sample of 206 people diagnosed with ME/CFS completed mailed or online self-report standardised measures of stigma, health, ability to participate in social roles and activities, and their satisfaction with this ability. Findings were compared to published data for three neurological conditions.
Results: Stigma scores were significantly correlated (p < .0001) with all self-report health and functional measures (range: −.30 to −.42). The ME/CFS sample reported higher levels of stigma (d = 1.30) and lower levels of health (d = 1.86–2.16) and functioning (d = 1.63) than the comparison conditions.
Conclusions: Consistent with studies over the last two decades, people with ME/CFS report higher levels of stigma when compared to the other conditions. The stigma is not just associated with health but also with specific measures of functional ability.
 

 
Gen Med Open, 2017          doi: 10.15761/GMO.1000117 Volume 1(3): 1-13
ISSN: 2515-4737
An analysis of Dutch hallmark studies confirms the outcome of the PACE trial: cognitive behaviour therapy with a graded activity protocol is not effective for chronic fatigue syndrome and Myalgic Encephalomyelitis
FNM Twisk1* and LAMM Corsius2  1ME-de-patiënten Foundation, Limmen, the Netherlands 2 Independent researchers, Etten-Leur, The Netherlands
Abstract Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS) are considered to be enigmatic diseases. Several studies propose that the combination of cognitive behaviour therapy with a graded activity protocol (CBT+), justified by a so-called (bio)psychosocial (explanatory) model, is an effective treatment option for CFS (ME).
 Objective A critical review of five Dutch hallmark studies that allegedly support this claim.
Methods An analysis of the five CBT+ studies with special attention to the patients studied, the criteria (subjective and objective measures and cut-off scores) used to select participants and to define improvement and recovery, the consistency of the definitions of caseness (being diagnosed as a CFS patient at entry) versus the definitions of improvement and recovery after CBT+, and the objective effects.
Results The studies investigated suffer from various methodological flaws. Apart from these methodological shortcomings, the claim that CBT+ is an effective treatment option for CFS is not substantiated by the data reported. Some studies investigated CFS patients, other studies investigated CF patients, labelled as CFS patients, or combinations of CFS and CF patients. No study investigated the effect of CBT+ in a group of patients meeting the (original) diagnostic criteria for ME. The effects of CBT+ on subjective measures, for example fatigue and disability, if present, are insufficient to achieve normal values. Impressive recovery and improvement rates are based on very loose criteria for subjective measures. Cut-off scores for subjective measures used to define improvement and recovery in studies show overlap with cut-off scores for CFS caseness in one or more of the other studies. More importantly, looking at the objective measures, the proof of clinical improvement after CBT+ is lacking.
Conclusion Solid evidence of effectiveness of CBT+ for CFS, let alone ME, is lacking in the five hallmark studies. The lack of objective improvement indicates CBT+ is ineffective. This finding confirms the outcome of the large-scale PACE-trial in the UK.

 
Elevated brain natriuretic peptide levels in chronic fatigue syndrome associate with cardiac dysfunction: a case control studyAuthorsCara Tomas, Andreas Finkelmeyer, Tim Hodgson, Laura MacLachlan, Guy A MacGowan, Andrew M Blamire, Julia L Newton
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
AbstractObjectives: To explore levels of the brain natriuretic peptide (BNP) and how these associate with the cardiac abnormalities recently identified in chronic fatigue syndrome (CFS).
Methods: Cardiac magnetic resonance examinations were performed using 3T Philips Intera Achieva scanner (Best, Netherlands) in CFS (Fukuda) participants and sedentary controls matched group wise for age and sex. BNP was also measured by using an enzyme immunoassay in plasma from 42 patients with CFS and 10 controls.
Results: BNP levels were significantly higher in the CFS cohort compared with the matched controls (P=0.013). When we compared cardiac volumes (end-diastolic and end-systolic) between those with high BNP levels (BNP >400 pg/mL) and low BNP (<400 pg/mL), there were significantly lower cardiac volumes in those with the higher BNP levels in both end-systolic and end-diastolic volumes (P=0.05). There were no relationships between fatigue severity, length of disease and BNP levels (P=0.2) suggesting that our findings are unlikely to be related to deconditioning.
Conclusion: This study confirms an association between reduced cardiac volumes and BNP in CFS. Lack of relationship between length of disease suggests that findings are not secondary to deconditioning. Further studies are needed to explore the utility of BNP to act as a stratification paradigm in CFS that directs targeted treatments.
PublicationTomas et al, Open Heart, 2017 Dec 27; 4(2):e000697

 
Ticks transmitting Lyme disease are found in a third of Britain, mainly the south
BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k692 (Published 12 February 2018) Cite this as: BMJ 2018;360:k692
Ticks responsible for transmitting Lyme disease are distributed widely around the UK, a team from Public Health England has found.1
Data from a surveillance scheme that has been running since 2005 showed that the number of sites where ticks have been found have nearly doubled from 2010 to 2016. Dividing Britain into squares of 10 km on each side, the 2016 data show that ticks were reported in 36% of the squares, up from 20% before 2010. In Greater London 80% of the grid squares contained ticks, compared with 67% in southeast England. The Midlands, by contrast, seemed relatively free of ticks.
The increases may result from better awareness of ticks, said the study authors, led by Benjamin Cull,

 
Pain Physician. 2018 Jan;21(1):E13-E24Cerebral Blood Flow and Heart Rate Variability in Chronic Fatigue Syndrome: A Randomized Cross-Over Study.Malfliet A1, Pas R2, Brouns R3, De Win J4, Hatem SM5, Meeus M6, Ickmans K7, van Hooff RJ3, Nijs J8.
AbstractBACKGROUND: Pain, fatigue, and concentration difficulties are typical features of chronic fatigue syndrome (CFS). The exact underlying mechanisms of these symptoms are still unknown, but available evidence suggests an important role for impaired pain modulation. As evidence also suggests that pain modulation is related to cardiovascular mechanisms, it seems logical to investigate whether cerebral blood flow (CBF) and heart rate variability (HRV) are altered in these patients.
OBJECTIVES:
We aimed to investigate the role of the cardiovascular system in pain modulation and symptoms of CFS; the response of CBF and HRV to physical stress and their relation to the change in temporal summation (TS) of pressure pain and self-reported symptoms was evaluated.
STUDY DESIGN: A controlled, randomized cross-over trial.
SETTING: University Hospital Brussels.
METHODS:
Twenty CFS patients and 20 sedentary healthy controls were included in this study. In both of the groups, the change in TS of pressure pain, CBF (using transcranial Doppler), and HRV (using finger plethysmography) was examined during physical and emotional stress (to control for potential bias), as well as their association mutually and with self-reported symptoms of pain, fatigue, and concentrations difficulties.
RESULTS:
There was no significant interaction or group (F-values ranging from .100 to 1.862, P-values ranging from .754 to .181) effect in CBF or HRV parameters. HRV and CBF did change during physical exercise, but the changes did not differ between patients and controls. While pain scores during TS at the trapezius site reduced in the control group after the physical exercise protocol (P = .037), they did not change in the CFS group (P = .108), suggesting impaired pain modulation. There were no significant correlations between CBF, HRV, TS, and self-reported symptoms (all P-values of correlation analyses > .01).
LIMITATIONS: Although effect sizes were medium to large, the study sample was relatively low. Also, the mild nature of the exercise bout is discussable. Nonetheless, this mild exercise was able to provoke endogenous pain modulation in the control group, which endorsed a proper execution of the cycling exercise. Moreover, mild exercises are more applicable to daily physical activities in CFS patients than vigorous exercises.
CONCLUSION: These results seem to refute the previously suggested alterations of CBF/HRV in CFS patients. These cardiovascular parameters appear not to explain pain before, during, and following exercise.Brain Nerve. 2018 Jan;70(1):35-40. doi: 10.11477/mf.1416200947
 
[Immunopathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)].[Article in Japanese]Yamamura T1, Ono H, Sato W.
AbstractA recent study on the pathogenesis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has revealed an elevation of inflammatory and anti-inflammatory cytokines in the sera and cerebrospinal fluids of the patients and presence of autoantibodies in subgroups of ME/CFS patients. Furthermore, investigator-initiated clinical trials have proved the efficacy of anti-CD20 antibody (rituximab), that eliminate B cells, in the treatment of ME/CFS. Based on these findings, we hypothesize that immune abnormalities, such as enhanced autoimmune responses, may play an essential role in the neuroinflammatory pathogenesis of ME/CFS.
PMID:29348373
DOI:10.11477/mf.1416200947

 
Clin Physiol Funct Imaging. 2018 Jan;38(1):128-137. doi: 10.1111/cpf.12393. Epub 2016 Sep 28
Static and dynamic functional connectivity in patients with chronic fatigue syndrome: use of arterial spin labelling fMRI.Boissoneault J1, Letzen J1, Lai S2, Robinson ME1, Staud R3.
Author informationAbstractStudies using arterial spin labelling (ASL) have shown that individuals with chronic fatigue syndrome (CFS) have decreased regional cerebral blood flow, which may be associated with changes in functional neural networks. Indeed, recent studies indicate disruptions in functional connectivity (FC) at rest in chronically fatigued patients including perturbations in static FC (sFC), that is average FC at rest between several brain regions subserving neurocognitive, motor and affect-related networks. Whereas sFC often provides information of functional network reorganization in chronic illnesses, investigations of temporal changes in functional connectivity between multiple brain areas may shed light on the dynamic characteristics of brain network activation associated with such maladies. We used ASL fMRI in 19 patients with CFS and 15 healthy controls (HC) to examine both static and dynamic changes in FC among several a priori selected brain regions during a fatiguing cognitive task. HC showed greater increases than CFS in static FC (sFC) between insula and temporo-occipital structures and between precuneus and thalamus/striatum. Furthermore, inferior frontal gyrus connectivity to cerebellum, occipital and temporal structures declined in HC but increased in CFS. Patients also showed lower dynamic FC (dFC) between hippocampus and right superior parietal lobule. Both sFC and dFC correlated with task-related fatigue increases. These data provide the first evidence that perturbations in static and dynamic FC may underlie chronically fatigued patients' report of task-induced fatigue. Further research will determine whether such changes in sFC and dFC are also characteristic for other fatigued individuals, including patients with chronic pain, cancer and multiple sclerosis.
KEYWORDS:
MRI ; arterial spin labelling; chronic fatigue; dynamic functional connectivity
PMID:27678090
PMCID:PMC5373941[Available on 2019-01-01]
DOI:10.1111/cpf.12393

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J Psychosom Res. 2018 Jan;104:55-60. doi: 10.1016/j.jpsychores.2017.11.011. Epub 2017 Nov 20
Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patients.Vangeel EB1, Kempke S2, Bakusic J3, Godderis L4, Luyten P5, Van Heddegem L6, Compernolle V6, Persoons P7, Lambrechts D8, Izzi B9, Freson K10, Claes S11.
Author informationAbstractOBJECTIVE:
Although the precise mechanisms are not yet understood, previous studies have suggested that chronic fatigue syndrome (CFS) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and trauma in early childhood. Consistent with findings suggesting that early life stress-induced DNA methylation changes may underlie dysregulation of the HPA axis, we previously found evidence for the involvement of glucocorticoid receptor (GR) gene (NR3C1) methylation in whole blood of CFS patients.
METHODS:
In the current study, we assessed NR3C1-1F region DNA methylation status in peripheral blood from a new and independent sample of 80 female CFS patients and 91 female controls. In CFS patients, history of childhood trauma subtypes was evaluated using the Childhood Trauma Questionnaire short form (CTQ-SF).
RESULTS:
Although absolute methylation differences were small, the present study confirms our previous findings of NR3C1-1F DNA hypomethylation at several CpG sites in CFS patients as compared to controls. Following multiple testing correction, only CpG_8 remained significant (DNA methylation difference: 1.3% versus 1.5%, p<0.001). In addition, we found associations between DNA methylation and severity of fatigue as well as with childhood emotional abuse in CFS patients, although these findings were not significant after correction for multiple testing.
CONCLUSIONS:
In conclusion, we replicated findings of NR3C1-1F DNA hypomethylation in CFS patients versus controls. Our results support the hypothesis of HPA axis dysregulation and enhanced GR sensitivity in CFS.
Copyright © 2017 Elsevier Inc. All rights reserved.
KEYWORDS:
Childhood trauma; Chronic fatigue syndrome; DNA methylation; Glucocorticoid receptor; HPA axis; NR3C1
PMID:29275786
DOI:10.1016/j.jpsychores.2017.11.011

 
Int J Radiat Biol. 2018 Jan 10:1-17. doi: 10.1080/09553002.2018.1422871. [Epub ahead of printChronic fatigue and immune deficiency syndrome (CFIDS), cellular metabolism, and ionizing radiation: a review of contemporary scientific literature and suggested directions for future research.Rusin A1, Seymour C2, Mothersill C1.
Author informationAbstractPURPOSE:
To investigate biochemical pathways known to be involved in radiation response and in CFIDS to determine if there might be common underlying mechanisms leading to symptoms experienced by those accidentally or deliberately exposed to radiation and those suffering from CFIDS. If such a link was established to suggest testable hypotheses to investigate the mechanisms with the aim of identifying new therapeutic targets.
CONCLUSIONS:
Evidence for involvement of the alpha-synuclein, cytochrome c oxidase, αB-crystallin, RNase L, and lactate dehydrogenase/STAT1 pathways is strong and suggests a common underlying mechanism involving mitochondrial dysfunction mediated by ROS and disruption of ATP production. The downstream effect of this is compromised energy production. Testable hypotheses are suggested to investigate the involvement of these pathways further.
KEYWORDS:
Chronic fatigue syndrome; atomic veterans; bystander effects of radiation; post-radiation syndrome; reactive oxygen species (ROS)
PMID:29297728
DOI:10.1080/09553002.2018.1422871

 
Brain Nerve. 2018 Jan;70(1):11-18. doi: 10.11477/mf.1416200944
[Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome].[Article in Japanese]
Kuratsune H1.
AbstractWe present here the Japanese clinical diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) that were proposed in 2016 by the Japanese Ministry of Health, Labour and Welfare study group. The clinical diagnosis criteria of ME/CFS were created to be used by healthcare agencies in charge of primary care practice. We also explain the current prognosis in ME/CFS and medical treatments used in major medical institutions in Japan.
PMID:29348370
DOI:10.11477/mf.1416200944

 
J Psychosom Res. 2018 Jan;104:29-34. doi: 10.1016/j.jpsychores.2017.11.007. Epub 2017 Nov 8
Chronic fatigue syndrome (CFS/ME) symptom-based phenotypes and 1-year treatment outcomes in two clinical cohorts of adult patients in the UK and The Netherlands.Collin SM1, Heron J2, Nikolaus S3, Knoop H3, Crawley E2.
AbstractOBJECTIVE:
We previously described symptom-based chronic fatigue syndrome (CFS/ME) phenotypes in clinical assessment data from 7041 UK and 1392 Dutch adult CFS/ME patients. Here we aim to replicate these phenotypes in a more recent UK patient cohort, and investigate whether phenotypes are associated with 1-year treatment outcome.
METHODS:
12 specialist CFS/ME services (11 UK, 1 NL) recorded the presence/absence of 5 symptoms (muscle pain, joint pain, headache, sore throat, and painful lymph nodes) which can occur in addition to the 3 symptoms (post-exertional malaise, cognitive dysfunction, and disturbed/unrefreshing sleep) that are present for almost all patients. Latent Class Analysis (LCA) was used to assign symptom profiles (phenotypes). Multinomial logistic regression models were fitted to quantify associations between phenotypes and overall change in health 1year after the start of treatment.
RESULTS:
Baseline data were available for N=918 UK and N=1392 Dutch patients, of whom 416 (45.3%) and 912 (65.5%) had 1-year follow-up data, respectively. 3- and 4-class phenotypes identified in the previous UK patient cohort were replicated in the new UK cohort. UK patients who presented with 'polysymptomatic' and 'pain-only' phenotypes were 57% and 67% less likely (multinomial odds ratio (MOR) 0.43 (95% CI 0.19-0.94) and 0.33 (95% CI 0.13-0.84)) to report that their health was "very much better" or "much better" than patients who presented with an 'oligosymptomatic' phenotype. For Dutch patients, polysymptomatic and pain-only phenotypes were associated with 72% and 55% lower odds of improvement (MOR 0.28 (95% CI 0.11, 0.69) and 0.45 (95% CI 0.21, 0.99)) compared with oligosymptomatic patients.
CONCLUSIONS:
Adult CFS/ME patients with multiple symptoms or pain symptoms who present for specialist treatment are much less likely to report favourable treatment outcomes than patients who present with few symptoms.
Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.
KEYWORDS:
Chronic fatigue syndrome; Latent class analysis; Phenotypes; Symptom profiles; Treatment outcomes
PMID:29275782
DOI:10.1016/j.jpsychores.2017.11.007

 
J Sch Health. 2018 Jan;88(1):74-89. doi: 10.1111/josh.12580.
Measuring School Functioning in Students With Chronic Fatigue Syndrome: A Systematic Review.Tollit M1, Politis J2, Knight S1.
Author informationAbstractBACKGROUND:
It is often surmised that school functioning is significantly impacted in chronic fatigue syndrome (CFS); however, how this phenomenon manifests itself has rarely been characterized.
METHODS:
This systematic review synthesized and critically appraised methods, constructs, and instruments used to assess school functioning in students with CFS. Searches were conducted in electronic databases (CINAHL, MEDLINE, PubMed, ERIC, and PsycINFO) to locate empirical studies that measured school functioning in children and adolescents with CFS.
RESULTS:
A total of 36 papers met the inclusion criteria. By far the most commonly reported school functioning construct measured related to school attendance. This was followed by academic functioning, achievement motivation, and educational services received. Little consistency was found in the measurement of these constructs across studies.
CONCLUSIONS:
The current review revealed that the school experiences of children and adolescents with CFS have rarely been characterized beyond school absenteeism. Improvements in current assessment methods are required to comprehensively understand the impact of CFS on school functioning. Completely understanding the multiple aspects of school functioning will help to inform targeted strategies to optimize educational outcomes for students with CFS.
© 2018, American School Health Association.
KEYWORDS:
child and adolescent health; chronic diseases; chronic fatigue syndrome; school functioning; school psychology
PMID:29224219
DOI:10.1111/josh.12580

 
Improvement of severe myalgic encephalomyelitis/chronic fatigue syndrome symptoms following surgical treatment of cervical spinal stenosis

• Peter C. Rowe, Colleen L. Marden, Scott Heinlein and Charles C. EdwardsII

Journal of Translational Medicine201816:21
https://doi.org/10.1186/s12967-018-1397-7
Received: 14 November 2017
Accepted: 24 January 2018

Published: 2 February 2018
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a potentially disabling disorder. Little is known about the contributors to severe forms of the illness. We describe three consecutive patients with severe ME/CFS whose symptoms improved after recognition and surgical management of their cervical spinal stenosis.
Methods
All patients satisfied clinical criteria for ME/CFS and orthostatic intolerance, and were later found to have cervical spinal stenosis. Overall function was assessed before and after surgery using the Karnofsky score and the SF-36 physical function subscale score.
Results
Neurological findings included > 3+ deep tendon reflexes in 2 of 3, a positive Hoffman sign in 2 of 3, tremor in 2 of 3, and absent gag reflex in 1 of 3. The cervical spine canal diameter in the three patients ranged from 6 to 8.5 mm. One had congenital cervical stenosis with superimposed spondylosis, and two had single- or two-level spondylosis. Anterior cervical disc replacement surgery in two patients and a hybrid anterior cervical disc fusion and disc replacement in the third was associated with a marked improvement in myelopathic symptoms, resolution of lightheadedness and hemodynamic dysfunction, improvement in activity levels, and improvement in global ME/CFS symptoms.
Conclusions
The prompt post-surgical restoration of more normal function suggests that cervical spine stenosis contributed to the pathogenesis of refractory ME/CFS and orthostatic symptoms. The improvements following surgery emphasize the importance of a careful search for myelopathic examination findings in those with ME/CFS, especially when individuals with severe impairment are not responding to treatment.
Keywords
Cervical stenosisCervical myelopathyChronic fatigue syndromeMyalgic encephalomyelitisPostural tachycardia syndromeOrthostatic intolerance
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1397-7

 
Eukaryotes in the gut microbiota in myalgic encephalomyelitis/chronic fatigue syndromeAlexandra H. Mandarano1, Ludovic Giloteaux1, Betsy A. Keller2, Susan M. Levine1, Maureen R. Hanson​1
Published January 22, 2018
PubMed 29375937
Abstract 
Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often suffer from gastrointestinal symptoms and many are diagnosed with irritable bowel syndrome (IBS). Previous studies, including from our laboratory, have demonstrated that the ME/CFS gut bacterial composition is altered and less diverse when compared to healthy individuals. Patients have increased biomarkers of inflammation and leaky gut syndrome. To further investigate dysbiosis in the ME/CFS gut microbiome, we sought to characterize the eukaryotes present in the gut of 49 individuals with ME/CFS and 39 healthy controls. Using 18S rRNA sequencing, we have identified eukaryotes in stool samples of 17 healthy individuals and 17 ME/CFS patients. Our analysis demonstrates a small, nonsignificant decrease in eukaryotic diversity in ME/CFS patients compared to healthy individuals. In addition, ME/CFS patients show a nonsignificant increase in the ratio of fungal phyla Basidiomycota to Ascomycota, which is consistent with ongoing inflammation in ME/CFS. We did not identify specific eukaryotic taxa that are associated with ME/CFS disease status.
Cite this as
Mandarano AH, Giloteaux L, Keller BA, Levine SM, Hanson MR. (2018) Eukaryotes in the gut microbiota in myalgic encephalomyelitis/chronic fatigue syndrome. PeerJ 6:e4282 https://doi.org/10.7717/peerj.4282
 
 
 

 
Front. Immunol., 15 February 2018 | https://doi.org/10.3389/fimmu.2018.00229
Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model
Jonas Blomberg1*,  Carl-Gerhard Gottfries2,  Amal Elfaitouri3,  Muhammad Rizwan1 and  Anders Rosén4

• 1Department of Medical Sciences, Uppsala University, Clinical Microbiology, Academic Hospital, Uppsala, Sweden
• 2Gottfries Clinic AB, Mölndal, Sweden
• 3Department of Infectious Disease and Tropical Medicine, Faculty of Public Health, Benghazi University, Benghazi, Libya
• 4Department of Clinical and Experimental Medicine, Division of Cell Biology, Linköping University, Linköping, Sweden

Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clinical picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metabolism. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy production and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of immunoglobulin variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.

Probiotics Antimicrob Proteins. 
2018 Feb 20. doi: 10.1007/s12602-018-9397-8. [Epub ahead of print]
A Systematic Review of Probiotic Interventions for Gastrointestinal Symptoms and Irritable Bowel Syndrome in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).Corbitt M1, Campagnolo N2,3, Staines D2,3, Marshall-Gradisnik S2,3.
AbstractGastrointestinal (GI) symptoms and irritable bowel (IB) symptoms have been associated with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The aim of this study was to conduct a systematic review of these symptoms in CFS/ME, along with any evidence for probiotics as treatment. Pubmed, Scopus, Medline (EBSCOHost) and EMBASE databases were searched to source relevant studies for CFS/ME. The review included any studies examining GI symptoms, irritable bowel syndrome (IBS) and/or probiotic use. Studies were required to report criteria for CFS/ME and study design, intervention and outcome measures. Quality assessment was also completed to summarise the level of evidence available. A total of 3381 publications were returned using our search terms. Twenty-five studies were included in the review. Randomised control trials were the predominant study type (n = 24). Most of the studies identified examined the effect of probiotic supplementation on the improvement of IB symptoms in IBS patients, or IB symptoms in CFS/ME patients, as well as some other significant secondary outcomes (e.g. quality of life, other gastrointestinal symptoms, psychological symptoms). The level of evidence identified for the use of probiotics in IBS was excellent in quality; however, the evidence available for the use of probiotic interventions in CFS/ME was poor and limited. There is currently insufficient evidence for the use of probiotics in CFS/ME patients, despite probiotic interventions being useful in IBS. The studies pertaining to probiotic interventions in CFS/ME patients were limited and of poor quality overall. Standardisation of protocols and methodology in these studies is required.
KEYWORDS:
Chronic fatigue syndrome; Gastrointestinal symptoms; Irritable bowel symptoms; Myalgic encephalomyelitis; Probiotics
PMID:    29464501 DOI:10.1007/s12602-018-9397-8



 
Metabolomics and Chronic Fatigue Syndrome—Testing an Exciting New Technology for Diagnosis and Management for ME/CFS and other illnessesThe OMF and the North American ME/CFS Metabolomics Study
Mitochondria – “Mitochondria” is not quite a household word, but when it comes to understanding complex chronic disease, it should be. Mitochondria are the hub of the wheel of metabolism.
More than 90% of the pathways that break down food into building blocks and 70% of the pathways that make new building blocks have at least one reaction that passes through mitochondria. These little bioreactors use the oxygen we breathe to turn food and drink into energy and to perform over 500 other important chemical reactions in the cell.
Mitochondria also have another key function: They stand guard over the cell, ready to defend it when things go wrong. When a virus attacks, or a toxin is detected, mitochondria stop what they were doing, change their shape and cellular locations, and take up arms to help defend the cell. Mitochondria then send messages in the form of metabolites to the nucleus of the cell and to neighboring cells to signal the danger so gene expression can be changed and neighboring cells can prepare for battle. Different signals are sent when the danger has passed to alert the cell that healing can proceed.
“Metabolomics is a new lens that allows us to ‘see’ this inner world of the cell in a new way that lends itself to scientific discovery. This new vision is leading to breakthroughs in our understanding of why patients with ME/CFS get stuck in a cycle of pain and suffering and disability.”– Dr. Robert Naviaux
Recent scientific discoveries in our lab have shown that several different chronic complex diseases can result when this “cell danger response” (CDR) gets stuck in the “on” position for too long. When the CDR gets stuck, normal healing can’t proceed.  If this happens, it could theoretically lead to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).
Metabolomics – Metabolomics is one of the hottest rising stars in the high tech race to gain a molecular understanding of health and disease. Metabolomics uses a machine called a “mass spectrometer” to measure hundreds of chemicals in our blood.
In our lab, at the University of California San Diego, with a single blood specimen, we can measure over 500 of these chemicals from over 60 different biochemical pathways.
These chemicals are the building blocks that cells use to grow and function, to fight and to heal. Like a Hubble telescope for medicine, metabolomics is allowing us to see deeper and with greater clarity into the universe of the cell than has ever been possible before. In a drop of blood, we can “eavesdrop” on the collective conversations of all the cells in the body.
In ME/CFS, as in many complex chronic diseases, many genes interact with many environmental factors encountered at times of vulnerability. Complex diseases are not predestined by our genes alone. Complex diseases are ecogenetic—resulting from the interaction of genes inherited from our ancestors and environmental factors we encounter in a lifetime. Our metabolism is the real-time readout of the gene-environment interaction. Metabolomics is a new lens that allows us to “see” this inner world of the cell in a new way that lends itself to scientific discovery.
This new vision is leading to breakthroughs in our understanding of why patients with ME/CFS get stuck in a cycle of pain and suffering and disability. But more importantly, metabolomics is also shedding light on how rational therapies designed to trigger a return to health might be just around the corner.
 

 
Association of chronic fatigue syndrome with premature telomere attrition

• Mangalathu S. Rajeevan Janna Murray, Lisa Oakley, Jin-Mann S. Lin and Elizabeth R. Unger

Journal of Translational Medicine201816:44
https://doi.org/10.1186/s12967-018-1414-x

 2018 Received: 23 October 2017 Accepted: 16 February 2018 Published: 27 February 2018
Abstract
Background
Chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), is a severely debilitating condition of unknown etiology. The symptoms and risk factors of ME/CFS share features of accelerated aging implicated in several diseases. Using telomere length as a marker, this study was performed to test the hypothesis that ME/CFS is associated with accelerated aging.
Methods
Participant (n = 639) data came from the follow-up time point of the Georgia CFS surveillance study. Using the 1994 CFS Research Case Definition with questionnaire-based subscale thresholds for fatigue, function, and symptoms, participants were classified into four illness groups: CFS if all criteria were met (n = 64), CFS-X if CFS with exclusionary conditions (n = 77), ISF (insufficient symptoms/fatigue) if only some criteria were met regardless of exclusionary conditions (n = 302), and NF (non-fatigued) if no criteria and no exclusionary conditions (n = 196). Relative telomere length (T/S ratio) was measured using DNA from whole blood and real-time PCR. General linear models were used to estimate the association of illness groups or T/S ratio with demographics, biological measures and covariates with significance set at p < 0.05.
Results
The mean T/S ratio differed significantly by illness group (p = 0.0017); the T/S ratios in CFS (0.90 ± 0.03) and ISF (0.94 ± 0.02) were each significantly lower than in NF (1.06 ± 0.04). Differences in T/S ratio by illness groups remained significant after adjustment for covariates of age, sex, body mass index, waist–hip ratio, post-exertional malaise and education attainment. Telomere length was shorter by 635, 254 and 424 base pairs in CFS, CFS-X and ISF, respectively, compared to NF. This shorter telomere length translates to roughly 10.1–20.5, 4.0–8.2 and 6.6–13.7 years of additional aging in CFS, CFS-X and ISF compared to NF respectively. Further, stratified analyses based on age and sex demonstrated that the association of ME/CFS with short telomeres is largely moderated by female subjects < 45 years old.
Conclusions
This study found a significant association of ME/CFS with premature telomere attrition that is largely moderated by female subjects < 45 years old. Our results indicate that ME/CFS could be included in the list of conditions associated with accelerated aging. Further work is needed to evaluate the functional significance of accelerated aging in ME/CFS.

 
Original Research ARTICLE
Front. Endocrinol. | doi: 10.3389/fendo.2018.00097
Higher prevalence of ‘low T3 syndrome’ in patients with chronic fatigue syndrome: A case-control study
Begoña Ruiz-Núñez1, 2*, Rabab Tarasse1, Emar Vogelaar3, Janneke Dijck-Brouwer1 and Frits Muskiet1

• 1Laboratory Medicine, University Medical Center Groningen, Netherlands
• 2Healthy Institute, Spain
• 3European Laboratory of Nutriënts (ELN), Netherlands

Chronic fatigue syndrome (CFS) is a heterogeneous disease with unknown cause(s). CFS symptoms resemble a hypothyroid state, possibly secondary to chronic (low-grade) (metabolic) inflammation. We studied 98 CFS patients (21-69 years, 21 males) and 99 age- and sex-matched controls (19-65 years, 23 males). We measured parameters of thyroid function, (metabolic) inflammation, gut wall integrity and nutrients influencing thyroid function and/or inflammation. Most remarkably, CFS patients exhibited similar TSH, but lower FT3 (difference of medians 0.1%), TT4 (11.9%), TT3 (12.5%), %TT3 (4.7%), SPINA-GD (14.4%), SPINA-GT (14.9%), 24-hour urinary iodine (27.6%) and higher %rT3 (13.3%). FT3 below the reference range, consistent with the 'low T3 syndrome', was found in 16/98 CFS patients vs. 7/99 controls (OR 2.56; 95% CI=1.00 - 6.54). Most observations persisted in two sensitivity analyses with more stringent cut-off values for BMI, hsCRP and WBC. We found possible evidence of (chronic) low-grade metabolic inflammation (ferritin and HDL-C). FT3, TT3, TT4 and rT3 correlated positively with hsCRP in CFS patients and all subjects. TT3 and TT4 were positively related to hsCRP in controls. Low circulating T3 and the apparent shift from T3 to rT3 may reflect more severely depressed tissue T3 levels. The present findings might be in line with recent metabolomic studies pointing at a hypometabolic state. They resemble a mild form of 'non thyroidal illness syndrome' and 'low T3 syndrome' experienced by a subgroup of hypothyroid patients receiving T4 monotherapy. Our study needs confirmation and extension by others. If confirmed, trials with e.g. T3 and iodide supplements might be indicated.
Keywords: chronic fatigue syndrome, thyroid, ‘low T3 syndrome’, Triiodothyronine, Reverse triiodothyronine, Urinary iodine, Inflammation, high sensitivity CRP.
Received: 28 Nov 2017; Accepted: 27 Feb 2018.
 

 
An Eye on "The Mitochondria Man" : Robert Naviaux and Chronic Fatigue Syndrome (ME/CFS)
Top of Form

This is the start of an "Eye On" series focusing on researchers new to the chronic fatigue syndrome/fibromyalgia research fields. Few researchers present more exciting possibilities for ME/CFS than Dr. Robert Naviaux at UC San Diego (UCSD).
Naviaux recently joined the Scientific Advisory Board of the Open Medicine Foundation (OMF) and he's believed to have co-authored a paper that is under review. Early reports suggest the Severe Patient Big Data study may, in its early stages, uncovered significant about the mitochondria in ME/CFS

In some ways Naviaux seems tailor-made for ME/CFS. Naviaux runs the Robert Naviaux Laboratory at UC San Diego, is the founder/ co-director of UCSD's Mitochondrial and Metabolic Disease Center, and co-founder and a former president of the Mitochondrial Medicine Society. This man is clearly a pioneer in the relatively new and emerging field of mitochondrial research but he has an interesting immune side as well.

Naviaux trained at the NIH in tumor immunology and natural killer cell biology, and at the Salk Institute in virology and gene therapy. If ME/CFS or FM turns out to have a viral/inflammation/mitochondrial connection it's hard to imagine someone better placed to take advantage of that.
Naviaux gained some renown in 2013 when he was able to reverse autism in a mouse model using a hypothesis that could help explain chronic fatigue syndrome and fibromyalgia as well. He proposed that a sustained "cell danger response" is causing the cells in autism to essentially to shut down, stop communicating with other cells and go into hibernation.

Naviaux believes that cells damaged by viruses, or toxins react defensively causing their membranes stiffen and the
“When cells are exposed to classical forms of dangers, such as a virus, infection or toxic environmental substance, a defense mechanism is activated. This results in changes to metabolism and gene expression, and reduces the communication between neighboring cells. Simply put, when cells stop talking to each other, children stop talking.” Naviaux
(That's an intriguing idea given the evidence of "immune exhaustion" in ME/CFS and FM, and the rather massive alterations of immune cell networks Gordon Broderick and Dr. Klimas have found in ME/CFS. Could immune cell shut downs be behind those network alterations? )

Everybody seems to believe that the innate or early immune response which causes inflammation is involved in ME/CFS but Naviaux has taken the conversation a step further by tying in the mitochondria. Naviaux knew the mitochondria were involved in inflammation - they can be huge emitters of free radicals - and looked for ways in which they interacted with the immune system. He found them in substances called "mitokines" such as ATP and adenosine that cells with distressed mitochondrial emit.

The purines and pyrimidines ( ATP, ADP, UTP, and UDP), produced by these damaged cells can effect everything from inflammation, neurotransmission, pain production, and autonomic nervous system activity. They bind to purinergic and other receptors on cells found from the circulatory to digestive to immune systems to the brain.

Sleeping Sickness Drug

Naviaux used a drug called suramin that battled sleeping sickness to reverse autism in his mouse model. An anti-purinergic signaling drug, suramin, Naviaux believes, stops the cell danger signal in its tracks. In two studies he's been able to show that the drug rebuilt the mouse's brain synapses, re -enabled stalled cell-to-cell signaling, improved its social behavior and motor coordination and normalized it's mitochondrial metabolism. The drug is now being tested in a small trial of autistic children.
Suramin is more of use for what it reveals than as a treatment possibility than a full-flung treatment. It can only be taken for couple of months but newer antipurinergic medicines might be able to be taken for longer or might just need to be taken intermittently.

As Naviaux developed his hypothesis that damaged cells are triggering purinergic signaling cascades in autism, Donald Staines in Australia was proposing vasoactive neuropeptides were doing much the same thing in ME/CFS. Staines also proposed that ATP and adenosine releases from cells with mitochondrial problems may be causing the purinergic signaling to go bananas in ME/CFS.

Meanwhile Alan Light's examination of physiological pathways linked to stress and distress in ME/CFS was uncovering issues with purinergic signaling as well. Light found that increased purinergic receptor activity was highly associated with post exertional fatigue after exercise in ME/CFS (but not MS). He, too, suggested that purinergic receptors in ME/CFS patients were reacting to ATP molecules emanating from stressed cells. Back in 2012 he proposed that purinergic receptor upregulation in ME/CFS was turning the microglia in the brain on and producing pain and fatigue in ME/CFS.

Naviaux and other ME/CFS researchers, then, may be coming from different directions and ending up in much the same place.

We don't know what Naviaux has found in ME/CFS - we're waiting on his publication for that; it could be something entirely different but his past research alone suggests that he is someone to watch.                                  
A member of the Health Rising Forums, Rachel Riggs, knows this first hand. After visiting Dr. Naviaux's lab she described a researcher who was very enthusiastic about ME/CFS, who mentioned linkages between autism and the disease - a disease, he thought, which put ME/CFS bodies in a kind of hibernation. Dr. Naviaux said his paper on ME/CFS will, if and when it is published, surprise a lot of people. Rachel had a palpable sense that the lab was on the cusp of something big.

Naviaux's got some big accomplishments behind him and some big toys to play with. His lab developed two advanced technologies; biocavity laser spectroscopy and mtDNA mutation detection by mass spectrometry, and recently created new bioinformatic methods that allow them to better analyze genetic data. Put all that together and Naviaux says he has the ability to "dissect the metabolic and molecular features of virtually any disease".

Naviaux appears to be all in ME/CFS. His biggest hurdle may be finding the money to fully study it. Hopefully the new approach by the NIH or the growing ability of ME/CFS donors to support exciting research will be enough.

Naviaux is part of an increasing focus on the mitochondria in ME/CFS research circles. The Chronic Fatigue Initiative has engaged Maureen Hanson to do a series of ME/CFS mitochondrial studies. Richard Deth, a mitochondrial expert, is working with Dr. Klimas at the Institute for Neuroimmune Institute in Florida. Dr. Saligan, a P2P report participant, and member of the NIH Intramural study is a bit of a wild card. His work on the stress response and catastrophizing has raised concerns, but his main research interest is focused on the physiological aspects of cancer fatigue.

Saligan has done studies on murine models of radiation induced fatigue, gene expression and cancer fatigue, prostate cancer and fatigue, inflammation and cancer fatigue, BDNF and fatigue, immunogenomic markers and fatigue, mitochondria and prostate fatigue, biomarkers and cancer fatigue and on and on and he's done one review on catastrophizing and fatigue.

 
Effect of tai chi versus aerobic exercise for fibromyalgia: comparative effectiveness randomized controlled trial
BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k851 (Published 21 March 2018)
Chenchen Wang, director and professor of medicine1,Christopher H Schmid, professor of biostatistics and co-director2,Roger A Fielding, director and professor of medicine3,William F Harvey, assistant professor of medicine1,Kieran F Reid, scientist III3,Lori Lyn Price, statistician4,Jeffrey B Driban, assistant professor of medicine1,Robert Kalish, associate professor of medicine5,Ramel Rones, tai chi instructor6,Timothy McAlindon, division chief and professor of medicine1
Abstract
Objectives To determine the effectiveness of tai chi interventions compared with aerobic exercise, a current core standard treatment in patients with fibromyalgia, and to test whether the effectiveness of tai chi depends on its dosage or duration.
Design Prospective, randomized, 52 week, single blind comparative effectiveness trial.
Setting Urban tertiary care academic hospital in the United States between March 2012 and September 2016.
Participants 226 adults with fibromyalgia (as defined by the American College of Rheumatology 1990 and 2010 criteria) were included in the intention to treat analyses: 151 were assigned to one of four tai chi groups and 75 to an aerobic exercise group.
Interventions Participants were randomly assigned to either supervised aerobic exercise (24 weeks, twice weekly) or one of four classic Yang style supervised tai chi interventions (12 or 24 weeks, once or twice weekly). Participants were followed for 52 weeks. Adherence was rigorously encouraged in person and by telephone.
Main outcome measures The primary outcome was change in the revised fibromyalgia impact questionnaire (FIQR) scores at 24 weeks compared with baseline. Secondary outcomes included changes of scores in patient’s global assessment, anxiety, depression, self efficacy, coping strategies, physical functional performance, functional limitation, sleep, and health related quality of life.
Results FIQR scores improved in all five treatment groups, but the combined tai chi groups improved statistically significantly more than the aerobic exercise group in FIQR scores at 24 weeks (difference between groups=5.5 points, 95% confidence interval 0.6 to 10.4, P=0.03) and several secondary outcomes (patient’s global assessment=0.9 points, 0.3 to 1.4, P=0.005; anxiety=1.2 points, 0.3 to 2.1, P=0.006; self efficacy=1.0 points, 0.5 to 1.6, P=0.0004; and coping strategies, 2.6 points, 0.8 to 4.3, P=0.005). Tai chi treatment compared with aerobic exercise administered with the same intensity and duration (24 weeks, twice weekly) had greater benefit (between group difference in FIQR scores=16.2 points, 8.7 to 23.6, P<0.001). The groups who received tai chi for 24 weeks showed greater improvements than those who received it for 12 weeks (difference in FIQR scores=9.6 points, 2.6 to 16.6, P=0.007). There was no significant increase in benefit for groups who received tai chi twice weekly compared with once weekly. Participants attended the tai chi training sessions more often than participants attended aerobic exercise. The effects of tai chi were consistent across all instructors. No serious adverse events related to the interventions were reported.
Conclusion Tai chi mind-body treatment results in similar or greater improvement in symptoms than aerobic exercise, the current most commonly prescribed non-drug treatment, for a variety of outcomes for patients with fibromyalgia. Longer duration of tai chi showed greater improvement. This mind-body approach may be considered a therapeutic option in the multidisciplinary management of fibromyalgia.

New Chronic Fatigue Syndrome Biomarkers in the Pipeline
Nicola M. Parry, DVM
July 31, 2017
 
Patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) have different circulating levels of two cytokines when compared with healthy individuals, a study has found. In addition, the circulating levels of 17 cytokines correlate with disease severity.
"Although only two cytokines were found to be different ([transforming growth factor-β (TGF-β)] higher and resistin lower) in ME/CFS patients compared with controls, 17 cytokines correlated with ME/CFS severity," the authors write. "Thirteen of these cytokines are proinflammatory and may contribute to many of the symptoms these patients experience for several years."
Jose G. Montoya, MD, from Stanford University School of Medicine in California, and colleagues published the results of their cross-sectional study online July 31 in the Proceedings of the National Academy of Sciences.
"There's been a great deal of controversy and confusion surrounding ME/CFS, even whether it is an actual disease," senior author Mark Davis, PhD, professor of immunology and microbiology and director of Stanford's Institute for Immunity, Transplantation and Infection, said in a news release. "Our findings show clearly that it's an inflammatory disease and provide a solid basis for a diagnostic blood test."
ME/CFS affects more than 1 million Americans and is characterized by unexplained chronic fatigue, as well as other symptoms including exertion intolerance, headaches, myalgias, and sleep and cognitive abnormalities. Although the pathogenesis of this disabling disorder remains incompletely understood, inflammation has long been considered to play a central role.
Surprisingly, however, traditional markers of inflammation that have been used in clinical practice, such as erythrocyte sedimentation rate and C-reactive protein, are rarely elevated in patients with ME/CFS. Nevertheless, studies have demonstrated changes in other inflammatory markers in this patient population.
For example, several studies have found increased numbers of circulating cytotoxic CD8+ cells expressing activation antigens in these patients; one study also described daily fluctuations of the pro-inflammatory adipokine leptin, and another study linked a distinct cytokine inflammatory profile with early disease.
The researchers therefore aimed to investigate whether patients with ME/CFS have an abnormal profile of circulating cytokines, and whether this profile correlates with disease severity and duration.
They analyzed blood samples from 192 ME/CFS patients and from 392 healthy individuals and performed immunological analyses of the samples, measuring the concentrations of 51 cytokines in each participant's blood.
When comparing patients with ME/CFS with healthy individuals, the investigators found differences in the circulating levels of only two of the 51 cytokines: TGF-β was increased (P = .0052) in patients with ME/CFS, and resistin was decreased (P = .0052). In addition, levels of resistin were significantly lower in patients with mild (P = .0370) and severe (P = .0208) ME/CFS.
Pro-inflammatory Cytokines Elevated
Concentrations of 17 cytokines correlated with disease severity, showing a statistically significant upward linear trend across the sequence of mild, moderate, and severe manifestations of ME/CFS: CCL11 (P = .0069), CXCL1 (P = .0266), CXCL10 (P = .0100), G-CSF (P = .0110), GM-CSF (P = .0063), interferon γ (P = .0101), interleukin 4 (IL-4; P = .0103), IL-5 (P = .0073), IL-7 (P = .0063), IL-12p70 (P = .0069), IL-13 (P = .0069), IL-17F (P = .0103), leptin (P = .0100), leukemia inhibitory factor (P = .0100), nerve growth factor (P = .0069), stem cell factor (P = .0145), and TGF-α (P = .0367).
Thirteen of these were pro-inflammatory. Elevations in these pro-inflammatory cytokines not only highlight the strong immune component of the disease but also likely contribute to many of the symptoms experienced by patients with ME/CFS, the authors write.
Although the researchers also examined the relationship between cytokine concentration and fatigue duration, they found that only the level of CXCL9 (monokine induced by interferon γ) inversely correlated with fatigue duration (P= .0123).
As TGF-β is predominantly considered to be an anti-inflammatory cytokine, the researchers explain that the elevated levels of TGF-β elevation in patients with ME/CFS may reflect down-regulatory activity by these patients' immune systems against continued inflammation. However, if this were true, TGF-β levels would be expected to correlate with ME/CFS severity, which was not the case in this study.
Thus, TGF-β may not always function to counteract inflammation. Instead, "its net effect may depend on the local immunological milieu at target tissues and the overall levels of TGF-β," they say.
Resistin has significant pro-inflammatory activity and is reportedly a marker of inflammation in patients with systemic lupus erythematosus and Crohn's disease. However, the authors are unclear why resistin levels showed an unusual trend, increasing in patients with mild to moderate ME/CFS, but decreasing in those with moderate to severe disease.
Acknowledging the cross-sectional design as one limitation of their study, the authors emphasize longitudinal studies are needed to determine whether patients with ME/CFS remain within their cytokine signature and disease severity category over time, or fluctuate among them.
"Future cytokine research in the peripheral blood of ME/CFS patients should embrace longitudinal designs and seek correlations with neuroradiology, neuroinflammation, and [cerebrospinal fluid]studies," the authors add.
Proc Natl Acad Sci U S A. Published online July 31, 2017. 

 
Update and new insights in encephalitis
A. Mailles

• Corresponding author. A. Mailles, Santé publique France, 12 rue du Val d'Osne, 94415 Saint-Maurice cedex, France.

J.-P. Stahl     K.C. Bloch   Editor: C. Pulcini
DOI: http://dx.doi.org/10.1016/j.cmi.2017.05.002
Publication History
Published online: May 10, 2017Accepted: May 1, 2017
; Received in revised form: April 30, 2017; Received: February 2, 2017;
ScienceDirect.
Abstract
Infectious encephalitis is a rare but severe medical condition resulting from direct invasion of the brain by viruses, bacteria, fungi or parasites, or indirect post-infectious immune or inflammatory disorders when the infectious agent does not cross the blood–brain barrier. Infectious encephalitis cases represent an interesting and accurate sentinel to follow up on trends in infectious diseases or to detect emerging infections. Using Pubmed and Embase, we searched the most relevant publications over the last years. We present here an update on the important findings and new data recently published about infectious encephalitis.

 
Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case–control study

• Tara Gomes, David N. Juurlink, Tony Antoniou, Muhammad M. Mamdani, J. Michael Paterson, 
• Wim van den Brink

 
Published: October 3, 2017 - https://doi.org/10.1371/journal.pmed.1002396
Abstract
Background
Prescription opioid use is highly associated with risk of opioid-related death, with 1 of every 550 chronic opioid users dying within approximately 2.5 years of their first opioid prescription. Although gabapentin is widely perceived as safe, drug-induced respiratory depression has been described when gabapentin is used alone or in combination with other medications. Because gabapentin and opioids are both commonly prescribed for pain, the likelihood of co-prescription is high. However, no published studies have examined whether concomitant gabapentin therapy is associated with an increased risk of accidental opioid-related death in patients receiving opioids. The objective of this study was to investigate whether co-prescription of opioids and gabapentin is associated with an increased risk of accidental opioid-related mortality.
Methods and findings
We conducted a population-based nested case–control study among opioid users who were residents of Ontario, Canada, between August 1, 1997, and December 31, 2013, using administrative databases. Cases, defined as opioid users who died of an opioid-related cause, were matched with up to 4 controls who also used opioids on age, sex, year of index date, history of chronic kidney disease, and a disease risk index. After matching, we included 1,256 cases and 4,619 controls. The primary exposure was concomitant gabapentin use in the 120 days preceding the index date. A secondary analysis characterized gabapentin dose as low (<900 mg daily), moderate (900 to 1,799 mg daily), or high (≥1,800 mg daily). A sensitivity analysis examined the effect of concomitant nonsteroidal anti-inflammatory drug (NSAID) use in the preceding 120 days. Overall, 12.3% of cases (155 of 1,256) and 6.8% of controls (313 of 4,619) were prescribed gabapentin in the prior 120 days. After multivariable adjustment, co-prescription of opioids and gabapentin was associated with a significantly increased odds of opioid-related death (odds ratio [OR] 1.99, 95% CI 1.61 to 2.47, p < 0.001; adjusted OR [aOR] 1.49, 95% CI 1.18 to 1.88, p < 0.001) compared to opioid prescription alone. In the dose–response analysis, moderate-dose (OR 2.05, 95% CI 1.46 to 2.87, p < 0.001; aOR 1.56, 95% CI 1.06 to 2.28, p = 0.024) and high-dose (OR 2.20, 95% CI 1.58 to 3.08, p < 0.001; aOR 1.58, 95% CI 1.09 to 2.27, p = 0.015) gabapentin use was associated with a nearly 60% increase in the odds of opioid-related death relative to no concomitant gabapentin use. As expected, we found no significant association between co-prescription of opioids and NSAIDs and opioid-related death (OR 1.11, 95% CI 0.98 to 1.27, p = 0.113; aOR 1.14, 95% CI 0.98 to 1.32, p =0.083). In an exploratory analysis of patients at risk of combined opioid and gabapentin use, we found that 46.0% (45,173 of 98,288) of gabapentin users in calendar year 2013 received at least 1 concomitant prescription for an opioid. This study was limited to individuals eligible for public drug coverage in Ontario, we were only able to identify prescriptions reimbursed by the government and dispensed from retail pharmacies, and information on indication for gabapentin use was not available. Furthermore, as with all observational studies, confounding due to unmeasured variables is a potential source of bias.
Conclusions  In this study we found that among patients receiving prescription opioids, concomitant treatment with gabapentin was associated with a substantial increase in the risk of opioid-related death. Clinicians should consider carefully whether to continue prescribing this combination of products and, when the combination is deemed necessary, should closely monitor their patients and adjust opioid dose accordingly. Future research should investigate whether a similar interaction exists between pregabalin and opioids.
 
Journal of Affective Disorders
Volume 225, Pages 13–17
Vegetarian diets and depressive symptoms among men
Joseph R. HibbelnKate Northstone, Jonathan Evans, Jean Golding
DOI: http://dx.doi.org/10.1016/j.jad.2017.07.051
 
Highlights
Little is known about mental health benefits or risks of vegetarian diets.
Vegetarian men had higher depression scores after adjustment for potential confounding factors.
Nutritional deficiencies may account for these findings, but reverse causation and residual confounding cannot be ruled out.
Abstract
Background
Vegetarian diets are associated with cardiovascular and other health benefits, but little is known about mental health benefits or risks.
Aims
To determine whether self-identification of vegetarian dietary habits is associated with significant depressive symptoms in men.
Method
Self-report data from 9668 adult male partners of pregnant women in the Avon Longitudinal Study of Parents and Children (ALSPAC) included identification as vegetarian or vegan, dietary frequency data and the Edinburgh Post Natal Depression Scale (EPDS). Continuous and binary outcomes were assessed using multiple linear and logistic regression taking account of potential confounding variables including: age, marital status, employment status, housing tenure, number of children in the household, religion, family history of depression previous childhood psychiatric contact, cigarette and alcohol consumption.
Results
Vegetarians [n = 350 (3.6% of sample)], had higher depression scores on average than non-vegetarians (mean difference 0.96 points [95%CI + 0.53, + 1.40]) and a greater risk for EPDS scores above 10 (adjusted OR = 1.67 [95% CI: 1.14,2.44]) than non-vegetarians after adjustment for potential confounding factors.
Conclusions
Vegetarian men have more depressive symptoms after adjustment for socio-demographic factors. Nutritional deficiencies (e.g. in cobalamin or iron) are a possible explanation for these findings, however reverse causation cannot be ruled out.
 

 
Original Investigation September 2017
Association of History of Dizziness and Long-term Adverse Outcomes With Early vs Later Orthostatic Hypotension Assessment Times in Middle-aged Adults
Stephen P. Juraschek, MD, PhD1,2,3,4; Natalie Daya, MHS1,2,3,4; Andreea M. Rawlings, PhD, MS1,2,3,4; et al Lawrence J. Appel, MD, MPH1,2,3,4; Edgar R. Miller III, MD, PhD1,2,3,4; B. Gwen Windham, MD, MHS5; Michael E. Griswold, PhD5,6; Gerardo Heiss, MD, MSc, PhD7; Elizabeth Selvin, PhD, MPH1,2,3,4
Author Affiliations Article Information

• 1Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland
• 2Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
• 3The Welch Center for Prevention, Epidemiology, and Clinical Research, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
• 4Johns Hopkins Medical Institutions, Baltimore, Maryland
• 5Department of Medicine, University of Mississippi Medical Center, Jackson
• 6Center of Biostatistics, University of Mississippi Medical Center, Jackson
• 7Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill

JAMA Intern Med. 2017;177(9):1316-1323. doi:10.1001/jamainternmed.2017.2937
 
Question  Are orthostatic hypotension assessments performed within 1 minute of standing as informative for dizziness and long-term outcomes as assessments performed after 1 minute?
Findings  In this cohort study of 11 429 adults with 4 orthostatic hypotension assessments performed 1 to 2 minutes after standing, orthostatic hypotension assessed within 1 minute of standing was associated with higher odds of dizziness and greater risk of falls, fracture, syncope, motor vehicle crash, and mortality than orthostatic hypotension assessed after 1 minute.
Meaning  Contrary to prevailing recommendations to delay orthostatic hypotension assessments by 3 minutes, these findings suggest that orthostatic hypotension should be assessed within 1 minute of standing.
Abstract
Importance  Guidelines recommend assessing orthostatic hypotension (OH) 3 minutes after rising from supine to standing positions. It is not known whether measurements performed immediately after standing predict adverse events as strongly as measurements performed closer to 3 minutes.
Objective  To compare early vs later OH measurements and their association with history of dizziness and longitudinal adverse outcomes.
Design, Setting, and Participants  This was a prospective cohort study of middle-aged (range, 44-66 years) participants in the Atherosclerosis Risk in Communities Study (1987-1989).
Exposures  Orthostatic hypotension, defined as a drop in blood pressure (BP) (systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg) from the supine to standing position, was measured up to 5 times at 25-second intervals.
Main Outcomes and Measures  We determined the association of each of the 5 OH measurements with history of dizziness on standing (logistic regression) and risk of fall, fracture, syncope, motor vehicle crashes, and all-cause mortality (Cox regression) over a median of 23 years of follow-up (through December 31, 2013).
Results  In 11 429 participants (mean age, 54 years; 6220 [54%] were women; 2934 [26%] were black) with at least 4 OH measurements after standing, after adjustment OH assessed at measurement 1 (mean [SD], 28 [5.4] seconds; range, 21-62 seconds) was the only measurement associated with higher odds of dizziness (odds ratio [OR], 1.49; 95% CI, 1.18-1.89). Measurement 1 was associated with the highest rates of fracture, syncope, and death at 18.9, 17.0, and 31.4 per 1000 person-years. Measurement 2 was associated with the highest rate of falls and motor vehicle crashes at 13.2 and 2.5 per 1000 person-years. Furthermore, after adjustment measurement 1 was significantly associated with risk of fall (hazard ratio [HR], 1.22; 95% CI, 1.03-1.44), fracture (HR, 1.16; 95% CI, 1.01-1.34), syncope (HR, 1.40; 95% CI, 1.20-1.63), and mortality (HR, 1.36; 95% CI, 1.23-1.51). Measurement 2 (mean [SD], 53 [7.5] seconds; range, 43-83 seconds) was associated with all long-term outcomes, including motor vehicle crashes (HR, 1.43; 95% CI, 1.04-1.96). Measurements obtained after 1 minute were not associated with dizziness and were inconsistently associated with individual long-term outcomes.
Conclusions and Relevance  In contrast with prevailing recommendations, OH measurements performed within 1 minute of standing were the most strongly related to dizziness and individual adverse outcomes, suggesting that OH be assessed within 1 minute of standing.

 
Journal of General Internal MedicineISSN: 0884-8734 (Print) 1525-1497 (Online)
Tricyclic and Tetracyclic Antidepressants for the Prevention of Frequent Episodic or Chronic Tension-Type Headache in Adults: A Systematic Review and Meta-Analysis

• Jeffrey L. JacksonEmail author,Josephine M. Mancuso,Sarah Nickoloff’,Rebecca Bernstein
• Cynthia Kay

First Online: 18 July 2017
BackgroundTension-type headaches are a common source of pain and suffering. Our purpose was to assess the efficacy of tricyclic (TCA) and tetracyclic antidepressants in the prophylactic treatment of tension-type headache.
MethodsWe searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the ISI Web of Science, and clinical trial registries through 11 March 2017 for randomized controlled studies of TCA or tetracyclic antidepressants in the prevention of tension-type headache in adults. Data were pooled using a random effects approach.
Key ResultsAmong 22 randomized controlled trials, eight included a placebo comparison and 19 compared at least two active treatments. Eight studies compared TCAs to placebo, four compared TCAs to selective serotonin reuptake inhibitors (SSRIs), and two trials compared TCAs to behavioral therapies. Two trials compared tetracyclics to placebo. Single trials compared TCAs to tetracyclics, buspirone, spinal manipulation, transcutaneous electrical stimulation, massage, and intra-oral orthotics. High-quality evidence suggests that TCAs were superior to placebo in reducing headache frequency (weighted mean differences (WMD): −4.8 headaches/month, 95% CI: −6.63 to −2.95) and number of analgesic medications consumed (WMD: −21.0 doses/month, 95% CI: −38.2 to −3.8). TCAs were more effective than SSRIs. Low-quality studies suggest that TCAs are superior to buspirone, but equivalent to behavioral therapy, spinal manipulation, intra-oral orthotics, and massage. Tetracyclics were no better than placebo for chronic tension-type headache.
ConclusionsTricyclic antidepressants are modestly effective in reducing chronic tension-type headache and are superior to buspirone. In limited studies, tetracyclics appear to be ineffective in the prophylactic treatment of chronic tension-type headache.
The views reflected in this manuscript are those of the authors and should not be construed, in any way, to represent the views of the Department of Veterans Affairs.
 

 
To Serve Or Not To Serve:  Ethical And Policy Implications Highlights
Some panels and commissions can have important public policy implications for our discipline. Ethical issues can arise about whether or not to serve on influential panels. Some policy commissions pursue missions that inadvertently instigate divisive friction.
A case study is presented regarding a decision not to serve on a controversial panel. Ethical challenges are explored regarding searching for alternative avenues for influencing policy.
Abstract The Institute of Medicine (IOM) is one of the nation’s more influential health related non-profit organizations. It plays a large role in shaping health policy by commissioning panels to develop “white papers” describing research and recommendations on a variety of health topics. These white paper publications are often used to help make policy decisions at the legislative and executive levels.
Such a prominent institution might seem like a natural ally for policy-related collaborative efforts. As community psychologists, we strongly endorse efforts to positively influence public policy at the national level. However, while serving on influential panels and commissions like the IOM might seem to be very much part of the ethos of our discipline, there are occasions when such institutions are pursuing a mission that inadvertently has the potential to instigate divisive friction among community activists and organizations.
A case study is presented whereby I describe my decision not to accept an invitation to serve on a controversial IOM panel. I explore the ethical challenges regarding maintaining my independence from this institution and its attempt to redefine chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME), as well as the process of searching for alternative avenues for collaborating with community activists to influence policy related to these debilitating illnesses.
Leonard A. Jason
Source: American Journal of Community Psychology. Published online: Sept. 18, 2017. doi:10.1002/ajcp.12181

Review Article: The Human Intestinal Virome In Health And Disease
S.R. Carding, N. Davis, L. Hoyles –
 First published: 4 September 2017
Summary - Background The human virome consists of animal-cell viruses causing transient infections, bacteriophage (phage) predators of bacteria and archaea, endogenous retroviruses and viruses causing persistent and latent infections. High-throughput, inexpensive, sensitive sequencing methods and metagenomics now make it possible to study the contribution dsDNA, ssDNA and RNA virus-like particles make to the human virome, and in particular the intestinal virome.
Aim
To review and evaluate the pioneering studies that have attempted to characterise the human virome and generated an increased interest in understanding how the intestinal virome might contribute to maintaining health, and the pathogenesis of chronic diseases.
Methods
 Relevant virome-related articles were selected for review following extensive language- and date-unrestricted, electronic searches of the literature.
Results
The human intestinal virome is personalised and stable, and dominated by phages. It develops soon after birth in parallel with prokaryotic communities of the microbiota, becoming established during the first few years of life. By infecting specific populations of bacteria, phages can alter microbiota structure by killing host cells or altering their phenotype, enabling phages to contribute to maintaining intestinal homeostasis or microbial imbalance (dysbiosis), and the development of chronic infectious and autoimmune diseases including HIV infection and Crohn's disease, respectively.
Conclusions
 Our understanding of the intestinal virome is fragmented and requires standardised methods for virus isolation and sequencing to provide a more complete picture of the virome, which is key to explaining the basis of viromedisease associations, and how enteric viruses can contribute to disease aetiologies and be rationalised as targets for interventions.
Source: http://bit.ly/2yAgxVh(also full text)

 
Reproducibility Of Peak Oxygen Consumption And The Impact Of Test Variability On Classification Of Individual Training Responses In Young Recreationally Active Adults
A Canadian study on exercise test from the School of Kinesiology and Health Studies, Queen's University, Kingston, ON, Canada
Brittany A. Edgett, Jacob T. Bonafiglia, James P. Raleigh, Mario P. Rotundo, Matthew D. Giles, Jonathan P. Whittal, Brendon J. Gurd
First published: 28 September 2017
Summary This study investigated whether VO2peak is reproducible across repeated tests before (PRE) and after (POST) training, and whether variability across tests impacts how individual responses are classified following 3 weeks of aerobic exercise training (cycle ergometry). Data from 45 young healthy adults (age: 20·1 ± 0·9 years; VO2peak, 42·0 ± 6·7 ml·min−1) from two previously published studies were utilized in the current analysis. Non-responders were classified as individuals who failed to demonstrate an increase or decrease in VO2peak that was greater than 2·0 times the typical error of measurement (107 ml·min−1) away from zero, while responders and adverse responders were above and below this cut-off, respectively.
 VO2peak tests at PRE (three total) and POST (three total) were highly reproducible (PRE and POST average and single measures ICCs: range 0·938–0·992), with low coefficients of variation (PRE:4·9 ± 3·1%, POST: 4·8 ± 2·7%). However, a potential learning effect was observed in the VO2peak tests prior to training, as the initial pretraining test was significantly lower than the third (p = 0·010, PRE 1: 2 946 ± 924 ml·min−1, PRE 3: 3 042 ± 919 ml·min−1). This resulted in fewer individuals classified as adverse responders for Test 3 compared to any combination of tests that included Test 1, suggesting that a single ramp test at baseline may not be sufficient to accurately classify the VO2peak response in young recreationally active individuals. Thus, it is our recommendation that the initial VO2peak test be used as a familiarization visit and not included for analysis.
Source: http://onlinelibrary.wiley.com/doi/10.1111/cpf.12459/full

 
Grey and white matter differences in Chronic Fatigue Syndrome – A voxel-based morphometry study
Andreas Finkelmeyer, JiabaoHe, Laura Maclachlan, Stuart Watson, Peter Gallagher, Julia L. Newton, Andrew M. Blamire
Highlights VBM study of patients with Chronic Fatigue Syndrome without depression. Patients show increased grey matter in insular cortex and parts of the limbic system. Patients show decrease in white matter in midbrain and temporal lobe. Findings suggest potentially altered processing of interoceptive signals.
Abstract
Objective Investigate global and regional grey and white matter volumes in patients with Chronic Fatigue Syndrome (CFS) using magnetic resonance imaging (MRI) and recent voxel-based morphometry (VBM) methods.
 Methods
 Forty-two patients with CFS and thirty healthy volunteers were scanned on a 3- Tesla MRI scanner. Anatomical MRI scans were segmented, normalized and submitted to a VBM analysis using randomisation methods. Group differences were identified in overall segment volumes and voxel-wise in spatially normalized grey matter (GM) and white matter (WM) segments.
 Results
Accounting for total intracranial volume, patients had larger GM volume and lower WM volume. The voxel-wise analysis showed increased GM volume in several structures including the amygdala and insula in the patient group. Reductions in WM volume in the patient group were seen primarily in the midbrain, pons and right temporal lobe.
Conclusion
Elevated GM volume in CFS is seen in areas related to processing of interoceptive signals and stress. Reduced WM volume in the patient group partially supports earlier findings of WM abnormalities in regions of the midbrain and brainstem.
 Source http://www.sciencedirect.com/science/article/pii/S221315821730236X#

 
Cellular Bioenergetics Is Impaired In Patients With Chronic Fatigue Syndrome.
Toma C, Brown A, Strassheim V, Elson J, Newton J, Manning P.
 Abstract
Chronic fatigue syndrome (CFS) is a highly debilitating disease of unknown aetiology. Abnormalities in bioenergetic function have been cited as one possible cause for CFS. Preliminary studies were performed to investigate cellular bioenergetic abnormalities in CFS patients. A series of assays were conducted using peripheral blood mononuclear cells (PBMCs) from CFS patients and healthy controls. These experiments investigated cellular patterns in oxidative phosphorylation (OXPHOS) and glycolysis. Results
showed consistently lower measures of OXPHOS parameters in PBMCs taken from CFS patients compared with healthy controls. Seven key parameters of OXPHOS were calculated: basal respiration, ATP production, proton leak, maximal respiration, reserve capacity, non-mitochondrial respiration, and coupling efficiency. While many of the parameters differed between the CFS and control cohorts, maximal respiration was determined to be the key parameter in mitochondrial function to differ between CFS and control PBMCs due to the consistency of its impairment in CFS patients found throughout the study (p ≤ 0.003). The lower maximal respiration in CFS PBMCs suggests that when the cells experience physiological stress they are less able to elevate their respiration rate to compensate for the increase in stress and are unable to fulfil cellular energy demands. The metabolic differences discovered highlight the inability of CFS patient PBMCs to fulfil cellular energetic demands both under basal conditions and when mitochondria are stressed during periods of high metabolic demand.
 Source: PlosOne http://bit.ly/2iBDTCV

 
Epigenetic Modifications And Glucocorticoid Sensitivity Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
 De Vega, Herrera, Vernon, McGowan
 
Abstract
Despite a heterogeneous patient population, immune and hypothalamic-pituitaryadrenal (HPA) axis function differences, such as enhanced negative feedback to glucocorticoids, are recurring findings in ME/CFS studies. Epigenetic modifications, such as CpG methylation, are known to regulate long-term phenotypic differences and previous work by our group found DNA methylome differences in ME/CFS, however the relationship between DNA methylome modifications, clinical and functional characteristics associated with ME/CFS has not been examined.
 
Methods
We examined the DNA methylome in peripheral blood mononuclear cells (PBMCs) of a larger cohort of female ME/CFS patients using the Illumina HumanMethylation450 BeadChip Array. In parallel to the DNA methylome analysis, we investigated in vitro glucocorticoid sensitivity differences by stimulating PBMCs with phytohaemagglutinin and suppressed growth with dexamethasone. We explored DNA methylation differences using bisulfite pyrosequencing and statistical permutation. Linear regression was implemented to discover epigenomic regions associated with self-reported quality of life and network analysis of gene ontology terms to biologically contextualize results.
 
Results
We detected 12,608 differentially methylated sites between ME/CFS patients and healthy controls predominantly localized to cellular metabolism genes, some of which were also related to self-reported quality of life health scores. Among ME/CFS patients, glucocorticoid sensitivity was associated with differential methylation at 13 loci.
 
Conclusions
Our results indicate DNA methylation modifications in cellular metabolism in ME/CFS despite a heterogeneous patient population, implicating these processes in immune and HPA axis dysfunction in ME/CFS. Modifications to epigenetic loci associated with differences in glucocorticoid sensitivity may be important as biomarkers for future clinical testing. Overall, these findings align with recent ME/CFS work that point towards impairment in cellular energy production in this patient population.
 
Source: http://bit.ly/2vdhr7w accessed Jul 31, 2017

 
Cytokine Signature Associated With Disease Severity In Chronic Fatigue Syndrome Patients
Authors Montoya, Holmes, Anderson, Maecker, Rosenberg-Hasson, Valencia. Chu, Younger, Tato & M. Davis Contributed by Mark M. Davis, June 28, 2017 (sent for review November 16, 2016; reviewed by Gordon Broderick, Ben Katz, and Anthony L. Komaroff)
 
Significance
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) devastates the lives of millions of people and has remained a mystery illness despite decades of research. It has long been suspected that inflammation is central to its pathogenesis. Although only two cytokines were found to be different (TGF-β higher and resistin lower) in ME/CFS patients compared with controls, 17 cytokines correlated with ME/CFS severity. Thirteen of these cytokines are proinflammatory and may contribute to many of the symptoms these patients experience for several years. Only CXCL9 (MIG) inversely correlated with fatigue duration.
 Abstract
Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.
 
Full text: http://m.pnas.org/content/early/2017/07/25/1710519114.

 
Dysregulation Of Cytokine Pathways Dysregulation of cytokine pathways in chronic fatigue syndrome and multiple sclerosis
 Matthew Sorenson, Jacob Furst, Herbert Mathews & Leonard A. Jason
 
Published online: 07 Jun 2017
Abstract
 Background: Cytokine studies in chronic fatigue syndrome (CFS) have yielded mixed findings. Purpose: This investigation evaluated whether network analysis of cytokine production differs between patients with CFS and multiple sclerosis (MS) as compared to a reference group of healthy controls.
 Methods: Three subgroups (N = 109) were included: 15 participants who met diagnostic criteria for CFS, 57 participants meeting criteria for MS, and 37 controls. Peripheral blood was obtained and production of a select cytokine profile was determined from stimulated and unstimulated mononuclear cells. Data were generated through the use of a multi-analyte bead suspension array. Pairwise associations were determined for each group, and these associations were used to create a graphical representation of the data. The graph was clustered using an eigenvector community algorithm and results visualized using edges to model the correlations by color and thickness to show direction and strength.
Results: The control and MS groups produced a three-neighborhood relationship regardless of cell condition. While producing a three-neighborhood relationship, the MS group differed significantly from the control group as it displayed stronger relationships among pro-inflammatory cytokines. In contrast, the CFS group displayed a three-neighborhood solution when unstimulated. However, when cells from the CFS group were stimulated, a two-neighborhood model was found that exhibited stronger inter-cytokine correlations. The model found in CFS was significantly different from that found in the control and MS groups.
 Conclusion: CFS was characterized by a pattern of global immunologic activation using network analysis, fundamentally different from those found for either MS or control groups.
 
Source: http://bit.ly/2w4VSH0 Submitted by Prof. Leonard Jason
 

 
Chronic Fatigue Syndrome Prevalence Is Grossly Overestimated
 
 Chronic fatigue syndrome prevalence is grossly overestimated using Oxford criteria compared to Centers for Disease Control (Fukuda) criteria in a U.S. population study –
James N. Baraniuk
Published online: 21 Jul 2017
Abstract: Background: Results from treatment studies using the low-threshold Oxford criteria for recruitment may have been overgeneralized to patients diagnosed by more stringent chronic fatigue syndrome (CFS) criteria.
 
Purpose: To compare the selectivity of Oxford and Fukuda criteria in a U.S. population.
 
Methods: Fukuda (Center for Disease Control (CDC)) criteria, as operationalized with the CFS Severity Questionnaire (CFSQ), were included in the nationwide rc2004 HealthStyles survey mailed to 6175 participants who were representative of the U.S. 2003 Census population. The 9 questionnaire items (CFS symptoms) were crafted into proxies for Oxford criteria (mild fatigue, minimal exclusions) and Fukuda criteria (fatigue plus ≥4 of 8 ancillary criteria at moderate or severe levels with exclusions). The comparative prevalence estimates of CFS were then determined. Severity scores for fatigue were plotted against the sum of severities for the eight ancillary criteria. The four quadrants of scatter diagrams assessed putative healthy controls, CFS, chronic idiopathic fatigue (CIF), and CFS-like with insufficient fatigue subjects.
Results: The Oxford criteria designated CFS in 25.5% of 2004 males and 19.9% of 1954 females. Based on quadrant analysis, 85% of Oxford-defined cases were inappropriately classified as CFS. Fukuda criteria identified CFS in 2.3% of males and 1.8% of females.
 Discussion: CFS prevalence using Fukuda criteria and quadrant analysis was near the upper limits of previous epidemiology studies. The CFSQ may have utility for on-line and outpatient screening. The Oxford criteria were untenable because they inappropriately selected healthy subjects with mild fatigue and CIF and mislabeled them as CFS.
Source: http://bit.ly/2x7ecwh

 
A Systematic Review and Meta-analysis of The Effect of Low Vitamin D on CognitionAlicia M. Goodwill, PhD; Cassandra Szoeke, PhD
J Am Geriatr Soc. 2017;65(10):2161-2168. 
 
Abstract
Background/Objective With an aging population and no cure for dementia on the horizon, risk factor modification prior to disease onset is an urgent health priority. Therefore, this review examined the effect of low vitamin D status or vitamin D supplementation on cognition in midlife and older adults without a diagnosis of dementia.
Design Systematic review and random effect meta-analysis.
Setting Observational (cross-sectional and longitudinal cohort) studies comparing low and high vitamin D status and interventions comparing vitamin D supplementation with a control group were included in the review and meta-analysis.
Participants Studies including adults and older adults without a dementia diagnosis were included.
Measurements Medline (PubMed), AMED, Psych INFO, and Cochrane Central databases were searched for articles until August 2016. The Newcastle-Ottawa Scale and Physiotherapy Evidence Database assessed methodological quality of all studies.
Results Twenty-six observational and three intervention studies (n = 19–9,556) were included in the meta-analysis. Low vitamin D was associated with worse cognitive performance (OR = 1.24, CI = 1.14–1.35) and cognitive decline (OR = 1.26, CI = 1.09–1.23); with cross-sectional yielding a stronger effect compared to longitudinal studies. Vitamin D supplementation showed no significant benefit on cognition compared with control (SMD = 0.21, CI = −0.05 to 0.46).

 
Short Sleep Duration Increases Metabolic Impact in Healthy Adults: A Population-Based Cohort Study
Han-Bing Deng, PhD  Tony Tam, PhD
Address correspondence to: Xiang Qian Lao, PhD, Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, NT, Hong Kong. Telephone: 852 22528763; Fax: 852 26063500; Email: Benny Chung-Ying Zee, PhD    Roger Yat-Nork Chung, PhD   Xuefen Su, PhD  Lei Jin, PhD
Ta-Chien Chan, PhD   Ly-Yun Chang, PhD   Eng-Kiong Yeoh, MBBS   Xiang Qian Lao, PhD   CHINA
 
Sleep, Volume 40, Issue 10, 1 October 2017, zsx130, https://doi.org/10.1093/sleep/zsx130
Published:22 July 2017
Abstract
Objectives
The metabolic impact of inadequate sleep has not been determined in healthy individuals outside laboratories. This study aims to investigate the impact of sleep duration on five metabolic syndrome components in a healthy adult cohort.
Methods
A total of 162121 adults aged 20–80 years (men 47.4%) of the MJ Health Database, who were not obese and free from major diseases, were recruited and followed up from 1996 to 2014. Sleep duration and insomnia symptoms were assessed by a self-administered questionnaire. Incident cases of five metabolic syndrome components were identified by follow-up medical examinations. Cox proportional hazard ratios (HRs) were calculated for three sleep duration categories “< 6 hours/day (short),” “6–8 hours/day (regular),” and “> 8 hours/day (long)” with adjustment for potential confounding factors. Analyses were stratified by insomnia symptoms to assess whether insomnia symptoms modified the association between sleep duration and metabolic syndrome.
Results
Compared to regular sleep duration, short sleep significantly (p < .001) increased the risk for central obesity by 12% (adjusted HR 1.12 [1.07–1.17]), for elevated fasting glucose by 6% (adjusted HR 1.06 [1.03–1.09]), for high blood pressure by 8% (adjusted HR 1.08 [1.04–1.13]), for low high-density lipoprotein–cholesterol by 7% (adjusted HR 1.07 [1.03–1.11]), for hypertriglyceridemia by 9% (adjusted HR 1.09 [1.05–1.13]), and for metabolic syndrome by 9% (adjusted HR 1.09 [1.05–1.13]). Long sleep decreased the risk of hypertriglyceridemia (adjusted HR 0.89 [0.84–0.94]) and metabolic syndrome (adjusted HR 0.93 [0.88–0.99]). Insomnia symptoms did not modify the effects of sleep duration.
Conclusions
Sleep duration may be a significant determinant of metabolic health.

 
Many Doctors, Even Specialists, Don't Adhere to Fibromyalgia Diagnostic Criteria
By Lorraine L. Janeczko  January 02, 2018
 
NEW YORK (Reuters Health) – Generalist doctors, and even many specialists, have relatively poor knowledge of the American College of Rheumatology 1990 and 2010 fibromyalgia diagnostic criteria, according to results of a survey conducted in Canada.
"Physicians do not have adequate and homogeneous knowledge of the fibromyalgia diagnostic criteria. Approximately half of physicians did not adhere to the criteria. Poor knowledge and adherence . . . may increase diagnosis delays and misdiagnoses. Knowledge translation strategies should be implemented to address this problem," lead author Dr. Dinesh Kumbhare of the University of Toronto and his coauthors write in Pain Medicine, online November 21.
"I think most physicians are aware of fibromyalgia, although many still 'don't believe in it' and communicate this (lack of belief) to their patients. Even among physicians who accept the science and existence of fibromyalgia, there is lack of understanding of it, which hampers their ability to effectively communicate about it with their patients," Dr. Eric L. Matteson, a professor of medicine at Mayo Clinic College of Medicine and Science in Rochester, Minnesota, told Reuters Health by email.
"In general, the results are unsurprising and reflect the lack of knowledge about this common pain condition. Many patients who are referred to me with chronic pain problems are wrongly diagnosed with fibromyalgia or are wrongly diagnosed as not having fibromyalgia," added Dr. Matteson, who was not involved in the study.
Dr. Kumbhare and his colleagues distributed a 37-item questionnaire to a convenience sample of 284 physicians who practice in urban clinical settings and diagnose chronic pain conditions: 100 family physicians, 69 anesthesiologists, 58 physical medicine and rehabilitation specialists, 29 rheumatologists, and 28 neurologists.
The questionnaire tested the physicians’ knowledge of the 1990 fibromyalgia classification criteria and the 2010 diagnostic criteria. The researchers assessed the homogeneity of the responses and whether specialist training affected the physicians’ knowledge.
Overall, 12% of the respondents used only the 1990 criteria in their practice, 27% used the 2010 criteria, 12% used both, and 49% used no criteria. Therefore, only 51% of respondents adhered to these sets of criteria in diagnosing fibromyalgia.
Doctors with specialist training were more familiar with the criteria, but their knowledge was not comprehensive. Even physicians categorized as having the “most specialist training” had mean scores of only 55.4% for the 1990 criteria and 72.4% for the 2010 criteria.
The authors suggest that doctors and medical students learn about the criteria and updates to them – and apply the criteria in daily practice. They specifically recommend continuing medical education seminars, dropdown menus that provide fibromyalgia diagnostic criteria in electronic medical records, and online training modules on fibromyalgia diagnosis. They also say medical and residency pain curricula should offer advanced courses on chronic pain and fibromyalgia diagnosis.
Dr. Matteson agreed. "The most important aspect of the survey is awareness-building. If the findings can be brought to the attention of educators and practitioners with resultant changes in practice, then they will influence patient care," he said.
Dr. Anne Louise Oaklander, an associate professor of neurology at Harvard Medical School and a neurologist at Massachusetts General Hospital, in Boston, told Reuters Health by email that the results did not surprise her: “Fibromyalgia isn’t a disease but, rather, a term agreed on by groups of physicians to describe a loose constellation of symptoms. The criteria for inclusion and exclusion are complex and have varied over the years; plus some of the features are impractical or difficult to apply or contradict medical experience."
"A minor weakness is that they assessed knowledge of earlier versions of the American College of Rheumatology diagnostic criteria (1990 and 2010) but not the latest changes to them in 2011 and 2016, which are the ones that doctors ideally should be using," said Dr. Oaklander, who was not involved in the study.
"Also, they included medical specialists other than rheumatologists, and I don’t think it’s realistic to expect doctors from other medical specialties to know the details developed by rheumatologists to guide rheumatologists," she concluded.
Dr. Kumbhare did not respond to requests for comment.
SOURCE: http://bit.ly/2CeAeTM
Pain Med 2017.
Reuters Health Information © 2017 

 
Brain nerve 2018 Jan;70(1):41-54. doi: 10.11477/mf.1416200948.
[Neurologic Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review].
[Article in Japanese]
Komaroff AL1, Takahashi R, Yamamura T, Sawamura M.
Author information
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by fatigue lasting for at least six months, post-exertional malaise, unrefreshing sleep, cognitive impairment and orthostatic intolerance. ME/CFS has been a controversial illness because it is defined exclusively by subjective complaints. However, recent studies of neuroimaging as well as analysis of blood markers, energy metabolism and mitochondrial function have revealed many objective biological abnormalities. Specifically, it is suspected that the symptoms of ME/CFS may be triggered by immune activation - either inside or outside the brain - through release of inflammatory cytokines. In this review, we summarize potentially important recent findings on ME/CFS, focusing on objective evidence.
PMID:
29348374
DOI:
10.11477/mf.1416200948
 

 
Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation

• Maike Kuhn†,Kurt-Wolfram Sühs†,Manas K. Akmatov, Frank Klawonn,Junxi Wang,
• Thomas Skripuletz,Volkhard Kaever,Martin Stangel†Email author and
• Frank Pessler†Email author

Journal of Neuroinflammation201815:20
Received: 11 October 2017 Accepted: 12 December 2017 Published: 17 January 2018
AbstractBackgroundVaricella zoster virus (VZV) reactivation spans the spectrum from uncomplicated segmental herpes zoster to life-threatening disseminated CNS infection. Moreover, in the absence of a small animal model for this human pathogen, studies of pathogenesis at the organismal level depend on analysis of human biosamples. Changes in cerebrospinal fluid (CSF) metabolites may reflect critical aspects of host responses and end-organ damage in neuroinfection and neuroinflammation. We therefore applied a targeted metabolomics screen of CSF to three clinically distinct forms of VZV reactivation and infectious and non-infectious disease controls in order to identify biomarkers for CNS involvement in VZV reactivation.
MethodsMetabolite profiles were determined by targeted liquid chromatography-mass spectrometry in CSF from patients with segmental zoster (shingles, n = 14), facial nerve zoster (n = 16), VZV meningitis/encephalitis (n = 15), enteroviral meningitis (n = 10), idiopathic Bell’s palsy (n = 11), and normal pressure hydrocephalus (n = 15).
ResultsConcentrations of 88 metabolites passing quality assessment clearly separated the three VZV reactivation forms from each other and from the non-infected samples. Internal cross-validation identified four metabolites (SM C16:1, glycine, lysoPC a C26:1, PC ae C34:0) that were particularly associated with VZV meningoencephalitis. SM(OH) C14:1 accurately distinguished facial nerve zoster from Bell’s palsy. Random forest construction revealed even more accurate classifiers (signatures comprising 2–4 metabolites) for most comparisons. Some of the most accurate biomarkers correlated only weakly with CSF leukocyte count, indicating that they do not merely reflect recruitment of inflammatory cells but, rather, specific pathophysiological mechanisms. Across all samples, only the sum of hexoses and the amino acids arginine, serine, and tryptophan correlated negatively with leukocyte count. Increased expression of the metabolites associated with VZV meningoencephalitis could be linked to processes relating to neuroinflammation/immune activation, neuronal signaling, and cell stress, turnover, and death (e.g., autophagy and apoptosis), suggesting that these metabolites might sense processes relating to end-organ damage.
ConclusionsThe results provide proof-of-concept for the value of CSF metabolites as (1) disease-associated signatures suggesting pathophysiological mechanisms, (2) degree and nature of neuroinflammation, and (3) biomarkers for diagnosis and risk stratification of VZV reactivation and, likely, neuroinfections due to other pathogens.

J Neurol Neurosurg Psychiatry 2016;87:1127-1132 doi:10.1136/jnnp-2016-313458
Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention

1. Andre Leite Gonçalves1,2, Adriana Martini Ferreira1, Reinaldo Teixeira Ribeiro2,3, Eliova Zukerman1, José Cipolla-Neto4, Mario Fernando Prieto Peres1

+ Author Affiliations:1Albert Einstein Hospital, São Paulo, Brazil ,2Department of Neurology, UNIFESP, São Paulo, Brazil ,3Neurology Department, FMABC, Santo Andre, Brazil ,4Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
Received 2 March 2016 ,Revised 5 April 2016 ,Accepted 21 April 2016 ,Published Online First 10 May 2016
Abstract
Introduction Melatonin has been studied in headache disorders. Amitriptyline is efficacious for migraine prevention, but its unfavourable side effect profile limits its use.
Methods A randomised, double-blind, placebo-controlled study was carried out. Men and women, aged 18–65 years, with migraine with or without aura, experiencing 2–8 attacks per month, were enrolled. After a 4-week baseline phase, 196 participants were randomised to placebo, amitriptyline 25 mg or melatonin 3 mg, and 178 took a study medication and were followed for 3 months (12 weeks). The primary outcome was the number of migraine headache days per month at baseline versus last month. Secondary end points were responder rate, migraine intensity, duration and analgesic use. Tolerability was also compared between groups.
Results Mean headache frequency reduction was 2.7 migraine headache days in the melatonin group, 2.2 for amitriptyline and 1.1 for placebo. Melatonin significantly reduced headache frequency compared with placebo (p=0.009), but not to amitriptyline (p=0.19). Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency. Melatonin was better tolerated than amitriptyline. Weight loss was found in the melatonin group, a slight weight gain in placebo and significantly for amitriptyline users.
Conclusions Melatonin 3 mg is better than placebo for migraine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg.
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

 
Use of Plant-Based Therapies and Menopausal Symptoms - A Systematic Review and Meta-analysisOscar H. Franco, MD, PhD1; Rajiv Chowdhury, MD, PhD2; Jenna Troup, MSc1; et al Trudy Voortman, PhD1,3; Setor Kunutsor, MD, PhD2; Maryam Kavousi, MD, PhD1; Clare Oliver-Williams, PhD2; Taulant Muka, MD, PhD1,3
Article Information1Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands

• 2Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
• 3Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts

 
Copyright 2016 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
JAMA. 2016;315(23):2554-2563. doi:10.1001/jama.2016.8012 editorial comment icon
Editorial
Comment
Abstract
Importance  Between 40% and 50% of women in Western countries use complementary therapies to manage menopausal symptoms.
Objective  To determine the association of plant-based therapies with menopausal symptoms, including hot flashes, night sweats, and vaginal dryness.
Data Sources  The electronic databases Ovid MEDLINE, EMBASE, and Cochrane Central were systematically searched to identify eligible studies published before March 27, 2016. Reference lists of the included studies were searched for further identification of relevant studies.
Study Selection  Randomized clinical trials that assessed plant-based therapies and the presence of hot flashes, night sweats, and vaginal dryness.
Data Extraction  Data were extracted by 2 independent reviewers using a predesigned data collection form.
Main Outcomes and Measures  Hot flashes, night sweats, and vaginal dryness.
Results  In total, 62 studies were identified, including 6653 individual women. Use of phytoestrogens was associated with a decrease in the number of daily hot flashes (pooled mean difference of changes, −1.31 [95% CI, −2.02 to −0.61]) and vaginal dryness score (pooled mean difference of changes, −0.31 [95% CI, −0.52 to −0.10]) between the treatment groups but not in the number of night sweats (pooled mean difference of changes, −2.14 [95% CI, −5.57 to 1.29]). Individual phytoestrogen interventions such as dietary and supplemental soy isoflavones were associated with improvement in daily hot flashes (pooled mean difference of changes, −0.79 [−1.35 to −0.23]) and vaginal dryness score (pooled mean difference of changes, −0.26 [−0.48 to −0.04]). Several herbal remedies, but not Chinese medicinal herbs, were associated with an overall decrease in the frequency of vasomotor symptoms. There was substantial heterogeneity in quality across the available studies, and 46 (74%) of the included randomized clinical trials demonstrated a high risk of bias within 3 or more areas of study quality.
Conclusions and Relevance  This meta-analysis of clinical trials suggests that composite and specific phytoestrogen supplementations were associated with modest reductions in the frequency of hot flashes and vaginal dryness but no significant reduction in night sweats. However, because of general suboptimal quality and the heterogeneous nature of the current evidence, further rigorous studies are needed to determine the association of plant-based and natural therapies with menopausal health.

 
Nature Genetics | Letter
Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number

• Jonathan J Lyons,1,Xiaomin Yu,1,Jason D Hughes,2,Quang T Le,3,Ali Jamil,1, Yun Bai,1, Nancy Ho,4, Ming Zhao,5, Yihui Liu,1, Michael P O'Connell,1, Neil N Trivedi,6, 7, ,1,
• Thomas DiMaggio,1, Nina Jones,8, Helen Matthews,9, Katie L Lewis,10, Andrew J Oler,11, Ryan J Carlson,1, Peter D Arkwright,12, Celine Hong,10, Sherene Agama,1, Todd M Wilson,1, Sofie Tucker,1, Yu Zhang,13,Joshua J McElwee,2, Maryland Pao,14,
• Sarah C Glover,15,Marc E Rothenberg,16,Robert J Hohman,5,Kelly D Stone,1,
• George H Caughey,6, 7,Theo Heller,4,Dean D Metcalfe,1,Leslie G Biesecker,10,
• Lawrence B Schwartz3,& Joshua D Milner1,et al.

Journal name:
Nature Genetics:Year published:(2016)                      DOI:
doi:10.1038/ng.3696
Received 26 July 2016 Accepted 16 September 2016  Published online 17 October 2016
Elevated basal serum tryptase levels are present in 4–6% of the general population, but the cause and relevance of such increases are unknown1, 2. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase–encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.

 
Mortality In Patients With Myalgic Encephalomyelitis And Chronic Fatigue Syndrome.
Stephanie L. McManimen, Andrew R. Devendorf, Abigail A. Brown, Billie C. Moore, James H. Moore, & Leonard A. Jason
 Center for Community Research, DePaul University

 Abstract Background: There is a dearth of research examining mortality in individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Some studies suggest there is an elevated risk of suicide and earlier mortality compared to national norms. However, findings are inconsistent as other researchers have not found significant increases in all-cause mortality for patients. 
 Objective: This study sought to determine if patients with ME or CFS are reportedly dying earlier than the overall population from the same cause.
 Methods: Family, friends, and caregivers of deceased individuals with ME or CFS were recruited through social media, patient newsletters, emails, and advocate websites. This study analyzed data including cause and age of death for 56 individuals that had ME or CFS. 
 
Results: The findings suggest patients in this sample are at a significantly increased risk of earlier all-cause (M = 55.9 years) and cardiovascular-related (M = 58.8 years) mortality, and they had a directionally lower mean age of death for suicide (M = 41.3 years) and cancer (M =66.3 years) compared to the overall U.S. population [M = 73.5 (all-cause), 77.7 (cardiovascular), 47.4 (suicide), and 71.1 (cancer) years of age]. 
 Conclusions: The results suggest there is an increase in risk for earlier mortality in patients with ME and CFS. Due to the small sample size, the findings should be replicated to determine if the directional differences for suicide and cancer mortality are significantly different from the overall U.S. population.
 
 
Source: http://bit.ly/2dYeqi1 

 
Randomized, Double-blind, Placebo-controlled Phase III Trial of Duloxetine Monotherapy in Japanese Patients With Chronic Low Back Pain
Shinichi Konno, MD, PhD; Natsuko Oda, MS; Toshimitsu Ochiai, MS; Levent Alev, MD
Disclosures
Spine. 2016;41(22):1709-1717. 
Abstract

Study Design. A 14-week, randomized, double-blind, multicenter, placebo-controlled study of Japanese patients with chronic low back pain (CLBP) who were randomized to either duloxetine 60 mg once daily or placebo.
Objective. This study aimed to assess the efficacy and safety of duloxetine monotherapy in Japanese patients with CLBP.
Summary of Background Data. In Japan, duloxetine is approved for the treatment of depression, diabetic neuropathic pain, and pain associated with fibromyalgia; however, no clinical study of duloxetine has been conducted for CLBP.
Methods. The primary efficacy measure was the change in the Brief Pain Inventory (BPI) average pain score from baseline to Week 14. Secondary efficacy measures included BPI pain (worst pain, least pain, pain right now), Patient's Global Impression of Improvement, Clinical Global Impressions of Severity, and Roland-Morris Disability Questionnaire, among other measures, and safety and tolerability.
Results. In total, 458 patients were randomized to receive either duloxetine (n = 232) or placebo (n = 226). The BPI average pain score improved significantly in the duloxetine group compared with that in the placebo group at Week 14 [-2.43 ± 0.11 vs. −1.96 ± 0.11, respectively; between-group difference (95% confidence interval), − 0.46 [-0.77 to-0.16]; P = 0.0026]. The duloxetine group showed significant improvement in many secondary measures compared with the placebo group, including BPI pain (least pain, pain right now) (between-group difference: −1.69 ± 0.10, P = 0.0009; −2.42 ± 0.12, P P = 0.0230, respectively), Patient's Global Impression of Improvement (2.46 ± 0.07, P = 0.0026), Clinical Global Impressions of Severity (-1.46 ± 0.06, P = 0.0019), and Roland-Morris Disability Questionnaire (-3.86 ± 0.22, P = 0.0439). Adverse events occurring at a significantly higher incidence in the duloxetine group were somnolence, constipation, nausea, dizziness, and dry mouth, most of which were mild or moderate in severity and were resolved or improved.
Conclusion. Duloxetine 60 mg was effective and well tolerated in Japanese CLBP patients.

 
Most patients who reach disease remission following anti-TNF therapy continue to report fatigue: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis
Katie L. Druce -
Musculoskeletal Research Collaboration (Epidemiology Group), Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
Yagnaseni Bhattacharya -
Gareth T. Jones -
Musculoskeletal Research Collaboration (Epidemiology Group), Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
Gary J. Macfarlane -
Musculoskeletal Research Collaboration (Epidemiology Group), Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
Neil Basu
Musculoskeletal Research Collaboration (Epidemiology Group), Institute of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK
Rheumatology (Oxford) (2016) 55 (10): 1786-1790.
https://doi.org/10.1093/rheumatology/kew241
Published: 21 June 2016Navbar ​

• Abstract

Objectives. RA-related fatigue is common and debilitating, but does not always respond to immunotherapy. In the context of anti-TNF therapy, we aimed to examine whether patients achieving disease remission experienced remission of fatigue.
Methods. Data from the British Society for Rheumatology Biologics Register for RA were used. In participants with severe baseline fatigue [36-item Short Form Health Survey (SF-36) vitality score ⩽12.5], we identified those in disease remission [28-joint DAS (DAS28) <2.6] by 6 months. Fatigue response was evaluated according to partial (SF-36 vitality score >12.5) and complete remission (SF-36 vitality score >50) at follow-up. Demographic (e.g. sex, age), clinical (e.g. inflammation, joint erosion and co-morbidities) and psychosocial (e.g. SF-36 domains and HAQ) characteristics were compared between responder and non-responder groups.
Results. Severe baseline fatigue was reported by 2652 participants, of whom 271 (10%) achieved a DAS28 <2.6 by 6 months. In total, 225 participants (83%) reported partial remission and were distinguished from those who did not by better health status on all psychosocial domains. Far fewer [n = 101 (37.3%)] reported full fatigue remission. In addition to reporting clinically poorer health status, they were distinguished on the basis of a history of hypertension, depression and stroke as well as baseline treatment use of steroids and antidepressants.
Conclusion. Despite achieving clinical remission, many RA patients do not achieve complete remission of their fatigue. Therefore, despite being important in overall disease control, reductions in disease activity are not always sufficient to ameliorate fatigue, so other symptom-specific management approaches must be considered for those for whom fatigue does not resolve.
fatigue, disease activity, remission
Clinical Science

 
Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome
Øystein Fluge,1 Olav Mella,1,2 Ove Bruland,1,3 Kristin Risa,1 Sissel E. Dyrstad,4 Kine Alme,1 Ingrid G. Rekeland,1 Dipak Sapkota,1 Gro V. Røsland,4 Alexander Fosså,5 Irini Ktoridou-Valen,1 Sigrid Lunde,1 Kari Sørland,1 Katarina Lien,6 Ingrid Herder,6 Hanne Thürmer,7 Merete E. Gotaas,8 Katarzyna A. Baranowska,8 Louis M.L.J. Bohnen,9Christoph Schäfer,9 Adrian McCann,10 Kristian Sommerfelt,11 Lars Helgeland,12 Per M. Ueland,2,10 Olav Dahl,1,2 and Karl J. Tronstad4
First published December 22, 2016 - 
Metabolism
Abstract
Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a debilitating disease of unknown etiology, with hallmark symptoms including postexertional malaise and poor recovery. Metabolic dysfunction is a plausible contributing factor. We hypothesized that changes in serum amino acids may disclose specific defects in energy metabolism in ME/CFS. Analysis in 200 ME/CFS patients and 102 healthy individuals showed a specific reduction of amino acids that fuel oxidative metabolism via the TCA cycle, mainly in female ME/CFS patients. Serum 3-methylhistidine, a marker of endogenous protein catabolism, was significantly increased in male patients. The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes. Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.

 

 
ORIGINAL RESEARCH |Ann Intern Med. Published online March 7, 2017. 
Cytokine Inhibition in Patients With Chronic Fatigue Syndrome: A Randomized Trial
Megan E. Roerink, MD; Sebastian J.H. Bredie, MD, PhD; Michael Heijnen; Charles A. Dinarello, MD; Hans Knoop, PhD; Jos W.M. Van der Meer, MD, PhD
Abstract
Background:
Interleukin-1 (IL-1), an important proinflammatory cytokine, is suspected to play a role in chronic fatigue syndrome (CFS).
Objective:
To evaluate the effect of subcutaneous anakinra versus placebo on fatigue severity in female patients with CFS.
Design:
Randomized, placebo-controlled trial from July 2014 to May 2016. Patients, providers, and researchers were blinded to treatment assignment. (ClinicalTrials.gov: NCT02108210)   Setting:University hospital in the Netherlands.
Patients:
50 women aged 18 to 59 years with CFS and severe fatigue leading to functional impairment.
Intervention:
Participants were randomly assigned to daily subcutaneous anakinra, 100 mg (n = 25), or placebo (n = 25) for 4 weeks and were followed for an additional 20 weeks after treatment (n = 50).
Measurements:
The primary outcome was fatigue severity, measured by the Checklist Individual Strength subscale (CIS-fatigue) at 4 weeks. Secondary outcomes were level of impairment, physical and social functioning, psychological distress, and pain severity at 4 nd 24 weeks.
Results:
At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons. There were no clinically important or statistically significant differences between groups in CIS-fatigue score at 4 weeks (mean difference, 1.5 points [95% CI, −4.1 to 7.2 points]) or the end of follow-up. No statistically significant between-group differences were seen for any secondary outcome at 4 weeks or the end of follow-up. One patient in the anakinra group discontinued treatment because of an adverse event. Patients in the anakinra group had more injection site reactions (68% [17 of 25] vs. 4% [1 of 25]).
Limitation:
Small sample size and wide variability in symptom duration; inclusion was not limited to patients with postinfectious symptoms.
Conclusion:
Peripheral IL-1 inhibition using anakinra for 4 weeks does not result in a clinically significant reduction in fatigue severity in women with CFS and severe fatigue.
Sex Differences in Microglia Activity within the Periaqueductal Gray of the Rat: A Potential Mechanism Driving the Dimorphic Effects of MorphineH.H. Doyle, L.N. Eidson, D.M. Sinkiewicz and A.Z. Murphy
Journal of Neuroscience 20 February 2017, 2906-16; DOI: https://doi.org/10.1523/JNEUROSCI.2906-16.2017
AbstractAlthough morphine remains the primary drug prescribed for alleviation of severe or persistent pain, both preclinical and clinical studies have shown that females require 2-3 times more morphine than males to produce comparable levels of analgesia. In addition to binding to the neuronal μ opioid receptor (MOR), morphine binds to the innate immune receptor toll-like receptor 4 (TLR4) localized primarily on microglia. Morphine action at TLR4 initiates a neuroinflammatory response that directly opposes the analgesic effects of morphine. Here we test the hypothesis that the attenuated response to morphine observed in females is the result of increased microglia activation in the periaqueductal gray (PAG), a central locus mediating the antinociceptive effects of morphine. We report that while no overall sex differences in the density of microglia were noted within the PAG of male or female rats, microglia exhibited a more “activated” phenotype in females at baseline, with the degree of activation a significant predictor of morphine ED50 values. Priming microglia with LPS induced greater microglia activation in the PAG of females compared with males that was accompanied by increased transcription levels of IL-1ß and a significant rightward shift in the morphine dose response curve. Blockade of morphine binding to PAG TLR4 with (+)-naloxone significantly potentiated morphine antinociception in females such that no sex differences in ED50 were observed. These results demonstrate that PAG microglia are sexually dimorphic in both basal and LPS-induced activation, and contribute to the sexually dimorphic effects of morphine in the rat.
SIGNIFICANCE STATEMENT
We demonstrate that PAG microglia contribute to the sexually dimorphic effects of morphine. Specifically, we report that increased activation of microglia in the PAG contributes to the attenuated response to morphine observed in females. Our data further implicate the innate immune receptor TLR4 as an underlying mechanism mediating these effects, and establish that TLR4 inhibition in the PAG of females reverses the sex differences in morphine responsiveness. These data suggest novel methods to improve current opioid-based pain management via inhibition of glial TLR4, and illustrate the necessity for sex-specific research and individualized treatment strategies for the management of pain in men and women.
Footnotes

• The authors report no conflict of interest
• National Institutes of Health Grant DA16272 awarded to A.Z.M. supported this work. (-)-Morphine sulfate and (+)-naloxone were kindly provided by the National Institute on Drug Abuse drug supply program. The authors thank Lauren Hanus and Alyssa Bartlett for their technical assistance.

 
Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

• Wilfred C. de Vega,Santiago Herrera,Suzanne D. Vernon and Patrick O. McGowanBMC Medical GenomicsBMC series – open, inclusive and trusted201710:11

DOI: 10.1186/s12920-017-0248-3  ©  The Author(s). 2017
Received: 20 December 2016 Accepted: 18 February 2017 Pub: 23 February 2017

Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating idiopathic disease characterized by unexplained fatigue that fails to resolve with sufficient rest. Diagnosis is based on a list of symptoms and exclusion of other fatigue-related health conditions. Despite a heterogeneous patient population, immune and hypothalamic-pituitary-adrenal (HPA) axis function differences, such as enhanced negative feedback to glucocorticoids, are recurring findings in ME/CFS studies. Epigenetic modifications, such as CpG methylation, are known to regulate long-term phenotypic differences and previous work by our group found DNA methylome differences in ME/CFS, however the relationship between DNA methylome modifications, clinical and functional characteristics associated with ME/CFS has not been examined.
Methods
We examined the DNA methylome in peripheral blood mononuclear cells (PBMCs) of a larger cohort of female ME/CFS patients using the Illumina HumanMethylation450 BeadChip Array. In parallel to the DNA methylome analysis, we investigated in vitro glucocorticoid sensitivity differences by stimulating PBMCs with phytohaemagglutinin and suppressed growth with dexamethasone. We explored DNA methylation differences using bisulfite pyrosequencing and statistical permutation. Linear regression was implemented to discover epigenomic regions associated with self-reported quality of life and network analysis of gene ontology terms to biologically contextualize results.
Results
We detected 12,608 differentially methylated sites between ME/CFS patients and healthy controls predominantly localized to cellular metabolism genes, some of which were also related to self-reported quality of life health scores. Among ME/CFS patients, glucocorticoid sensitivity was associated with differential methylation at 13 loci.
Conclusions
Our results indicate DNA methylation modifications in cellular metabolism in ME/CFS despite a heterogeneous patient population, implicating these processes in immune and HPA axis dysfunction in ME/CFS. Modifications to epigenetic loci associated with differences in glucocorticoid sensitivity may be important as biomarkers for future clinical testing. Overall, these findings align with recent ME/CFS work that point towards impairment in cellular energy production in this patient population

 
Trial of Amitriptyline, Topiramate, and Placebo for Pediatric Migraine
Scott W. Powers, Ph.D., Christopher S. Coffey, Ph.D., Leigh A. Chamberlin, R.D., M.Ed., Dixie J. Ecklund, R.N., M.S.N., Elizabeth A. Klingner, M.S., Jon W. Yankey, M.S., Leslie L. Korbee, B.S., Linda L. Porter, Ph.D., and Andrew D. Hershey, M.D., Ph.D., for the CHAMP Investigators*
N Engl J Med 2017; 376:115-124 January 12, 2017DOI: 10.1056/NEJMoa1610384
Share:
Background
Which, medication, if any, to use to prevent the headache of pediatric migraine has not been established.
Methods
We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment.
Results
A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt.
Conclusions
There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281).

 
Vitamin D and Statin-Related Myalgia
Philip J. Gregory, PharmD
Disclosures | March 10, 2017
·         Statin-Associated Side Effects

Do low vitamin D levels increase the risk for myalgia in patients who are taking statins?
Response from Philip J. Gregory, PharmD 
Associate Professor, Pharmacy Practice, Center for Drug Information & Evidence-Based Practice, Creighton University, Omaha, Nebraska

About 1%-2% of patients who take hydroxy-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins for hyperlipidemia develop muscle pain. This myalgia can feel like the aches and pains experienced with the flu. Muscles may feel sore or stiff and be sensitive to touch.[1] In some cases, statin-related myalgia can lead to poor adherence or discontinuation of the drug.[2]
The mechanism for statin-related myalgia is not fully understood, but vitamin D has been speculated to play a role.
Vitamin D deficiency itself is associated with symptoms of myalgia that resemble those caused by statins.[1,3] There has been speculation that statins themselves might affect vitamin D levels. Because low-density lipoprotein (LDL)-cholesterol is a vitamin D carrier and statins reduce LDL cholesterol, it has been proposed that statins could decrease vitamin D levels. On the other hand, both vitamin D and some statins are metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Owing to competitive inhibition at CYP3A4, it has been proposed that statins could increase levels of vitamin D.
Clinical trials and observational studies have produced mixed resuotlts in terms of the actual effect of statins on vitamin D levels. Overall, a meta-analysis of clinical trials found increased vitamin D levels in statin users.[4]
Several retrospective studies have shown that low vitamin D levels (measured as 25-hydroxyvitamin D) are associated with a higher risk for statin-induced myalgia. In a study by Shantha and colleagues,[5]patients with vitamin D levels in the lowest quartile had a 1.21 times increased risk for statin-induced myalgia compared with those in the highest quartile. Levels of 15 ng/mL or lower positively predicted the development of myalgia in statin users.
In a cross-sectional study, statin-treated patients with vitamin D levels of less than 15 ng/mL had a 1.9 times increased odds of myalgia compared with non-statin users; however, statin users with higher vitamin D levels did not have an increased risk for myalgia compared with non-statin users.[6]

 
A retrospective chart review in veterans taking statins found that levels of vitamin D were approximately 10 ng/dL lower in those who experienced statin-induced myalgia compared with those who did not.[7]
A meta-analysis of seven observational studies found that vitamin D levels were significantly lower in statin-treated patients who had symptoms of myalgia compared with those who were asymptomatic. The mean difference in vitamin D levels between the groups was approximately 9.4 ng/mL.[2]
Not all studies have found an association between low vitamin D and myalgia, especially in studies evaluating patients with symptoms confirmed to be caused by statins.[8,9] The discrepancies in findings may be because of the nonspecific nature of muscle symptoms. Some evidence shows that up to 50% of self-reported symptoms of muscle pain in statin users may not be because of statins specifically. Therefore, low vitamin D levels may contribute to muscle pain symptoms more generally, including in patients with statin-induced myalgia or nonspecific myalgia.[9]
Assessing and treating low vitamin D levels may be worth considering before starting or restarting a statin in patients who develop muscle pain while taking a statin.
A retrospective chart review found that replenishing vitamin D before a statin rechallenge in previously intolerant patients increases statin tolerability and adherence.[10]
In uncontrolled studies, some authors have used vitamin D2 (ergocalciferol) supplements (from 50,000 units to 100,000 units per week) in statin-treated patients with muscle symptoms and low vitamin D levels and reported resolution of myalgia in about 90% of patients. In these studies, low vitamin D levels were considered to be less than 32 ng/mL.[11,12]
 
  
Open Access Copyright: © 2016
The PACE Trial Invalidates the Use of Cognitive Behavioral and Graded Exercise Therapy in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: A Review

Mark Vink* Family Physician, Soerabaja Research Center, Amsterdam, The Netherlands
Received date: 12 Jan 2016; Accepted date: 24 Mar 2016; Published date: 30 Mar 2016.
. J Neurol Neurobiol 2(3): doi http://dx.doi.org/10.16966/2379- 7150.124 Copyright: © 2016 Vink M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. * Corresponding author: Mark Vink, Family Physician, Soerabaja Research Center, Amsterdam, The Netherlands, E-mail: markvink.md@outlook.com
Introduction Following an extensive review of the literature, the American Institute of Medicine (IOM) concluded that “myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are serious, debilitating conditions that affect millions of people in the United States and around the world”; that it is a “medical - not a psychiatric or psychological - illness” without a “known cause or effective treatment” which “can cause significant impairment and disability” [1] rendering 25% of patients homebound or bedridden [2] yet “the term chronic fatigue syndrome can result in trivialization and stigmatization” of this “complex, multisystem, and often devastating disorder” [1] . Most doctors are unaware of the seriousness of ME or that it has been classified as a neurological disease by the World Health Organization (WHO) since 1969 [3]; therefore, patients often receive “hostility from their health care provider” and are “subjected to treatment strategies that exacerbate their symptoms” (i.e., CBT and GET) [1]. ISSN 2379-7150 Abstract The main findings reported in the PACE trial were that cognitive behavioral therapy (CBT) and graded exercise therapy (GET) were moderately effective treatments for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), and fear avoidance beliefs constituted the strongest mediator of both therapies. These findings have been challenged by patients and, more recently, a number of top scientists, after public health expert Tuller, highlighted methodological problems in the trial. As a doctor who has been bedridden with severe ME for a long period, I analyzed the PACE trial and its follow-up articles from the perspectives of a doctor and a patient. During the PACE trial the eligibility criteria, both subjective primary outcomes, and most of the recovery criteria were altered, creating an overlap of the eligibility and recovery criteria; consequently, 13% of patients were considered “recovered,” with respect to 1 or 2 primary outcomes, as soon as they entered the trial. In addition, 46% of patients reported an increase in ME/CFS symptoms, 31% reported musculoskeletal and 19% reported neurological adverse events. Therefore the proportion negatively affected by CBT and GET would be between 46% and 96%, most likely estimated at 74%, as shown in a large survey recently conducted by the ME Association. Medication with such high rates of adverse events would be withdrawn with immediate effect. There was no difference in long-term outcomes between adaptive pacing therapy, CBT, GET and specialist medical care, and none of them were effective, invalidating the biopsychosocial model and use of CBT and GET for ME/CFS. The discovery that an increase in exercise tolerance did not lead to an increase in fitness means that an underlying physical problem prevented this; validates that ME/CFS is a physical disease and that none of the treatments studied addressed this issue.

​Dietary and nutrition interventions for the therapeutic
treatm ent of chronic fatigue syndrome/myalgic
encephalomyelitis: a systematic review
N. Campagnolo,1,2S. Johnston,1,2A. Collatz,1,2 D. Staines1.2 & S. Marshall-Gradisnik1,2
School of Medical Science, Griffith University, Gold Coast, QLD, Australia
National Centre for Neuroimmuno logy and Emerging Diseases, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD,
Australia
 J Hum Nutr Diet.
doi: 10.1111/jhn.12435
This is an open access article under the terms of
the Creative Commons Attribution-
NonCommercial-NoDerivs License, which permits
use and distribution in any medium, provided the
original work is properly cited, the use is non-
commercial and no modifications or adaptations
are made.

Abstract
Background: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/
ME) is characterised by unexplained fatigue for at least 6 months accompa-
nied by a diverse but consistent set of symptoms. Diet modification and
nutritional supplements could be used to improve patient outcomes, such
fatigue and quality of life. We reviewed and discussed the evidence for
nutritional interventions that may assist in alleviating symptoms of CFS/
ME.
Methods: Medline, Cinahl and Scopus were systematically searched from
1994 to May 2016. All studies on nutrition intervention were included
where CFS/ME patients modified their diet or supplemented their habitual
diet on patient-centred outcomes (fatigue, quality of life, physical activity
and/or psychological wellbeing).
Results: Seventeen studies were included that meet the inclusion criteria. Of
these, 14 different interventions were investigated on study outcomes. Many
studies did not show therapeutic benefit on CFS/ME. Improvements in fati-
gue were observed for nicotinamide adenine dinucleotide hydride (NADH),
probiotics, high cocoa polyphenol rich chocolate, and a combination of
NADH and coenzyme Q10.
Conclusions: This review identified insufficient evidence for the use of
nutritional supplements and elimination or modified diets to relieve CFS/
ME symptoms. Studies were limited by the number of studies investigating
the interventions, small sample sizes, study duration, variety of instruments
used, and studies not reporting dietary intake method. Further research is
warranted in homogeneous CFS/ME populations.



Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channelsAuthors·         T. Nguyen,S. Johnston,L. Clarke,P. Smith,D. Staines,S. Marshall-Gradisnik

• First published: 23 November 2016Full publication history
• DOI: 10.1111/cei.12882View/save citation
• Cited by: 0 articles

SummaryTransient 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 CD56dimCD16+NK cells and CD56brightCD16dim/– 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 CD56brightCD16dim/– 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 CD56brightCD16dim/–NK cells showed a significant increase in Ca2+ flux in CFS/ME patients compared with HC. By comparison, unstimulated CD56dimCD16+ NK cells showed no significant difference in both Ca2+ flux and TRPM3 expression. PregS-stimulated CD56dimCD16+ NK cells increased TRPM3 expression significantly in CFS/ME, but this was not associated with a significant increase in Ca2+ flux. Furthermore, TG-stimulated CD56dimCD16+ 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.

 

Fecal metagenomic profiles in subgroups of patients with myalgic encephalomyelitis/chronic fatigue syndrome

• Dorottya Nagy-Szakal†,Brent L. Williams†,Nischay Mishra,Xiaoyu Che,Bohyun Lee,
• Lucinda Bateman,Nancy G. Klimas,Anthony L. Komaroff,Susan Levine,Jose G. Montoya,
• Daniel L. Peterson,Devi Ramanan,Komal Jain,Meredith L. Eddy,Mady Hornig and
• W. Ian LipkinEmail authorView ORCID ID profile
• Microbiome20175:44

DOI: 10.1186/s40168-017-0261-y

©  The Author(s). 2017
Received: 11 January 2017 Accepted: 4 April 2017 Published: 26 April 2017
 
AbstractBackgroundMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling.
ResultsTopological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways.
ConclusionsIndependent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.
KeywordsMyalgic encephalomyelitis Chronic fatigue syndrome Microbiota-gut-brain axis Metagenomic Topological data analysis Irritable bowel syndrome Metabolic pathway

 
Modern Clinical Medicine Research, Vol. 1, No. 1, April 2017
Access to Medical Care for Individuals with Myalgic Encephalomyelitis and Chronic Fatigue Syndrome:
A Call for Centers of Excellence
Madison Sunnquist1 , Laura Nicholson1 , Leonard A. Jason1*, and Kenneth J. Friedman2 1 Center for Community Research, DePaul University, Chicago, Illinois, United States 2 Green Mountain College, Poultney, Vermont, United States Email: ljason@depaul.edu
Abstract. The current study sought to better understand the experience of individuals with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) in accessing care for their debilitating illness. Of 898 participants, less than half had ever seen an ME or CFS specialist, though 99% of participants were interested in specialist care. Participants cited geographic and financial barriers as most frequently precluding access to specialists. Furthermore, satisfaction with specialist care greatly exceeded satisfaction with non-specialist care. These findings suggested that individuals with ME and CFS represent a medically-underserved population, due to lack of available care. The CFS Advisory Committee and NIH Pathways to Prevention Working Group recommended the creation of ME and CFS Centers of Excellence to improve the healthcare access of patients with ME and CFS. The current study documents the need for these centers, as they would ameliorate geographic and financial barriers to quality care. Keywords: Myalgic encephalomyelitis, chronic fatigue syndrome, healthcare access, specialist care,

 
Baby thought to have been shaken has rare syndrome, family court finds
BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2136 (Published 02 May 2017)Cite this as: BMJ 2017;357:j2136
Clare Dyer
A baby who was thought to have been shaken by one of her parents actually has a rare syndrome that affects her blood vessels, Ehlers-Danlos syndrome type IV, a family court has heard.
Effie Stillwell was taken from her parents and placed with foster carers last September, after she collapsed, at nearly 3 months old, and was taken to hospital unresponsive and with difficulty breathing. Retinal haemorrhages and bleeding on the brain were identified, and police began a criminal investigation. But the medical evidence that emerged during the family court hearing persuaded Buckinghamshire County Council to drop its application for a care order.
 
Gluten-free diet is not recommended for people without celiac disease
BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2135 (Published 03 May 2017)Cite this as: BMJ 2017;357:j2135
Zosia Kmietowicz
Gluten is not associated with a risk of coronary heart disease in people without celiac disease—and restricting gluten may result in a low intake of whole grains, which are associated with cardiovascular benefits, a study in The BMJ has found.1
The researchers said that promoting gluten-free diets among people without celiac disease should not be encouraged.
The number of people without celiac disease who avoid gluten has increased in recent years

 
Long term gluten consumption in adults without celiac disease and risk of coronary heart disease: prospective cohort studyBMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j1892 (Published 02 May 2017)Cite this as: BMJ 2017;357:j1892
Benjamin Lebwohl, assistant professor1 2, Yin Cao, instructor3 4 5, Geng Zong, postdoctoral fellow5, 
Frank B Hu, professor5 6, Peter H R Green, professor1, Alfred I Neugut, Eric B Rimm, Laura Sampson, Lauren W Dougherty, Edward GiovannucciWalter, C Willett, professor5 6 7, Qi Sun, Andrew T Chan,
Correspondence to: A T Chan ACHAN@mgh.harvard.edu
Accepted 4 April 2017

AbstractObjective To examine the association of long term intake of gluten with the development of incident coronary heart disease.
Design Prospective cohort study.
Setting and participants 64 714 women in the Nurses’ Health Study and 45 303 men in the Health Professionals Follow-up Study without a history of coronary heart disease who completed a 131 item semiquantitative food frequency questionnaire in 1986 that was updated every four years through 2010.
Exposure Consumption of gluten, estimated from food frequency questionnaires.
Main outcome measure Development of coronary heart disease (fatal or non-fatal myocardial infarction).
Results During 26 years of follow-up encompassing 2 273 931 person years, 2431 women and 4098 men developed coronary heart disease. Compared with participants in the lowest fifth of gluten intake, who had a coronary heart disease incidence rate of 352 per 100 000 person years, those in the highest fifth had a rate of 277 events per 100 000 person years, leading to an unadjusted rate difference of 75 (95% confidence interval 51 to 98) fewer cases of coronary heart disease per 100 000 person years. After adjustment for known risk factors, participants in the highest fifth of estimated gluten intake had a multivariable hazard ratio for coronary heart disease of 0.95 (95% confidence interval 0.88 to 1.02; P for trend=0.29). After additional adjustment for intake of whole grains (leaving the remaining variance of gluten corresponding to refined grains), the multivariate hazard ratio was 1.00 (0.92 to 1.09; P for trend=0.77). In contrast, after additional adjustment for intake of refined grains (leaving the variance of gluten intake correlating with whole grain intake), estimated gluten consumption was associated with a lower risk of coronary heart disease (multivariate hazard ratio 0.85, 0.77 to 0.93; P for trend=0.002).
Conclusion Long term dietary intake of gluten was not associated with risk of coronary heart disease. However, the avoidance of gluten may result in reduced consumption of beneficial whole grains, which may affect cardiovascular risk. The promotion of gluten-free diets among people without celiac disease should not be

A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS)? Navena Navaneetharaja, Verity Griffiths, Tom Wileman and Simon R. Carding http://www.mdpi.com/2077-0383/5/6/55  
  Published: 6 June 2016 
This article provides a comprehensive review of the current evidence supporting an infectious aetiology for ME/CFS leading us to propose the novel concept that the intestinal microbiota and in particular members of the virome are a source of the “infectious” trigger of the disease.  
Such an approach has the potential to identify disease biomarkers and influence therapeutics, providing much-needed approaches in preventing and managing a disease desperately in need of confronting. 
  
Center of Excellence for ME (http://ldifme.org/a-uk-centre/) Invest in ME Research wish to establish a Centre of Excellence for ME – a centre which would exist to bring discovery, knowledge, and effective treatments to patients with ME and possibly, in future, other illnesses that are caused by acquired dysregulation of both the immune system and the nervous system. 
The proposed centre would become a Centre of Excellence in the treatment of ME in Europe and would attract researchers, physicians and healthcare staff from around the UK and Europe and USA. It will be based at Europe’s largest grouping of scientific institutes – Norwich Research Park.  
International collaboration is facilitated by the annual Invest in ME International Conference and Biomedical Resarchers into ME Colloquium (http://bit.ly/1Wpsxg8 ), and now also by the European ME Research Group (http://bit.ly/28RuFIY) formed by the European ME Alliance (http://bit.ly/28X1QOU), which is a member of the European Federation of Neurological Associations (http://bit.ly/1WKm2mE). Source : http://bit.ly/28V7XTj  

 
       vol. 112 no. 49
       > Steven W. Cole,  15142–15147, doi: 10.1073/pnas.1514249112
Myeloid differentiation architecture of leukocyte transcriptome dynamics in perceived social isolation
Steven W. Colea,b, John P. Capitanioc,d, Katie Chunc,d, Jesusa M. G. Arevaloa,b, Jeffrey Maa,b, and
 John T. Cacioppoe,f,g,1
Edited by Burton H. Singer, University of Florida, Gainesville, FL, and approved October 21, 2015 (received for
Significance
Perceived social isolation (PSI) (loneliness) is linked to increased risk of chronic disease and mortality, and previous research has implicated up-regulated inflammation and down-regulated antiviral gene expression (the conserved transcriptional response to adversity; CTRA) as a potential mechanism for such effects. The present studies used integrative analyses of transcriptome regulation in high-PSI humans and rhesus macaques to define the basis for such effects in neuroendocrine-related alterations in myeloid immune cell population dynamics. CTRA up-regulation also preceded increases in PSI, suggesting a reciprocal mechanism by which CTRA gene expression may both propagate PSI and contribute to its related disease risks.
Abstract
To define the cellular mechanisms of up-regulated inflammatory gene expression and down-regulated antiviral response in people experiencing perceived social isolation (loneliness), we conducted integrative analyses of leukocyte gene regulation in humans and rhesus macaques. Five longitudinal leukocyte transcriptome surveys in 141 older adults showed up-regulation of the sympathetic nervous system (SNS), monocyte population expansion, and up-regulation of the leukocyte conserved transcriptional response to adversity (CTRA). Mechanistic analyses in a macaque model of perceived social isolation confirmed CTRA activation and identified selective up-regulation of the CD14++/CD16− classical monocyte transcriptome, functional glucocorticoid desensitization, down-regulation of Type I and II interferons, and impaired response to infection by simian immunodeficiency virus (SIV). These analyses identify neuroendocrine-related alterations in myeloid cell population dynamics as a key mediator of CTRA transcriptome skewing, which may both propagate perceived social isolation and contribute to its associated health risks.
Footnotes
       ↵1To whom correspondence should be addressed. Email: Cacioppo@uchicago.edu.
       Author contributions: S.W.C., J.P.C., and J.T.C. designed research; S.W.C., J.P.C., K.C., J.M.G.A., J.M., and J.T.C. performed research; S.W.C. contributed new reagents/analytic tools; S.W.C., J.P.C., and J.T.C. analyzed data; and S.W.C., J.P.C., and J.T.C. wrote the paper.
       The authors declare no conflict of interest.
       This article is a PNAS Direct Submission.
        www.pnas.org/lookup/suppl/doi:10.1073/pnas.1514249112/-/DCSupplemental.
Freely available online through the PNAS open access option.

 
Progressive Brain Changes In Patients With Chronic Fatigue Syndrome: A Longitudinal MRI Study
Zack Y. Shan, PhD, Richard Kwiatek, MBBS, Richard Burnett, MBBS, Peter Del Fante, MBBS, Donald R.Staines, MBBS, Sonya M.Marshall-Gradisnik, PhD, and Leighton R.Barnden, PhD 
Abstract 
Purpose To examine progressive brain changes associated with chronic fatigue syndrome (CFS). 
Materials and Methods We investigated progressive brain changes with longitudinal MRI in 15 CFS and 10 normal controls (NCs) scanned twice 6 years apart on the same 1.5 Tesla (T) scanner. MR images yielded gray matter (GM) volumes, white matter (WM) volumes, and T1- and T2-weighted signal intensities (T1w and T2w). Each participant was characterized with Bell disability scores, and somatic and neurological symptom scores. We tested for differences in longitudinal changes between CFS and NC groups, inter group differences between pooled CFS and pooled NC populations, and correlations between MRI and symptom scores using voxel based morphometry. The analysis methodologies were first optimized using simulated atrophy. 
Results We found a significant decrease in WM volumes in the left inferior fronto-occipital fasciculus (IFOF) in CFS while in NCs it was unchanged (family wise error adjusted cluster level P value, PFWE < 0.05). This longitudinal finding was consolidated by the group comparisons which detected significantly decreased regional WM volumes in adjacent regions (PFWE < 0.05) and decreased GM and blood volumes in contralateral regions (PFWE < 0.05). Moreover, the regional GM and WM volumes and T2w in those areas showed significant correlations with CFS symptom scores (PFWE < 0.05). 
Conclusion The results suggested that CFS is associated with IFOF WM deficits which continue to deteriorate at an abnormal rate.  
Source & complete research: http://onlinelibrary.wiley.com/doi/10.1002/jmri.25283/epdf   

The Biological Challenge Of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome: A Solvable Problem.
Professor Jonathan Edwards, along with several ME/CFS patients and a carer with scientific backgrounds have coauthored a peer-reviewed editorial (http://bit.ly/1OwHnQX) on the disease that appears in the latest issue of the journal Fatigue: Biomedicine, Health & Behavior (http://bit.ly/1OwH5JM). 
The article is titled, The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem (http://bit.ly/1OwHnQX). The paper has gained over 1600 views in the three days since publication, making it already Fatigue’s second most-read paper since the journal began in 2013. 
The paper is an overview of the most promising developments in biomedical research into ME/CFS. The authors “call on the wider biomedical research community to actively target this condition” and make a “concerted effort.” 
Simon McGrath, an ME/CFS patient well-known for his blogs (http://bit.ly/1WVGHqP) on the science of the illness, was one of the editorial’s authors. He said, “We felt it was time to make the case for biomedical research, aiming to summarise the most promising research, while acknowledging its limitations”. 
He added, “The aim of the paper is to provide a ‘way in’ to biological ME/CFS research for researchers who might be interested but were overwhelmed by the vast literature of mainly unconfirmed findings, or those who doubted there was anything of merit in biological research.” 
The paper includes what he described as “the most interesting studies, including the two-day exercise challenge, changes in gene expression after moderate exercise, and brain scans indicating microglia activation”. The editorial also highlights the promising rituximab treatment pilot studies and ongoing trial (http://bit.ly/1V75emz). 

 
http://www.ncbi.nlm.nih.gov/pubmed/27362406
Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients.
Nguyen T, Johnston S, Chacko A, Gibson D, Cepon J, Smith P, Staines D, Marshall-Gradisnik S.
Abstract
BACKGROUND: Mast cells (MCs) mediate inflammation through neuropeptides and cytokines, along with histamine and reactive oxygen species (ROS). Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
(CFS/ME) is an illness characterized by an unexplained disabling fatigue with multiple physiological impairments as well as dysregulated cytokine profiles.
OBJECTIVE: To determine mast cell phenotypes in isolated human PBMCs, in healthy controls and in CFS/ME patients. Second, determine receptor expression of RAGE and its ligand high mobility group box 1 protein (HMGB1).
METHOD: Moderately severe CFS/ME patients (n=12, mean age 39.25±SD3.52 years), severe CFS/ME patients (n=6, mean age 43.00±SD4.02 years) and healthy controls (n=13, mean age 42.69±SD3.87 years) were included in this study. CFS/ME patients were classified according to the 2011 International Consensus Criteria. LSRFortessa X-20 Flow cytometry was used for the identification of phenotypic peripheral mast cell population in PBMCs using an exclusion marker Lin2 cocktail (anti-CD3, anti-CD14, anti-CD19, anti-CD20 and anti-CD56) and inclusion markers (CD117, CD34, FCεRI, chymase, HLA-DR and CD154) following comparative investigation. HMGB1 and soluble RAGE expression in plasma was measured by sandwich ELISA assay.
RESULTS: There was a significant increase in CD117+CD34+FCεRI-chymase- mast cell populations in moderate and severe CFS/ME patients compared with healthy controls. There was a significant increase in CD40 ligand and MHC-II receptors on differentiated mast cell populations in the severe CFS/ME compared with healthy controls and moderate CFS/ME.
There were no significant differences between groups for HMGB1 and sRAGE.
CONCLUSIONS: This preliminary study investigates mast cell phenotypes from PBMCs in healthy controls. We report significant increase of naïve MCs in moderate and severe CFS/ME patients compared with healthy controls. Moreover, a significant increase in CD40 ligand and MHC-II receptors on differentiated mast cells in severe CFS/ME patients.
Peripheral MCs may be present in CFS/ME pathology however, further investigation to determine their role is required.
PMID:27362406DOI:10.12932/AP0711

 
fulltext- http://openheart.bmj.com/content/3/1/e000381.long
Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study
Julia L Newton, Andreas Finkelmeyer, George Petrides, James Frith, Tim Hodgson, Laura Maclachlan, Guy MacGowan, and Andrew M Blamire
Abstract
Objectives To explore potential mechanisms that underpin the cardiac abnormalities seen in chronic fatigue syndrome (CFS) using non-invasive cardiac impedance, red cell mass and plasma volume measurements.
Methods Cardiac MR (MR) examinations were performed using 3 T Philips Intera Achieva scanner (Best, NL) in participants with CFS (Fukuda;
n=47) and matched case-by-case controls. Total volume (TV), red cell volume (RCV) and plasma volume (PV) measurements were performed (41 CFS and 10 controls) using the indicator dilution technique using simultaneous 51-chromium labelling of red blood cells and 125-iodine labelling of serum albumin.
Results The CFS group length of history (mean±SD) was 14±10 years. Patients with CFS had significantly reduced end-systolic and end-diastolic volumes together with reduced end-diastolic wall masses (all p<0.0001). Mean±SD RCV was 1565±443 mL with 26/41 (63%) having values below 95% of expected. PV was 2659±529 mL with 13/41 (32%) <95% expected.
There were strong positive correlations between TV, RCV and PV and cardiac end-diastolic wall mass (all p<0.0001; r2=0.5).
Increasing fatigue severity correlated negatively with lower PV (p=0.04; r2=0.2). There were no relationships between any MR or volume measurements and length of history, suggesting that deconditioning was unlikely to be the cause of these abnormalities.
Conclusions This study confirms an association between reduced cardiac volumes and blood volume in CFS. Lack of relationship between length of disease, cardiac and plasma volumes suggests findings are not secondary to deconditioning. The relationship between plasma volume and severity of fatigue symptoms suggests a potential therapeutic target in CFS.

 
fulltext- https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168...
Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome
Ludovic Giloteaux, Julia K. Goodrich, William A. Walters, Susan M.
Levine, Ruth E. Ley and Maureen R. Hanson
Abstract
Background Gastrointestinal disturbances are among symptoms commonly reported by individuals diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). However, whether ME/CFS is associated with an altered microbiome has remained uncertain. Here, we profiled gut microbial diversity by sequencing 16S ribosomal ribonucleic acid (rRNA) genes from stool as well as inflammatory markers from serum for cases (n = 48) and controls (n  = 39). We also examined a set of inflammatory markers in blood: C-reactive protein (CRP), intestinal fatty acid-binding protein (I-FABP), lipopolysaccharide (LPS), LPS-binding protein (LBP), and soluble CD14 (sCD14).
Results We observed elevated levels of some blood markers for microbial translocation in ME/CFS patients; levels of LPS, LBP, and sCD14 were elevated in ME/CFS subjects. Levels of LBP correlated with LPS and
sCD14 and LPS levels correlated with sCD14. Through deep sequencing of bacterial rRNA markers, we identified differences between the gut microbiomes of healthy individuals and patients with ME/CFS.
We observed that bacterial diversity was decreased in the ME/CFS specimens compared to controls, in particular, a reduction in the relative abundance and diversity of members belonging to the Firmicutes phylum. In the patient cohort, we find less diversity as well as increases in specific species often reported to be pro-inflammatory species and reduction in species frequently described as anti-inflammatory.
Using a machine learning approach trained on the data obtained from 16S rRNA and inflammatory markers, individuals were classified correctly as ME/CFS with a cross-validation accuracy of 82.93 %.
Conclusions Our results indicate dysbiosis of the gut microbiota in this disease and further suggest an increased incidence of microbial translocation, which may play a role in inflammatory symptoms in ME/CFS.

 
http://www.ncbi.nlm.nih.gov/pubmed/27329758
Attentional and interpretive bias towards illness-related information in chronic fatigue syndrome: A systematic review.
Hughes A, Hirsch C, Chalder T, Moss-Morris R.
Abstract
PURPOSE: Chronic fatigue syndrome (CFS) is characterized by severe and debilitating fatigue. Studies based on self-report measures suggest negative illness representations, related symptom interpretations, and heightened symptom focusing are maintaining factors of fatigue. This study reviews studies which have investigated these cognitive biases using experimental methods, to (1) review the evidence for information processing biases in CFS; (2) determine the nature of these biases, that is the stages cognitive biases occur and for what type of stimuli; and (3) provide directions for future methodologies in this area.
METHODS: Studies were included that measured attention and interpretation bias towards negative and illness-related information in people with CFS and in a comparison group of healthy controls. PubMed, Ovid, CINAHL, PsycINFO, Web of Science, and EThOS were searched until December 2014.
RESULTS: The evidence for cognitive biases was dependent on the methodology employed as well as the type and duration of the stimuli presented.
Modified Stroop studies found weak evidence of an attentional bias in CFS populations, whereas visual-probe studies consistently found an attentional bias in CFS groups for health-threatening information presented for 500 ms or longer. Interpretative bias studies which required elaborative processing, as opposed to a spontaneous response, found an illness-related interpretive bias in the CFS group compared to controls.
CONCLUSIONS: Some people with CFS have biases in the way they attend to and interpret somatic information. Such cognitive processing biases may maintain illness beliefs and symptoms in people with CFS. This review highlights methodological issues in experimental design and makes recommendations to aid future research to forge a consistent approach in cognitive processing research. Statement of contribution What is already known on this subject?
Studies based on self-report measures suggest negative illness representations, related symptom interpretations, and heightened symptom focusing contribute to the maintenance of chronic fatigue. Experimental studies in other clinical populations, such as patients with anxiety, depression, and chronic pain, have identified illness-specific biases in how information is implicitly attended to and interpreted, which has a causal role in these conditions. What does this study add? This is the first review of implicit cognitive processes in chronic fatigue syndrome (CFS).
Sustained attention and negative interpretations of somatic information may reinforce negative illness beliefs. Cognitive processes have a role to play in the cognitive behavioural model of CFS.
© 2016 The British Psychological Society.

 
http://www.ncbi.nlm.nih.gov/pubmed/27255790
Distress in significant others of patients with chronic fatigue syndrome: A systematic review of the literature.
Harris K, Band RJ, Cooper H, Macintyre VG, Mejia A, Wearden AJ.
Abstract
Statement of contribution What is already known on this subject?
Chronic fatigue syndrome (CFS/ME) entails considerable economic, social, and personal costs. Uncertainties exist around diagnosis and management. This may lead to particular difficulties for significant others trying to support patients. What does this study add? Few studies have examined distress and its correlates in significant others of people with CFS/ME. Significant others report elevated levels of distress on quantitative measures.
PURPOSE:The objective of this study was to systematically review existing empirical research assessing levels and correlates of distress in significant others of patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).
METHODS:Systematic searches in CINAHL, Web of Science and PsycINFO were conducted in August 2014. The search was repeated in January 2015 to check for newly published articles. Studies published in English with quantitative, qualitative, or mixed designs exploring distress, poor subjective health, poor mental health, reduced quality of life and well-being, and symptoms of depression and anxiety in significant others (>18 years) of children and adults with CFS/ME were included.
Quality appraisal of included studies was carried out. Quantitative and qualitative studies were summarized separately.
RESULTS: Six articles met eligibility criteria. Two quantitative studies with significant others of adult patients, and one quantitative and two mixed-methods studies with significant others of child patients showed moderate to high levels of distress. One qualitative study (adult patients) found minimal evidence of distress and that acceptance of CFS/ME was related to better adjustment. In the quantitative and mixed-methods studies, significant others who attributed some level of responsibility for symptoms to the patient, or who were female, or whose partners had poorer mental health, had higher levels of distress.
CONCLUSIONS:The small number of studies to date, the contrary evidence from a qualitative study, and the limited data available on levels of distress in significant others of patients with CFS/ME mean that our conclusion that distress levels are elevated is provisional. We recommend that future qualitative studies focus on this particular topic. Further longitudinal studies exploring correlates of distress within the context of a predictive theoretical model would be helpful.
© 2016 The British Psychological Society.

 
fultext- https://www.dovepress.com/getfile.php?fileID=30423
Epidemiological characteristics of chronic fatigue- syndrome/myalgic encephalomyelitis in Australian patients
Samantha C Johnston, Donald R Staines, Sonya M Marshall-Gradisnik
National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute Queensland, 2School of Medical Sciences, Griffith University, Parklands, QLD, Australia
Abstract
Background: No epidemiological investigations have previously been conducted in Australia according to the current clinical definitions of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The aim of this study was to describe sociodemographic and illness characteristics of Australian patients with CFS/ME.
Methods: A cross-sectional survey on the medical history of patients enrolled in an Australian CFS/ME research database between April 2013 and April 2015. Participants were classified according to Fukuda criteria and International Consensus Criteria.
Results: A total of 535 patients diagnosed with CFS/ME by a primary care physician were identified. The mean age of all patients was 46.4 years (standard deviation 12.0); the majority were female (78.61%), Caucasian, and highly educated. Of these, 30.28% met Fukuda criteria.
A further 31.96% met both Fukuda criteria and International Consensus Criteria. There were 14.58% reporting chronic fatigue but did not meet criteria for CFS/ME and 23.18% were considered noncases due to exclusionary conditions. Within those meeting CFS/ME criteria, the most common events prior to illness included cold or flu, gastrointestinal illness, and periods of undue stress.
Of the 60 symptoms surveyed, fatigue, cognitive, and short-term memory symptoms, headaches, muscle and joint pain, unrefreshed sleep, sensory disturbances, muscle weakness, and intolerance to extremes of temperature were the most commonly occurring symptoms (reported by more than two-thirds of patients). Significant differences in symptom occurrence between Fukuda- and International Consensus Criteria-defined cases were also identified.
Conclusion: This is the first study to summarize sociodemographic and illness characteristics of a cohort of Australian CFS/ME patients.
This is vital for identifying potential risk factors and predictors associated with CFS/ME and for guiding decisions regarding health care provision, diagnosis, and management.

 
http://www.ncbi.nlm.nih.gov/pubmed/27143625
Factors determining fatigue in the chronic fatigue syndrome: a path analysis.
Tobback E, Hanoulle I, Mariman A, Delesie L, Pevernagie D, Vogelaers D
Abstract
OBJECTIVES: To explore the interrelationship of different dimensions (fatigue, neuroticism, sleep quality, global mental and physical
health) in patients with chronic fatigue syndrome (CFS).
METHODS: Patients meeting the Fukuda criteria of CFS filled out two independent fatigue scales (Fatigue Questionnaire, FQ and Checklist Individual Strength, CIS), NEO-Five Factor Inventory (NEO-FFI), Pittsburgh Sleep Quality Index (PSQI) and Medical Outcomes Study 36-item Short Form Health Survey (SF36). Exploratory and confirmatory path analyses were performed.
RESULTS: Out of 226 eligible patients, 167 subjects were included (mean age 39.13 years, SD 10.14, 92% female). In a first exploratory path analysis, using FQ for assessment of fatigue, night-time PSQI sleep quality had a direct effect on SF36 physical quality of life
(PQoL) and no effect on FQ fatigue. This was confirmed by a subsequent path analysis with CIS fatigue and by confirmatory path analyses in 81 patients. These unexpected results raised the question whether FQ or CIS fatigue sufficiently operationalizes fatigue in CFS patients.
CONCLUSIONS: Poor sleep quality seems to directly impact on mental quality of life (MQoL) and PQoL without mediation of fatigue assessed with FQ and CIS. A more cohesive framework needs to be developed with more comprehensive clinical tools for the different dimensions in the construct of CFS.

 
Ann Rheum Dis doi:10.1136/annrheumdis-2016-209724
EULAR revised recommendations for the management of fibromyalgia
Professor G J Macfarlane et al
Correspondence to Professor G J Macfarlane, Epidemiology Group, University of Aberdeen, School of Medicine, Medical Sciences and Nutrition, Polwarth Building, Foresterhill, Aberdeen, Scotland AB25 2ZD, UK; g.j.macfarlane@abdn.ac.uk
Received 15 April 2016 Revised 10 June 2016 Accepted 14 June 2016 Published Online First 4 July 2016
Abstract
Objective The original European League Against Rheumatism recommendations for managing fibromyalgia assessed evidence up to 2005. The paucity of studies meant that most recommendations were ‘expert opinion’.
Methods A multidisciplinary group from 12 countries assessed evidence with a focus on systematic reviews and meta-analyses concerned with pharmacological/non-pharmacological management for fibromyalgia. A review, in May 2015, identified eligible publications and key outcomes assessed were pain, fatigue, sleep and daily functioning. The Grading of Recommendations Assessment, Development and Evaluation system was used for making recommendations.
Results 2979 titles were identified: from these 275 full papers were selected for review and 107 reviews (and/or meta-analyses) evaluated as eligible. Based on meta-analyses, the only ‘strong for’ therapy-based recommendation in the guidelines was exercise. Based on expert opinion, a graduated approach, the following four main stages are suggested underpinned by shared decision-making with patients. Initial management should involve patient education and focus on non-pharmacological therapies. In case of non-response, further therapies (all of which were evaluated as ‘weak for’ based on meta-analyses) should be tailored to the specific needs of the individual and may involve psychological therapies (for mood disorders and unhelpful coping strategies), pharmacotherapy (for severe pain or sleep disturbance) and/or a multimodal rehabilitation programme (for severe disability).
Conclusions These recommendations are underpinned by high-quality reviews and meta-analyses. The size of effect for most treatments is relatively modest. We propose research priorities clarifying who will benefit from specific interventions, their effect in combination and organisation of healthcare systems to optimise outcome.

 
British Journal of General PracticeChronic fatigue syndrome: is the biopsychosocial model responsible for patient dissatisfaction and harm?Keith J Geraghty, Aneez Esmail
DOI: 10.3399/bjgp16X686473 Published 1 August 2016

In 1977 George Engel wrote about the need for an ‘integrated approach’ in medicine that moved the focus beyond biological mechanisms of disease to include all pertinent aspects of illness presentation, setting out a ‘biopsychosocial model’.1 Around the same time, McEvedy and Beard asserted that the disease ‘benign myalgic encephalomyelitis’, described by Ramsay at the Royal Free Hospital, London, was nothing more than a case of ‘mass hysteria’.2 In the 1980s, doctors combined theories of neurasthenia, hysteria, and somatoform illness, to reconstitute ME as ‘chronic fatigue syndrome’. Psychiatrists argued that CFS was best understood using a biopsychosocial (BPS) framework, being perhaps triggered by viral illness (biology), but maintained by certain personality traits (psychology) and social conditions (sociology).3 Although the BPS model holds much utility in understanding ‘illness’ in a wider context, many sufferers of CFS reject the notion that their illness is psychologically or socially derived. Significant numbers of patients report difficult interactions with doctors that leave them feeling dissatisfied, disbelieved, and distressed. In this article, we question whether or not the BPS model generates ‘harms’ for CFS patients, and we ask if other, alternative approaches might be more preferable to both patients and GPs.

 
 
PloS One:2016 Jul 18;11(7):e0159386. doi: 10.1371/journal.pone.0159386. eCollection 2016.
Neuromuscular Strain Increases Symptom Intensity in Chronic Fatigue Syndrome.Rowe PC1, Fontaine KR2, Lauver M1, Jasion SE1, Marden CL1, Moni M1, Thompson CB3, Violand RL4.
Author information

• 1Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
• 2Department of Health Behavior, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama, United States of America.
• 3Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
• 4Rick Violand, PT LLC, Ellicott City, Maryland, United States of America.

AbstractChronic fatigue syndrome (CFS) is a complex, multisystem disorder that can be disabling. CFS symptoms can be provoked by increased physical or cognitive activity, and by orthostatic stress. In preliminary work, we noted that CFS symptoms also could be provoked by application of longitudinal neural and soft tissue strain to the limbs and spine of affected individuals. In this study we measured the responses to a straight leg raise neuromuscular strain maneuver in individuals with CFS and healthy controls. We randomly assigned 60 individuals with CFS and 20 healthy controls to either a 15 minute period of passive supine straight leg raise (true neuromuscular strain) or a sham straight leg raise. The primary outcome measure was the symptom intensity difference between the scores during and 24 hours after the study maneuver compared to baseline. Fatigue, body pain, lightheadedness, concentration difficulties, and headache scores were measured individually on a 0-10 scale, and summed to create a composite symptom score. Compared to individuals with CFS in the sham strain group, those with CFS in the true strain group reported significantly increased body pain (P = 0.04) and concentration difficulties (P = 0.02) as well as increased composite symptom scores (all P = 0.03) during the maneuver. After 24 hours, the symptom intensity differences were significantly greater for the CFS true strain group for the individual symptom of lightheadedness (P = 0.001) and for the composite symptom score (P = 0.005). During and 24 hours after the exposure to the true strain maneuver, those with CFS had significantly higher individual and composite symptom intensity changes compared to the healthy controls. We conclude that a longitudinal strain applied to the nerves and soft tissues of the lower limb is capable of increasing symptom intensity in individuals with CFS for up to 24 hours. These findings support our preliminary observations that increased mechanical sensitivity may be a contributor to the provocation of symptoms in this disorder.
PMID:27428358
PMCID:PMC4948885
DOI:10.1371/journal.pone.0159386

 
 
2016 May 31;49(1):27. doi: 10.1186/s40659-016-0087-2.
Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients.Nguyen T1,2, Staines D3,4, Nilius B5, Smith P3, Marshall-Gradisnik S3,4.
Author information

• 1The National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute, Griffith University, Parklands Drive, Southport, Mailbox 68, Gold Coast, 4222, Australia. thao.nguyen2@griffithuni.edu.au.
• 2School of Medical Science, Griffith University, Gold Coast, Australia. thao.nguyen2@griffithuni.edu.au.
• 3The National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute, Griffith University, Parklands Drive, Southport, Mailbox 68, Gold Coast, 4222, Australia.
• 4School of Medical Science, Griffith University, Gold Coast, Australia.
• 5Department of Molecular Cell Biology, Laboratory of Ion Channel Research, KU Leuven University, 49 Herestraat, Leuven, B-3000, Belgium.

AbstractBACKGROUND:
Transient receptor potential melastatin 3 (TRPM3) cation channels are ubiquitously expressed by multiple cells and have an important regulatory role in calcium-dependent cell signalling to help maintain cellular homeostasis. TRPM3 protein expression has yet to be determined on Natural Killer (NK) cells and B lymphocytes. Multiple single nucleotide polymorphisms have been reported in TRPM3 genes from isolated peripheral blood mononuclear cells, NK and B cells in Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) patients and have been proposed to correlate with illness presentation. The object of the study was to assess TRPM3 surface expression on NK and B lymphocytes from healthy controls, followed by a comparative investigation examining TRPM3 surface expression, and cytoplasmic and mitochondrial calcium influx in CD19(+) B cells, CD56(bright) and CD56(dim) cell populations from CFS/ME patients.
RESULTS:
TRPM3 cell surface expression was identified for NK and B lymphocytes in healthy controls (CD56(bright) TRPM3 35.72 % ± 7.37; CD56(dim) 5.74 % ± 2.00; B lymphocytes 2.05 % ± 0.19, respectively). There was a significant reduction of TRPM3 surface expression on CD19(+) B cells (1.56 ± 0.191) and CD56(bright) NK cells (17.37 % ± 5.34) in CFS/ME compared with healthy controls. Anti-CD21 and anti-IgM conjugated biotin was cross-linked with streptavidin,and subsequently treatment with thapsigargin. This showed a significant reduction in cytoplasmic calcium ion concentration in CD19(+) B lymphocytes. CD56(bright) NK cells also had a significant decrease in cytoplasmic calcium in the presence of 2-APB and thapsigargin in CFS/ME patients.
CONCLUSIONS:
The results from this preliminary investigation identify, for the first time, TRPM3 surface expression on both NK and B lymphocytes in healthy controls. We also report for the first time, significant reduction in TRPM3 cell surface expression in NK and B lymphocytes, as well as decreased intracellular calcium within specific conditions in CFS/ME patients. This warrants further examination of these pathways to elucidate whether TRPM3 and impaired calcium mobilisation has a role in CFS/ME.
KEYWORDS:
Calcium signalling; Chronic fatigue syndrome; Myalgic encephalomyelitis; Transient receptor potential
 
PMID:27245705 PMCID:PMC4888729 DOI:10.1186/s40659-016-0087-2

 
Gastrointestinal disease and microbial translocation in patients with systemic sclerosis: An observational study on the effect of nutritional intervention and implications for the role of the microbioma in the pathogenesis of the disease
Authors: Luchetti MM et al.
Summary: This study had the broad and ambitious aims of evaluating serum biomarkers for monitoring gastrointestinal (GI) disease in scleroderma with and without dietary intervention to determine whether altering the gut microbiome influenced autoimmune disease. Various biomarkers were measured in 25 healthy controls and in 38 scleroderma patients with GI involvement at baseline and after 6 months of changing to a diet low in meat and dairy products. At baseline, levels of soluble CD14 (sCD14, a marker of immune system activation), lipopolysaccharide (LPS, a marker of microbial translocation) and intestinal-type fatty acid-binding protein (I-FABP, a marker of enterocyte damage) were significantly higher in scleroderma patients than in healthy controls. There was a strong correlation between sCD14/ I-FABP and LPS/I-FABP in the serum of scleroderma patients. After 6 months of dietary intervention there was a reduction in all three biomarkers in the scleroderma patients and a marked improvement in GI symptoms, wellbeing and quality of life.
Comment: This study demonstrates that markers of microbial translocation and immune activation are elevated in scleroderma patients with GI involvement, and that dietary intervention was associated with improvements in biomarker levels as well as symptoms. It provides support for dietary intervention in scleroderma patients with GI symptoms and hints at a possible role of the gut microbiome in the immunopathogenesis of scleroderma.
Abstract OP0032. Ann Rheum Dis. 2016;75(Suppl2):65

 
J Clin Pathol 2016;69:777-783 doi:10.1136/jclinpath-2015-203447
Computer-based-limited and personalised education management maximise appropriateness of vitamin D, vitamin B12 and folate retesting
Michela Pelloso1, Daniela Basso1, Andrea Padoan2, Paola Fogar1, Mario Plebani1,2
1Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy
2Department of Medicine–DIMED, University of Padova, Padova, Italy
Correspondence to Dr Michela Pelloso, Department of Laboratory Medicine, University-Hospital of Padova, Via Giustiniani 2, Padova 35128, Italy; michela.pelloso@gmail.com
     Received 7 October 2015
     Revised 12 January 2016
     Accepted 13 January 2016
     Published Online First 2 February 2016
Abstract
Aim To identify the best management strategy for improving the appropriateness of vitamin D, vitamin B12 and folate retesting.
Methods The study was conducted between 3 November 2012 and 8 June 2015, with inpatients and outpatients being considered separately. After an observational reference period (3 November 2012 to 14 September 2013), an information technology (IT)-based permissive strategy (16 September 2013 to 27 July 2014) followed by a limiting strategy was used to manage the demand for inpatient retesting. For outpatients, an educational strategy period (28 July 2014 to 16 December 2014) with direct contact between medical personnel and general practitioners (GPs) was followed by a post-educational period without any restriction. Data from a total of 66 496 patients for vitamin D, 14 618 for vitamin B12 and 14 445 for folate were retrieved from the laboratory IT system. The main outcomes measures were inappropriate vitamin D, vitamin B12 and folate retesting. The minimal retesting intervals were 90 (vitamin D) or 180 days (vitamin B12 and folate).
Results In the absence of a laboratory demand strategy, the frequency of inappropriate retesting for vitamin D, vitamin B12 and folate was 60%, 94% and 93%, respectively, for inpatients, and 27%, 87% and 87%, respectively, for outpatients. A limiting IT-based demand management strategy reduced inappropriate retesting for vitamin D (36%), but not for vitamin B12 and folate. The educational strategy was followed by a reduction in inappropriate retesting among outpatients (16% for vitamin D, 72% for vitamin B12 and folate).
Conclusions Laboratory demand management based on an IT-limiting management strategy or on education of the referring physicians appears helpful in maximising appropriate retesting.

 
Immunologic Research pp 1-11
Severe somatoform and dysautonomic syndromes after HPV vaccination: case series and review of literature
Beniamino Palmieri,Dimitri Poddighe,Maria Vadalà,Carmen Laurino,Carla Carnovale,Emilio Clementi

1. 1.Department of General Surgery and Surgical SpecialtiesUniversity of Modena and Reggio Emilia Medical School, Surgical ClinicModenaItaly
2. 2.Department of PaediatricsASST Melegnano e MartesanaVizzolo PredabissiItaly
3. 3.Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, National Research Council-Institute of Neuroscience, University Hospital L. SaccoUniversity of MilanoMilanItaly

First Online:
09 August 2016
DOI: 10.1007/s12026-016-8820-z
Abstract
Human papilloma virus (HPV) is recognized as a major cause for cervical cancer among women worldwide. Two HPV vaccines are currently available: Gardasil® and Cervarix®. Both vaccines enclose viral antigenic proteins, but differ as to the biological systems of culture and the adjuvant components. Recently, a collection of symptoms, indicating nervous system dysfunction, has been described after HPV vaccination. We retrospectively described a case series including 18 girls (aged 12–24 years) referred to our “Second Opinion Medical Network” for the evaluation of “neuropathy with autonomic dysfunction” after HPV vaccination. All girls complained of long-lasting and invalidating somatoform symptoms (including asthenia, headache, cognitive dysfunctions, myalgia, sinus tachycardia and skin rashes) that have developed 1–5 days (n = 11), 5–15 days (n = 5) and 15–20 days (n = 2) after the vaccination. These cases can be included in the recently described immune dysfunction named autoimmune/inflammatory syndrome induced by adjuvants (ASIA). HPV vaccine, through its adjuvant component, is speculated to induce an abnormal activation of the immune system, involving glia cells in the nervous system too. Further researches should aim at defining the pathological and clinical aspects of these post-vaccination diseases and identifying a genetic background predisposing to these adverse reactions.
 
 

Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study
Van-Mai Cao-Lormeaux , PhD† et al,
Summary
Background
Between October, 2013, and April, 2014, French Polynesia experienced the largest Zika virus outbreak ever described at that time. During the same period, an increase in Guillain-Barré syndrome was reported, suggesting a possible association between Zika virus and Guillain-Barré syndrome. We aimed to assess the role of Zika virus and dengue virus infection in developing Guillain-Barré syndrome.
Methods
In this case-control study, cases were patients with Guillain-Barré syndrome diagnosed at the Centre Hospitalier de Polynésie Française (Papeete, Tahiti, French Polynesia) during the outbreak period. Controls were age-matched, sex-matched, and residence-matched patients who presented at the hospital with a non-febrile illness (control group 1; n=98) and age-matched patients with acute Zika virus disease and no neurological symptoms (control group 2; n=70). Virological investigations included RT-PCR for Zika virus, and both microsphere immunofluorescent and seroneutralisation assays for Zika virus and dengue virus. Anti-glycolipid reactivity was studied in patients with Guillain-Barré syndrome using both ELISA and combinatorial microarrays.
Findings
42 patients were diagnosed with Guillain-Barré syndrome during the study period. 41 (98%) patients with Guillain-Barré syndrome had anti-Zika virus IgM or IgG, and all (100%) had neutralising antibodies against Zika virus compared with 54 (56%) of 98 in control group 1 (p<0·0001). 39 (93%) patients with Guillain-Barré syndrome had Zika virus IgM and 37 (88%) had experienced a transient illness in a median of 6 days (IQR 4–10) before the onset of neurological symptoms, suggesting recent Zika virus infection. Patients with Guillain-Barré syndrome had electrophysiological findings compatible with acute motor axonal neuropathy (AMAN) type, and had rapid evolution of disease (median duration of the installation and plateau phases was 6 [IQR 4–9] and 4 days [3–10], respectively). 12 (29%) patients required respiratory assistance. No patients died. Anti-glycolipid antibody activity was found in 13 (31%) patients, and notably against GA1 in eight (19%) patients, by ELISA and 19 (46%) of 41 by glycoarray at admission. The typical AMAN-associated anti-ganglioside antibodies were rarely present. Past dengue virus history did not differ significantly between patients with Guillain-Barré syndrome and those in the two control groups (95%, 89%, and 83%, respectively).
Interpretation
This is the first study providing evidence for Zika virus infection causing Guillain-Barré syndrome. Because Zika virus is spreading rapidly across the Americas, at risk countries need to prepare for adequate intensive care beds capacity to manage patients with Guillain-Barré syndrome.

Sleep Medicine Reviews December 2016Volume 30, Pages 43–52
The effect of meditative movement on sleep quality: A systematic review
Fang Wang,x et al
Department of Psychology, Guang'an Men Hospital of China Academy of Chinese Medical Sciences, Beijing, China
,
DOI: http://dx.doi.org/10.1016/j.smrv.2015.12.001
SummaryThe purpose of this systematic review was to identify and assess evidence related to the efficacy of meditative movement (MM) on sleep quality. We conducted a comprehensive review of relevant studies drawn from English and Chinese databases. Only randomized controlled trials (RCTs) reporting outcomes of the effects of MM (tai chi, qi gong, and yoga) on sleep quality were taken into consideration. Twenty-seven RCTs fulfilled our inclusion criteria and formed the basis for this review. Due to clinical heterogeneity, no meta-analysis was performed. Seventeen studies received a Jadad score of ≥3 and were considered high-quality studies. Findings of the 17 studies showed that MM has beneficial effects for various populations on a range of sleep measures. Improvement in sleep quality was reported in the majority of studies and was often accompanied by improvements in quality of life, physical performance, and depression. However, studies to date generally have significant methodological limitations. Additional RCTs with rigorous research designs focusing on sleep quality or insomnia and testing specific hypotheses are needed to clearly establish the efficacy of MM in improving sleep quality and its potential use as an intervention for various populations.
Keywords:
Meditative movement, Sleep quality, Systematic review
 

 
Behavioral Sleep Medicine Volume 14, Issue 2, 2016The Use of Media as a Sleep Aid in AdultsDOI:10.1080/15402002.2014.963582
Liese Exelmansa* & Jan Van den Bulcka
pages 121-133
Abstract
A sample of 844 adults, aged 18–94 years old, was queried about media habits and sleep behavior in face-to-face interviews with standardized questionnaires. A substantial proportion of this sample reported using books (39.8%), television (31.2%), music (26.0%), Internet (23.2%), and videogames (10.3%) as a sleep aid. The use of media as sleep aids was associated with increased fatigue and higher scores on the Pittsburgh Sleep Quality Index (PSQI), indicating poorer sleep quality. There was no relationship with sleep duration. Finally, results suggest that media use coincides with later bedtimes, but also later rise times, a process called time shifting.
 

 
BMC Med. 2015 Feb 6;13:28. doi: 10.1186/s12916-014-0259-2Central pathways causing fatigue in neuro-inflammatory and autoimmune illnesses.Morris G, Berk M, Walder K, Maes M.
AbstractBACKGROUND:
The genesis of severe fatigue and disability in people following acute pathogen invasion involves the activation of Toll-like receptors followed by the upregulation of proinflammatory cytokines and the activation of microglia and astrocytes. Many patients suffering from neuroinflammatory and autoimmune diseases, such as multiple sclerosis, Parkinson's disease and systemic lupus erythematosus, also commonly suffer from severe disabling fatigue. Such patients also present with chronic peripheral immune activation and systemic inflammation in the guise of elevated proinflammtory cytokines, oxidative stress and activated Toll-like receptors. This is also true of many patients presenting with severe, apparently idiopathic, fatigue accompanied by profound levels of physical and cognitive disability often afforded the non-specific diagnosis of chronic fatigue syndrome.
DISCUSSION:
Multiple lines of evidence demonstrate a positive association between the degree of peripheral immune activation, inflammation and oxidative stress, gray matter atrophy, glucose hypometabolism and cerebral hypoperfusion in illness, such as multiple sclerosis, Parkinson's disease and chronic fatigue syndrome. Most, if not all, of these abnormalities can be explained by a reduction in the numbers and function of astrocytes secondary to peripheral immune activation and inflammation. This is also true of the widespread mitochondrial dysfunction seen in otherwise normal tissue in neuroinflammatory, neurodegenerative and autoimmune diseases and in many patients with disabling, apparently idiopathic, fatigue. Given the strong association between peripheral immune activation and neuroinflammation with the genesis of fatigue the latter group of patients should be examined using FLAIR magnetic resonance imaging (MRI) and tested for the presence of peripheral immune activation.
SUMMARY:
It is concluded that peripheral inflammation and immune activation, together with the subsequent activation of glial cells and mitochondrial damage, likely account for the severe levels of intractable fatigue and disability seen in many patients with neuroimmune and autoimmune diseases.This would also appear to be the case for many patients afforded a diagnosis of Chronic Fatigue Syndrome.
PMID:
25856766
[PubMed - indexed for MEDLINE]
PMCID:
PMC4320458

 Pain:
January 2016 - Volume 157 - Issue 1 - p 174–185
doi: 10.1097/j.pain.0000000000000348
Research Paper
Internet-delivered cognitive-behavioral treatment for adolescents with chronic pain and their parents: a randomized controlled multicenter trialPalermo, Tonya M.a,b,*; Law, Emily F.a,b; Fales, Jessicac; Bromberg, Maggie H.b; Jessen-Fiddick, Triciab; Tai, Gabrielleb

Abstract
Abstract: Internet-delivered interventions are emerging as a strategy to address barriers to care for individuals with chronic pain. This is the first large multicenter randomized controlled trial of Internet-delivered cognitive-behavioral therapy (CBT) for pediatric chronic pain. Participants included were 273 adolescents (205 females and 68 males), aged 11 to 17 years with mixed chronic pain conditions and their parents, who were randomly assigned in a parallel-group design to Internet-delivered CBT (n = 138) or Internet-delivered Education (n = 135). Assessments were completed before treatment, immediately after treatment, and at 6-month follow-up. All data collection and procedures took place online. The primary analysis used linear growth models. Results demonstrated significantly greater reduction on the primary outcome of activity limitations from baseline to 6-month follow-up for Internet CBT compared with Internet education (b = −1.13, P = 0.03). On secondary outcomes, significant beneficial effects of Internet CBT were found on sleep quality (b = 0.14, P = 0.04), on reducing parent miscarried helping (b = −2.66, P = 0.007) and protective behaviors (b = −0.19, P = 0.001), and on treatment satisfaction (P values < 0.05). On exploratory outcomes, benefits of Internet CBT were found for parent-perceived impact (ie, reductions in depression, anxiety, self-blame about their adolescent's pain, and improvement in parent behavioral responses to pain). In conclusion, our Internet-delivered CBT intervention produced a number of beneficial effects on adolescent and parent outcomes, and could ultimately lead to wide dissemination of evidence-based psychological pain treatment for youth and their families.
© 2016 International Association for the Study of Pain

 
Cumulative Use of Strong Anticholinergics
and Incident Dementia
A Prospective Cohort Study
Shelly L. Gray, PharmD, MS; Melissa L. Anderson, MS; Sascha Dublin, MD, PhD; Joseph T. Hanlon, PharmD, MS;
Rebecca Hubbard, PhD; RodWalker, MS; Onchee Yu, MS; Paul K. Crane,MD, MPH; Eric B. Larson, MD, MPH
IMPORTANCE Many medications have anticholinergic effects. In general, anticholinergicinduced
cognitive impairment is considered reversible on discontinuation of anticholinergic
therapy. However, a few studies suggest that anticholinergicsmay be associated with an
increased risk for dementia.
OBJECTIVE To examine whether cumulative anticholinergic use is associated with a higher
risk for incident dementia.
DESIGN, SETTING, AND PARTICIPANTS Prospective population-based cohort study using data
from the Adult Changes in Thought study in Group Health, an integrated health care delivery
system in Seattle,Washington.We included 3434 participants 65 years or older with no
dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from
2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All
participants were followed up every 2 years. Data through September 30, 2012, were
included in these analyses.
EXPOSURES Computerized pharmacy dispensing data were used to ascertain cumulative
anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs)
dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use
related to prodromal symptoms. Cumulative exposure was updated as participants were
followed up over time.
MAIN OUTCOMES AND MEASURES Incident dementia and Alzheimer disease using standard
diagnostic criteria. Statistical analysis used Cox proportional hazards regression models
adjusted for demographic characteristics, health behaviors, and health status, including
comorbidities.
RESULTS The most common anticholinergic classes used were tricyclic antidepressants,
first-generation antihistamines, and bladder antimuscarinics. During a mean follow-up of 7.3
years, 797 participants (23.2%) developed dementia (637 of these [79.9%] developed
Alzheimer disease). A 10-year cumulative dose-response relationship was observed for
dementia and Alzheimer disease (test for trend, P < .001). For dementia, adjusted hazard
ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95%CI, 0.74-1.16)
for TSDDs of 1 to 90; 1.19 (95%CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95%CI, 0.94-1.62)
for TSDDs of 366 to 1095; and 1.54 (95%CI, 1.21-1.96) for TSDDs greater than 1095. A similar
pattern of results was noted for Alzheimer disease. Results were robust in secondary,
sensitivity, and post hoc analyses.
CONCLUSIONS AND RELEVANCE Higher cumulative anticholinergic use is associated with an
increased risk for dementia. Efforts to increase awareness among health care professionals
and older adults about this potential medication-related risk are important to minimize
anticholinergic use over time.
JAMA Intern Med. doi:10.1001/jamainternmed.2014.7663
Published online January 26, 2015.
Invited Commentary
Supplemental content at
jamainternalmedicine.com
Author Affiliations: School of Pharmacy, University ofWashington, Seattle (Gray); Group Health Research Institute, Seattle,Washington (Anderson, Dublin,
Hubbard,Walker, Yu, Larson); Department of Epidemiology, University ofWashington, Seattle (Dublin); Division of Geriatric Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (Hanlon); Department of Biostatistics, University ofWashington, Seattle (Hubbard); currently with the Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania,Philadelphia (Hubbard); Division of General Internal Medicine, University ofWashington, Seattle (Crane,Larson).
 
Corresponding Author: Shelly L.
Gray, PharmD,MS, School of Pharmacy, University ofWashington, PO Box 357630, Seattle,WA 98195
(slgray@uw.edu).

 
ENDO 2016: The Endocrine Society Annual Meeting
Endocrine Society Advises Against Compounded Hormone Use
Miriam E Tucker  | April 01, 2016
BOSTON — The Endocrine Society has issued a new scientific statement advising clinicians to avoid using custom-compounded hormones to treat menopausal symptoms, female sexual dysfunction, and thyroid disorders.
"Custom-compounded hormones should be reserved for situations in which a patient is allergic to or does not tolerate any of the FDA-approved therapies and treatment is necessary for his or her health," lead author Nanette Santoro, MD, professor and chair of obstetrics and gynecology at the University of Colorado School of Medicine in Aurora, said during a press briefing here at ENDO 2016, the annual meeting of the Endocrine Society. The statement was published online April 1, 2016 in the Journal of Clinical Endocrinology and Metabolism.
The statement is the latest in a series from medical societies, including the American College of Obstetricians and Gynecologists and the North American Menopause Society, cautioning against the use of custom-compounded, so-called "bioidentical" hormones. Nonetheless, many physicians are still prescribing them.
Indeed, Dr Santoro cited survey data that up to a quarter or a third of all menopause therapy prescriptions are for custom-compounded products, garnering about $1 billion in annual sales. "This to us seems somewhat absurd when we have a large variety of what are technically the same bioidentical hormones that are FDA approved….It's kind of unfortunate that we live in an era where this has become so widespread it's a very big business."
Custom-compounded products are potentially dangerous, she said, because added excipients can affect absorption, and those or other added ingredients could be contaminated or adulterated. Moreover, she noted, FDA-approved hormone products have well-characterized pharmacokinetics and efficacy and safety profiles. In contrast, "There's no such thing in the world of custom-compounded bioidentical hormones."
Endocrinologist Mark Sklar, MD, told Medscape Medical News that he agrees with the Endocrine Society's new statement and stance. "I think that there's no real reason to compound, especially gonadal hormones like estrogen or testosterone, because there are very good commercially available hormones now. They're well-made and well-tested, and there's consistency. With compounding there's not consistency in dosage."
Dr Sklar, who is an assistant professor of medicine and endocrinology at Georgetown University Medical Center and George Washington University Medical Center, Washington, DC, added, "People who advocate compounding tell patients that the compounded medications don't have the same side effects. The article states, as I previously believed, that there are probably side effects; they're just not tested with the compounded agents like they are with the commercially available hormones. So I do agree with the statement and would not promote compounding in my practice."
"Numerous FDA-Approved Formulations"
Aimed at primary-care clinicians as well as endocrinologists, the Endocrine Society's new document provides detailed reviews of the biology and pharmacology of sex steroids and thyroid-hormone action, including available clinical-trial data for the FDA-approved products
Key points

•          There are numerous FDA-approved formulations, both oral and nonoral, that have been recommended for menopausal hormone therapy, and therefore there is no rationale for use of nonapproved products. Nonoral estradiol may be associated with a reduced risk for venous thromboembolism and stroke.
•          Micronized progesterone (MP), which has a superior metabolic profile and possibly lower risk of breast cancer, is preferred by some experts as first-line progestin therapy for women taking menopausal hormone therapy. Although biochemically it is apparently beneficial, evidence demonstrating a benefit of MP on clinical outcomes is lacking.
•          There is no rationale for using compounded progesterone preparations of unknown pharmacokinetics, because there are many on-label pharmaceutical-grade preparations available and a real risk of harm associated with inadequate progesterone dosing.
•          There are no randomized, double-blind, placebo-controlled trials demonstrating efficacy of compounded bioidentical hormone therapy in alleviating menopausal symptoms or other clinical conditions.
•          Moreover, there are no comparative-effectiveness studies of equivalent doses of compounded bioidentical hormones compared with FDA-approved hormone treatments.
•          Transdermal patches, gels, and intramuscular preparations of bioidentical testosterone are available and FDA approved for use in men with hypogonadism.
•          There are currently no FDA-approved testosterone preparations for women.
•          Custom-compounded testosterone for women can result in overdosing and cause harm.
•          There are currently no FDA-approved preparations of dehydroepiandrosterone (DHEA), and there are no indications for its use except perhaps for some women with a low libido associated with adrenal insufficiency.
•          Non–FDA-approved preparations of DHEA have all the caveats related to dosing, pharmacokinetics, and safety associated with estradiol, progesterone, and testosterone.
•          The use of custom-compounded bioidentical DHEA is unlikely to be beneficial and is potentially harmful to patients.
•          Vaginal DHEA is currently undergoing testing as an alternative to vaginal estrogen for the treatment of menopausal vaginal atrophy, but there is no vaginal DHEA preparation that is FDA approved for clinical use at this time.
•          Levothyroxine (LT4) is bioidentical and a highly effective and safe therapy and is the treatment of choice for hypothyroidism. The complex tissue-specific deiodinase system converts T4 to T3 and supplies the proper amount of T3 to each of the body's tissues according to its requirements.
•          Clinicians should evaluate patients with persistent symptoms (despite adequate LT4 therapy) for other causes of their symptoms and encourage patients to engage in healthy lifestyle measures.
•          Some of these patients may benefit from combination LT4/LT3 therapy, desiccated thyroid hormone, or compounded thyroid hormone, as long as symptoms and thyroid-stimulating hormone (TSH) (free T4) are monitored carefully.

Asked whether there was any type of patient for whom he might use a compounded hormone formulation, Dr Sklar replied, "Not with estrogen or testosterone. I don't see any reason for that." He had previously tried it with thyroid hormone, "but the levels were very variable and not reliable at all.
"The only indication I might try compounding is women who need testosterone, since there is no good commercially available testosterone. Sometimes you have to resort to compounding to get that….Some women complain of low libido. Low-dose testosterone sometimes works for that. But I don't use it that often."
In a written statement, Dagmar Anderson, vice president of communications for the International Academy of Compounding Pharmacists (IACP), told Medscape Medical News, "IACP believes the patient has the choice to opt for a compounded medication, and that decision should be made with his/her physician."
J Clin Endocrinol Metab. Published online April 1, 2016. Abstract

Med Sci Sports Exerc .2016 Apr 26. [Epub ahead of print]
Graded vs Intermittent Exercise Effects on Lymphocytes in Chronic Fatigue  Syndrome.Broadbent S1, Coutts R.
1School of Health and Human Sciences, Southern Cross University, Lismore NSW, Australia.
AbstractPURPOSE:
There is increasing evidence of immune system dysfunction in Chronic Fatigue Syndrome (CFS) but little is known of the regular exercise effects on immune cell parameters. This pilot study investigated the effects of graded and intermittent exercise on CD4 lymphocyte subset counts and activation compared to usual care.
METHODS:
24 CFS patients (50.2 ± 10 yr) were randomised to Graded exercise (GE), Intermittent exercise (IE) or usual care (UC) groups; 18 sedentary non-CFS participants (50.6 ± 10 yr) were controls (CTL) for blood and immunological comparisons. Outcome measures were pre- and post-intervention flow cytometric analyses of circulating lymphocyte subset cell counts, expression of CD3, CD4, CD25 and CD134, full blood counts and V[Combining Dot Above]O2peak RESULTS: Pre-intervention, CD3 cell counts and expression of CD4, CD25, CD134 and CD4CD25CD134 were significantly lower in GE, IE and UC compared to CTL (f < 0.05). Total lymphocyte concentration was significantly lower in GE and IE groups compared to CTL. There were significant post-intervention increases in (i) expression of CD4 and CD4CD25CD134 for GE and IE, but CD25 and CD134 for IE only; (ii) circulating counts of CD3 and CD4 for GE, and CD3, CD4, CD8, CD3CD4CD8, CD3CD16CD56, CD19 and CD45 for IE; (iii) neutrophil concentration for GE; (iv) V[Combining Dot Above]O2peak and elapsed test time for IE and GE, V[Combining Dot Above]Epeak for IE.
CONCLUSIONS:
Twelve weeks of GE and IE training significantly improved CD4 lymphocyte activation and aerobic capacity without exacerbating CFS symptoms. IE may be a more effective exercise modality with regard to enhanced CD4 activation in CFS patients.
PMID:
27116645
[PubMed - as supplied by publisher]

 
http://www.ncbi.nlm.nih.gov/pubmed/27020075
J Psychosom Res. 2016 Apr;83:40-5. doi:
10.1016/j.jpsychores.2016.02.004. 
Treatment expectations influence the outcome of multidisciplinary rehabilitation treatment in patients with CFS.
Vos-Vromans DC, Huijnen IP, Rijnders LJ, Winkens B, Knottnerus JA, Smeets RJ.
Abstract
OBJECTIVE: To improve the effectiveness of treatment in patients with chronic fatigue syndrome it is worthwhile studying factors influencing outcomes. The aims of this study were (1) to assess the association of expectancy and credibility on treatment outcomes, and (2) to identify baseline variables associated with treatment expectancy and credibility.
METHODS: 122 patients were included in a randomized controlled trial of whom 60 received cognitive behavioural therapy (CBT) and 62 multidisciplinary rehabilitation treatment (MRT). Expectancy and credibility were measured with the credibility and expectancy questionnaire. Outcomes of treatment, fatigue, and quality of life (QoL), were measured at baseline and post-treatment. Multiple linear regressions were performed to analyse associations.
RESULTS: In explaining fatigue and the physical component of the QoL, the effect of expectancy was significant for MRT, whereas in CBT no such associations were found. The main effect of expectancy on the mental component of QoL was not significant. For credibility, the overall effect on fatigue and the physical component of QoL was not significant. In explaining the mental component of QoL, the interaction between treatment and credibility was significant.
However, the effects within each group were not significant. In the regression model with expectancy as dependent variable, only treatment centre appeared significantly associated. In explaining credibility, treatment centre, treatment allocation and depression contributed significantly.
CONCLUSIONS: For clinical practice it seems important to check the expectations of the patient, since expectations influence the outcome after MRT.
Copyright © 2016. Published by Elsevier Inc.

 
http://translational-medicine.biomedcentral.com/articles/10.1186/s1...
Altered neuroendocrine control and association to clinical symptoms in adolescent chronic fatigue syndrome: a cross-sectional study
Vegard Bruun Wyller, Valieria Vitelli, Dag Sulheim, Even Fagermoen, Anette Winger, Kristin Godang and Jens Bollerslev Journal of Translational Medicine201614:121
Abstract
Background: Chronic fatigue syndrome (CFS) is a common and disabling disorder, and a major threat against adolescent health. The pathophysiology is unknown, but alteration of neuroendocrine control systems might be a central element, resulting in attenuation of the hypothalamus–pituitary–adrenalin (HPA) axis and enhancement of the sympathetic/adrenal medulla (SAM) system.
This study explored differences in neuroendocrine control mechanisms between adolescent CFS patients and healthy controls, and whether characteristics of the control mechanisms are associated with important clinical variables within the CFS group.
Methods: CFS patients 12–18 years of age were recruited nation-wide to a single referral center as part of the NorCAPITAL project. A broad case definition of CFS was applied. A comparable group of healthy controls were recruited from local schools. A total of nine hormones were assayed and subjected to network analyses using the ARACNE algorithm. Symptoms were charted by a questionnaire, and daily physical activity was recorded by an accelerometer.
Results: A total of 120 CFS patients and 68 healthy controls were included. CFS patients had significantly higher levels of plasma norepinephrine, plasma epinephrine and plasma FT4, and significantly lower levels of urine cortisol/creatinine ratio. Subgrouping according to other case definitions as well as adjusting for confounding factors did not alter the results. Multivariate linear regression models as well as network analyses revealed different interrelations between hormones of the HPA axis, the SAM system, and the thyroid system in CFS patients and healthy controls. Also, single hormone degree centrality was associated with clinical markers within the CFS group.
Conclusion: This study reveals different interrelation between hormones of the HPA axis, the SAM system, and the thyroid system in CFS patients and healthy controls, and an association between hormone control characteristics and important clinical variables in the CFS group. These results add to the growing insight of CFS disease mechanisms.
Trial registration Clinical Trials NCT01040429

 
http://www.ncbi.nlm.nih.gov/pubmed/24433278
Suicidal ideation in patients with fibromyalgia: a cross-sectional study.
Calandre EP1, Navajas-Rojas MA, Ballesteros J, Garcia-Carrillo J, Garcia-Leiva JM, Rico-Villademoros F.
Abstract
Chronic pain, sleep disturbances, and depression, which are relevant symptoms of fibromyalgia syndrome, have been demonstrated to be associated with an increased likelihood of suicidal behaviors.
Mortality from suicide has been shown to be greater among patients with fibromyalgia. This study aimed to assess the prevalence of suicidal ideation among a sample of patients with fibromyalgia and to evaluate its relationship with the clinical symptomatology of fibromyalgia.
Baseline data from fibromyalgia patients willing to participate in different clinical studies were collected. Outcome measures included the Fibromyalgia Impact Questionnaire, the Beck Depression Inventory, the Pittsburgh Sleep Quality Index, the Brief Pain Inventory, and the SF-12 Health Survey.
The scores for these scales were compared between patients with and without suicidal ideation. The presence of suicidal ideation was assessed using the answer provided to item 9 of the Beck Depression Inventory.
The results were adjusted by age, sex, total comorbidity, and time since diagnosis with multiple linear regression. The sample comprised 373 patients of whom one hundred and seventy-nine (48%) reported suicidal
ideation: 148 (39.7%) reported passive suicidal ideation and 31 (8.3%) active suicidal ideation.
Suicidal ideation was markedly associated with depression, anxiety, sleep quality, and global mental health, whereas only weak relationships were observed between suicidal ideation and both pain and general physical health.

 
http://www.ncbi.nlm.nih.gov/pubmed/27125909
Ubiquinol-10 supplementation improves autonomic nervous function and cognitive function in chronic fatigue syndrome.
Fukuda S, Nojima J, Kajimoto O, Yamaguti K, Nakatomi Y, Kuratsune H, Watanabe Y.
Abstract
The aim of this study was to evaluate the benefit of oral ubiquinol-10 supplementation in CFS patients using an open-label study and a randomized, double-blinded, placebo-controlled (RCT) study.
Twenty patients with CFS were randomly enrolled in an 8-week open-label oral ubiquinol-10 (150 mg ubiquinol-10/day) study. The patients and the attending physicians were not blinded to the supplementation.
Forty-three patients with CFS were randomly assigned to receive either ubiquinol-10 (150 mg/day) or placebo every day for 12 weeks. The patients and the attending physicians were blinded to the supplementation, and a total of 31 patients (N = 17 in the ubiquinol group and 14 in the placebo group) completed the study.
The beneficial effects of ubiquinol-10 were observed in the open-label study we conducted prior to the RCT. The RCT results suggest that supplementation with ubiquinol-10 for 12 weeks is effective for improving several CFS symptoms.
© 2016 International Union of Biochemistry and Molecular Biology.

 
http://www.ncbi.nlm.nih.gov/pubmed/27118360
Q fever: a contemporary case series from a Belgian hospital.
Vanderbeke L, Peetermans WE, Saegeman V, De Munter P.
Abstract
OBJECTIVES: Q fever is a global zoonosis that can cause both acute and chronic infections in humans through aerogenic transmission. Although Q fever was discovered already 80 years ago, this infectious disease remains largely unknown. We studied a case series in a Belgian tertiary care hospital.
METHODS: A laboratory and file query at our department was performed to detect patients who were newly diagnosed with Q fever from 01 January 2005 to 01 October 2014.
RESULTS: In total, 10 acute Q fever and 5 chronic Q fever infections were identified. An aspecific flu-like illness was the prevailing manifestation of acute Q fever, while this was infective endocarditis in chronic Q fever cases. Noteworthy are the high percentage of myocarditis cases in the acute setting and one case of amyloidosis as a manifestation of chronic Q fever. No evolution from acute to chronic Q fever was noted; overall outcome for both acute and chronic Q fever was favourable with a 94% survival rate.
DISCUSSION: Q fever is an infectious disease characterised by a variable clinical presentation. Detection requires correct assessment of the clinical picture in combination with a laboratory confirmation.
Treatment and follow-up are intended to avoid a negative outcome.

 
http://www.ncbi.nlm.nih.gov/pubmed/27123773
Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study.
Shan ZY, Kwiatek R, Burnet R, Del Fante P, Staines DR, Marshall-Gradisnik SM, Barnden LR.
Abstract
PURPOSE: To examine progressive brain changes associated with chronic fatigue syndrome (CFS).
MATERIALS AND METHODS: We investigated progressive brain changes with longitudinal MRI in 15 CFS and 10 normal controls (NCs) scanned twice
6 years apart on the same 1.5 Tesla (T) scanner. MR images yielded gray matter (GM) volumes, white matter (WM) volumes, and T1- and T2-weighted signal intensities (T1w and T2w). Each participant was characterized with Bell disability scores, and somatic and neurological symptom scores. We tested for differences in longitudinal changes between CFS and NC groups, inter group differences between pooled CFS and pooled NC populations, and correlations between MRI and symptom scores using voxel based morphometry. The analysis methodologies were first optimized using simulated atrophy.
RESULTS: We found a significant decrease in WM volumes in the left inferior fronto-occipital fasciculus (IFOF) in CFS while in NCs it was unchanged (family wise error adjusted cluster level P value, PFWE < 0.05). This longitudinal finding was consolidated by the group comparisons which detected significantly decreased regional WM volumes in adjacent regions (PFWE < 0.05) and decreased GM and blood volumes in contralateral regions (PFWE < 0.05). Moreover, the regional GM and WM volumes and T2w in those areas showed significant correlations with CFS symptom scores (PFWE < 0.05).
CONCLUSION: The results suggested that CFS is associated with IFOF WM deficits which continue to deteriorate at an abnormal rate. J. Magn.
Reson. Imaging 2016.
© 2016 The Authors Journal of Magnetic Resonance Imaging published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.

 
http://fibromyalgianewstoday.com/2016/04/04/leptin-tied-to-bodily-p...9
Leptin Tied to Bodily Pain, Predicts Fibromyalgia Pain Levels, Researchers Say
Magdalena Kegel
Leptin – a factor well-known for its role in controlling appetite – might be a driver of bodily pain, according to a new report.
Investigating levels of the molecule in both women with fibromyalgia and healthy women has provided scientists with clues of the underlying processes of pain signaling and might lead to better future pain treatments.
Last week, Fibromyalgia News Today reported on the scientific progress of a research team from the University of Alabama at Birmingham, investigating brain-immune interactions in fibromyalgia patients. The study described the team’s efforts to understand leptin’s role in pain signaling.
Earlier research has shown that the appetite-controlling molecule is also regulated by sleep and infection, and has been linked to inflammatory diseases such as rheumatoid arthritis, lupus, and multiple sclerosis.
The report, titled “Association of Leptin with Body Pain in Women,“ is actually composed of two studies. The first small pilot study followed three women over 25 days who were affected by fibromyalgia, analyzing both leptin and pain on a daily basis.
The findings, published in the Journal of Women’s Health, show that leptin levels fluctuated along with reported pain, with higher levels on days when women experienced more pain.
The second study explored previously collected data from the Women’s Health Initiative (WHI) Observational Study. The study, performed between 1993 and 1998, offered the research team blood samples and data on bodily pain, as well as participants’ BMI levels. The group consisted of 5,676 postmenopausal women, representative of the general population.
Analyzing this large group of women, the researchers found that both leptin and BMI were associated with bodily pain, independent of each other.
The evidence of a link between leptin and pain in the second study was rather weak. This could have been a consequence of blood samples and pain ratings not taken on the same occasion, since the first study indicated that leptin levels could fluctuate several times over consecutive days, making the prospect of finding a link small. Most women in the large sample also were not likely to suffer from a pain condition.
However, the researchers believe a potential link between leptin and pain might be more evident in pain conditions, as was the case in the three fibromyalgia women. They also caution that, given the daily fluctuations, levels need to be measured on consecutive occasions to provide a more clear picture of the factor’s role in pain signaling.
While none of the studies presents evidence that leptin causes pain, the results point researchers in a direction worth exploring for pain conditions such as fibromyalgia.

 
http://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-016-059...
Tracking post-infectious fatigue in clinic using routine Lab tests
Jeanna M. Harvey, Gordon Broderick Alanna Bowie, Zachary M. Barnes, Ben Z. Katz, Maurice R. G. O’Gorman, Suzanne D. Vernon, Mary Ann Fletcher, Nancy G. Klimas and, Renee Taylor
Abstract
Background: While biomarkers for chronic fatigue syndrome (CFS) are beginning to emerge they typically require a highly specialized clinical laboratory. We hypothesized that subsets of commonly measured laboratory markers used in combination could support the diagnosis of post-infectious CFS (PI-CFS) in adolescents following infectious mononucleosis (IM) and help determine who might develop persistence of symptoms.
Methods: Routine clinical laboratory markers were collected prospectively in 301 mono-spot positive adolescents, 4 % of whom developed CFS (n  = 13). At 6, 12, and 24 months post-diagnosis with IM, 59 standard tests were performed including metabolic profiling, liver enzyme panel, hormone profiles, complete blood count (CBC), differential white blood count (WBC), salivary cortisol, and urinalysis. Classification models separating PI-CFS from controls were constructed at each time point using stepwise subset selection.
Results: Lower ACTH levels at 6 months post-IM diagnosis were highly predictive of CFS (AUC p  = 0.02). ACTH levels in CFS overlapped with healthy controls at 12 months, but again showed a trend towards a deficiency at 24 months.
Conversely, estradiol levels depart significantly from normal at 12 months only to recover at 24 months (AUC p = 0.02). Finally, relative neutrophil count showed a significant departure from normal at 24 months in CFS (AUC p = 0.01). Expression of these markers evolved differently over time between groups.
Conclusions: Preliminary results suggest that serial assessment of stress and sex hormones as well as the relative proportion of innate immune cells measured using standard clinical laboratory tests may support the diagnosis of PI-CFS in adolescents with IM.

 
http://www.ncbi.nlm.nih.gov/pubmed/27110826
Diagnostics (Basel). 2016 Apr 22;6(2). pii: E16.
The Relationship between Age and Illness Duration in Chronic Fatigue Syndrome.
Kidd E, Brown A, McManimen S, Jason LA, Newton JL, Strand EB.
Abstract
Chronic fatigue syndrome (CFS) is a debilitating illness, but it is unclear if patient age and illness duration might affect symptoms and functioning of patients. In the current study, participants were categorized into four groups based upon age (under or over age 55) and illness duration (more or less than 10 years). The groups were compared on functioning and symptoms.
Findings indicated that those who were older with a longer illness duration had significantly higher levels of mental health functioning than those who were younger with a shorter or longer illness duration and the older group with a shorter illness duration.
The results suggest that older patients with an illness duration of over 10 years have significantly higher levels of mental health functioning than the three other groups.
For symptoms, the younger/longer illness duration group had significantly worse immune and autonomic domains than the older/longer illness group.
In addition, the younger patients with a longer illness duration displayed greater autonomic and immune symptoms in comparison to the older group with a longer illness duration.
These findings suggest that both age and illness duration need to be considered when trying to understand the influence of these factors on patients.

 
http://www.ncbi.nlm.nih.gov/pubmed/27105483
Fibromyalgia syndrome pathology and environmental influences on afflictions with medically unexplained symptoms.
Albrecht PJ, Rice FL.
Abstract
Fibromyalgia syndrome (FMS) is a clinical disorder predominant in females with unknown etiology and medically unexplained symptoms (MUS), similar to other afflictions, including irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS), post-traumatic stress disorder (PTSD), Gulf War illness (GFI), and others.
External environmental stimuli drive behavior and impact physiologic homeostasis (internal environment) via autonomic functioning. These environments directly impact the individual affective state (mind), which feeds back to regulate physiology (body).
FMS has emerged as a complex disorder with pathologies identified among neurotransmitter and enzyme levels, immune/cytokine functionality, cortical volumes, cutaneous innervation, as well as an increased frequency among people with a history of traumatic and/or emotionally negative events, and specific personality trait profiles. Yet, quantitative physical evidence of pathology or disease etiology among FMS has been limited (as with other afflictions with MUS).
Previously, our group published findings of increased peptidergic sensory innervation associated with the arterio-venous shunts (AVS) in the glabrous hand skin of FMS patients, which provides a plausible mechanism for the wide-spread FMS symptomology.
This review focuses on FMS as a model affliction with MUS to discuss the implications of the recently discovered peripheral innervation alterations, explore the role of peripheral innervation to central sensitization syndromes (CSS), and examine possible estrogen-related mechanisms through which external and internal environmental factors may contribute to FMS etiology and possibly other afflictions with MUS.
PMID:27105483 [PubMed - as supplied by publisher]

 
http://www.ncbi.nlm.nih.gov/pubmed/27098385
J Health Psychol. 2016. pii: 1359105316643376. [Epub ahead of print]
The psychological impact of dependency in adults with chronic fatigue syndrome/myalgic encephalomyelitis: A qualitative exploration.
Williams AM, Christopher G, Jenkinson E.
Abstract
Chronic fatigue syndrome/myalgic encephalomyelitis can limit functional capacity, producing various degrees of disability and psychological distress.
Semi-structured interviews explored the experiences of adults with chronic fatigue syndrome/myalgic encephalomyelitis being physically dependent on other people for help in daily life, and whether physical dependency affects their psychological well-being.
Thematic analysis generated six themes: loss of independence and self-identity, an invisible illness, anxieties of today and the future, catch-22, internalised anger, and acceptance of the condition.
The findings provide insight into the psychological impact of dependency. Implications for intervention include better education relating to chronic fatigue syndrome/myalgic encephalomyelitis for family members, carers, and friends; ways to communicate their needs to others who may not understand chronic fatigue syndrome/myalgic encephalomyelitis; and awareness that acceptance of the condition could improve psychological well-being.

 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508058/
PLoS One. 2015 Jul 20;10(7):e0132774. doi:
10.1371/journal.pone.0132774. eCollection 2015.
Achieving Remission in Gulf War Illness: A Simulation-Based Approach to Treatment Design.
Craddock TJ, Del Rosario RR, Rice M, Zysman JP, Fletcher MA, Klimas NG, Broderick G.
Abstract
Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting up to one-third of the 700,000 returning veterans of the 1991 Persian Gulf War and for which there is no known cure. GWI symptoms span several of the body's principal regulatory systems and include debilitating fatigue, severe musculoskeletal pain, cognitive and neurological problems.
Using computational models, our group reported previously that GWI might be perpetuated at least in part by natural homeostatic regulation of the neuroendocrine-immune network. In this work, we attempt to harness these regulatory dynamics to identify treatment courses that might produce lasting remission.
Towards this we apply a combinatorial optimization scheme to the Monte Carlo simulation of a discrete ternary logic model that represents combined hypothalamic-pituitary-adrenal (HPA), gonadal (HPG), and immune system regulation in males.
In this work we found that no single intervention target allowed a robust return to normal homeostatic control. All combined interventions leading to a predicted remission involved an initial inhibition of Th1 inflammatory cytokines (Th1Cyt) followed by a subsequent inhibition of glucocorticoid receptor function (GR).
These first two intervention events alone ended in stable and lasting return to the normal regulatory control in 40% of the simulated cases.
Applying a second cycle of this combined treatment improved this predicted remission rate to 2 out of 3 simulated subjects (63%).
These results suggest that in a complex illness such as GWI, a multi-tiered intervention strategy that formally accounts for regulatory dynamics may be required to reset neuroendocrine-immune homeostasis and support extended remission.

 
http://translational-medicine.biomedcentral.com/articles/10.1186/s1...
ERK1/2, MEK1/2 and p38 downstream signalling molecules impaired in CD56dimCD16+ and D56brightCD16dim/− natural killer cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients
Teilah Kathryn Huth, Donald Staines, and Sonya Marshall-Gradisnik
Abstract
Background: Natural Killer (NK) cell effector functions are dependent on phosphorylation of the mitogen-activated protein kinases (MAPK) pathway to produce an effective immune response for the clearance of target cells infected with viruses, bacteria or malignantly transformed cells. Intracellular signals activating NK cell cytokine production and cytotoxic activity are propagated through protein phosphorylation of MAPKs including MEK1/2, ERK1/2, p38 and JNK.
Reduced NK cell cytotoxic activity is consistently reported in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) patients and intracellular signalling by MAPK in NK cells remains to be investigated. Therefore, the purpose of this paper was to investigate MAPK downstream signalling molecules in NK cell phenotypes from CFS/ME patients.
Methods: Flow cytometric protocols were used to measure phosphorylation of the MAPK pathway in CD56brightCD16dim/− and
CD56dimCD16+ NK cells following stimulation with K562 tumour cells or
phorbol-12-myristate-13-acetate plus ionomycin. NK cell cytotoxic activity, degranulation, lytic proteins and cytokine production were also measured as markers for CD56brightCD16dim/− and CD56dimCD16+ NK cell function using flow cytometric protocols.
Results: CFS/ME patients (n = 14) had a significant decrease in ERK1/2 in CD56dimCD16+ NK cells compared to the non-fatigued controls (n =
11) after incubation with K562 cells. CD56brightCD16dim/− NK cells from CFS/ME patients had a significant increase in MEK1/2 and p38 following incubation with K562 cells.
Conclusions: This is the first study to report significant differences in MAPK intracellular signalling molecules in CD56dimCD16+ and CD56brightCD16dim/− NK cells from CFS/ME patients. The current results highlight the importance of intracellular signalling through the MAPK pathway for synergistic effector function of CD56dimCD16+ and CD56brightCD16dim/− NK cells to ensure efficient clearance of target cells. In CFS/ME patients, dysfunctional MAPK signalling may contribute to reduced NK cell cytotoxic activity.

 
http://www.tandfonline.com/doi/abs/10.1080/21641846.2016.1167470?jo...
A comparative polysomnography analysis of sleep in healthy controls and patients with chronic fatigue syndrome
Zoe M. Gotts, Vincent Deary, Julia L. Newton & Jason G. Ellis
ABSTRACT
Background: Sleep disturbance affects almost 95% of people with chronic fatigue syndrome (CFS). However, existing studies of sleep in CFS have shown mixed results and methodological issues prevent between-study comparisons.
Purpose: To redress this, the present study aimed to investigate whether there are differences in the sleep of patients with CFS and healthy controls, using a comparative analysis of polysomnography over three consecutive nights.
Methods: Twenty-two patients with CFS (1994 Centers for Disease Control and Prevention
criteria) and 22 healthy controls underwent three nights of polysomnographic sleep assessment. Groups were compared on their objective sleep variables derived from the third night of assessment, to allow for participant adaptation to the sleep study.
Results: 9.1% of patients met criteria for an objectively verifiable sleep disorder.
Differences in sleep were observed between CFS patients and healthy controls on four objectively derived sleep variables (wake after sleep onset, sleep efficiency, percentage wake and REM Latency). In addition, people with CFS reported more severe symptoms of insomnia than healthy controls.
Conclusions: The study reports on key differences in sleep between people with CFS and healthy individuals.
The potential presence of a sleep disorder in this patient population is high, it is therefore important that during early evaluation, a detailed history of sleep is taken to rule out a sleep disorder in CFS. In addition, patients with CFS show poorer sleep as defined by objectively derived measures and also self-report poorer quality sleep. Improving sleep is a potential treatment target in CFS.

 
http://www.ncbi.nlm.nih.gov/pubmed/25801843
CNS Neurol Disord Drug Targets. 2015;14(7):838-54.
The Toll-Like Receptor Radical Cycle Pathway: A New Drug Target in Immune-Related Chronic Fatigue.
Lucas K, Morris G, Anderson G, Maes M.
Abstract
In this review we discuss that peripheral and central activation of the Toll-like receptor 2/4 (TLR2/4) Radical Cycle may underpin the pathophysiology of immune-related chronic fatigue secondary to other medical diseases and conditions.
The TLR Radical Cycle plays a role in illnesses and conditions that are disproportionately commonly comorbid with secondary chronic fatigue, including a) neuroinflammatory disorders, e.g. Parkinson's disease, stroke, depression, psychological stressors, and b) systemic disorders, e.g. (auto)immune disorders, chronic obstructive pulmonary disease, ankylosing spondylitis, chronic kidney disease, inflammatory bowel disease, cardiovascular disease, incl. myocardial infarction, cancer and its treatments.
Increased TLR signaling is driven by activated immuneinflammatory and oxidative and nitrosative stress pathways, pathogen derived molecular patterns, including lipopolysaccharides, and damage associated molecular patterns (DAMPs).
Newly formed redox-derived DAMPs, secondary to oxidative processes, may further activate the TLR complex leading to an auto-amplifying TLR Radical feedback loop. Increased gut permeability with translocation of gram negative bacteria and LPS, which activates the TLR Radical Cycle, is another pathway that may play a role in most of the abovementioned diseases and the secondary fatigue accompanying them.
It is concluded that secondary fatigue may be associated with activation of the TLR Radical Cycle pathway due to activated immune-inflammatory pathways, classical and redox-derived DAMPs and PAMPs plays a role in its pathophysiology.
Such an activation of the TLR Radical Cycle pathway may also explain why the abovementioned conditions are primed for an increased expression of secondary chronic fatigue.
Targeting the TLR Radical Cycle pathway may be an effective method to treat TLR-Radical Cycle-related diseases such as secondary chronic fatigue.
PMID:25801843 [PubMed - indexed for MEDLINE]

 
http://www.ncbi.nlm.nih.gov/pubmed/27045557
Expert Rev Clin Pharmacol. 2016 Apr 5. [Epub ahead of print]
Efficacy of rintatolimod (Ampligen) in the treatment of chronic fatigue syndrome/ myalgic encephalomyelitis (cfs/me).
Mitchell WM.
Abstract
Chronic fatigue syndrome/ Myalgic encephalomyelitis (CFS/ME) is a poorly understood seriously debilitating disorder in which disabling fatigue is an universal symptom in combination with a variety of variable symptoms. The only drug in advanced clinical development is rintatolimod, a mismatched double stranded polymer of RNA (dsRNA).
Rintatolimod is a restricted Toll-Like Receptor 3 (TLR3) agonist lacking activation of other primary cellular inducers of innate immunity (e.g.- cytosolic helicases). Rintatolimod also activates interferon induced proteins that require dsRNA for activity (e.g.- 2'-5' adenylate synthetase, protein kinase R).
Rintatolimod has achieved statistically significant improvements in primary endpoints in Phase II and Phase III double-blind, randomized, placebo-controlled clinical trials with a generally well tolerated safety profile and supported by open-label trials in the United States and Europe.
The chemistry, mechanism of action, clinical trial data, and current regulatory status of rintatolimod for CFS/ME including current evidence for etiology of the syndrome are reviewed.

 
fulltext- http://bmjopen.bmj.com/content/6/4/e010277.full
BMJ Open 2016;6:e010277 doi:10.1136/bmjopen-2015-010277
How do women with chronic fatigue syndrome/myalgic encephalomyelitis rate quality and coordination of healthcare services? A cross-sectional study
Anne Helen Hansen, Olaug S Lian
Abstract
Objective: To test the association between self-rated health and self-rated degree of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), and CFS/ME patients' assessment of quality of primary care, specialist care and coordination of care.
Design: Cross-sectional study.
Setting: Self-reported questionnaire data from women members of The Norwegian ME Association obtained in 2013.
Participants: 431 women with CFS/ME aged 16–73 years.
Main outcome measure: The participants' assessment of quality in primary care, specialist care and in coordination of care (good/very good or poor/very poor). Main explanatory variables: self-rated health and self-rated degree of CFS/ME.
Results: Quality of care was rated poor by 60.6% in primary care, by 47.7% in specialist care, and by 71.2% regarding coordination of care.
Poorer self-rated health increased the probability of rating quality in primary care poor, particularly among women 40 years and over (OR 2.38, 95% CI 1.63 to 3.49), women with university education (OR 2.57, CI 1.68 to 3.94), and owing to less frequent general practitioner (GP) visits (OR 2.46, CI 1.60 to 3.78). Poorer self-rated health increased the probability of rating quality poor in specialist care (OR 1.38, CI
1.05 to 1.82), but not in coordination of care. A more severe CFS/ME was associated with a higher probability of rating quality in primary care poor (OR 0.61, CI 0.38 to 0.93). Frequent visitors and those with a long GP relationship were less likely to report primary care quality as poor.
Conclusions: A large proportion of women with CFS/ME rated quality of care poor/very poor in primary care, specialist care and in coordination of care. The dissatisfaction was higher for primary care than for specialist care. Overall, poorer self-rated health and a more severe CFS/ME were associated with lower quality scores in primary and specialist care, but not in coordination of care. Healthcare services, as assessed by women with CFS/ME, do have a large potential for improvement.

 
fulltext- http://www.sciencedirect.com/science/article/pii/S2213158216300584
Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome
Leighton R. Barnden, Richard Kwiatek, Benjamin Crouch, Richard Burnet, Peter Del Fante
Highlights
• For the first time in CFS, we performed MRI regressions with steady state BP and HR.
• Vasomotor centre, midbrain and hypothalamus correlations were abnormal in CFS.
• MRI group comparisons between CFS and controls detected no differences.
• Regulatory nuclei and peripheral effectors/sensors appear to function correctly.
• Signalling between brainstem/midbrain regulatory nuclei appears to be impaired.
Abstract
Autonomic changes are often associated with the chronic fatigue syndrome (CFS), but their pathogenetic role is unclear and brain imaging investigations are lacking. The vasomotor centre and, through it, nuclei in the midbrain and hypothalamus play a key role in autonomic nervous system regulation of steady state blood pressure
(BP) and heart rate (HR).
In this exploratory cross-sectional study, BP and HR, as indicators of autonomic function, were correlated with volumetric and T1- and T2-weighted spin-echo (T1w and T2w) brain MRI in 25 CFS subjects and 25 normal controls (NC).
Steady state BP (systolic, diastolic and pulse pressure) and HR in two postures were extracted from 24 h blood pressure monitoring.
We performed (1) MRI versus autonomic score interaction-with-group regressions to detect locations where regression slopes differed in the CFS and NC groups (collectively indicating abnormality in CFS), and (2) MRI regressions in the CFS and NC groups alone to detect additional locations with abnormal correlations in CFS.
Significant CFS regressions were repeated controlling for anxiety and depression (A&D). Abnormal regressions were detected in nuclei of the brainstem vasomotor centre, midbrain reticular formation and hypothalamus, but also in limbic nuclei involved in stress responses and in prefrontal white matter.
Group comparisons of CFS and NC did not find MRI differences in these locations. We propose therefore that these regulatory nuclei are functioning correctly, but that two-way communication between them is impaired in CFS and this affects signalling to/from peripheral effectors/sensors, culminating in inverted or magnified correlations.
This single explanation for the diverse abnormal correlations detected here consolidates the conclusion for a brainstem/midbrain nerve conduction deficit inferred earlier (Barnden et al., 2015). Strong correlations were also detected in isolated NC regressions.

 
http://www.ncbi.nlm.nih.gov/pubmed/26088214
Curr Rheumatol Rev. 2015;11(2):109-15.
Cytokine and immune system abnormalities in fibromyalgia and other central sensitivity syndromes.
Staud R.
Abstract
The nervous system as well as the immune system use common signaling molecules for intra- and inter-system communications. Specifically, both entities produce a similar array of peptide and non-peptide transmitters that act on a common set of receptors present in the two systems. One important set of such signaling molecules are cytokines.
The wide distribution of cytokine receptors throughout the body, including the immune and the nervous system allows direct communication between these two entities. In addition to cytokines the nervous system and immune system also communicate with each other using shared ligands such as neurotransmitters and neuroendocrine hormones, and their respective receptors.
Some of the most important clinical interactions between these two systems are associated with the "sickness response" as well as pain and analgesia. This "sickness response" which has been frequently attributed to inflammatory cytokines, strongly resembles the core symptoms of fibromyalgia and other Central Sensitivity Syndromes (CSS).
Therefore a large number of research studies have focused on the relationship between peripheral cytokines and CSS. However, a lack of consistent associations was observed between CSS symptoms and peripheral cytokines which seem to suggest that maybe cytokines abnormalities of the central nervous system contribute to the pathogenesis of these illnesses.
Better knowledge of cytokine -nervous system interactions may ultimately benefit the development of interventions that improve CSS manifestations including the "sickness response" and chronic pain.
PMID:26088214 [PubMed - indexed for MEDLINE]

 
http://www.nejm.org/doi/full/10.1056/NEJMoa1505425#t=article
Randomized Trial of Longer-Term Therapy for Symptoms Attributed to Lyme Disease
Anneleen Berende, M.D., Hadewych J.M. ter Hofstede, M.D., Ph.D., Fidel J. Vos, M.D., Ph.D., Henriët van Middendorp, Ph.D., Michiel L. Vogelaar, M.Sc., Mirjam Tromp, Ph.D., Frank H. van den Hoogen, M.D., Ph.D., A. Rogier T. Donders, Ph.D., Andrea W.M. Evers, Ph.D., and Bart Jan Kullberg, M.D., Ph.D.
Background: The treatment of persistent symptoms attributed to Lyme disease remains controversial. We assessed whether longer-term antibiotic treatment of persistent symptoms attributed to Lyme disease leads to better outcomes than does shorter-term treatment.
Methods: In a randomized, double-blind, placebo-controlled trial conducted in Europe, we assigned patients with persistent symptoms attributed to Lyme disease — either related temporally to proven Lyme disease or accompanied by a positive IgG or IgM immunoblot assay for Borrelia burgdorferi — to receive a 12-week oral course of doxycycline, clarithromycin plus hydroxychloroquine, or placebo. All study groups received open-label intravenous ceftriaxone for 2 weeks before initiating the randomized regimen.
The primary outcome measure was health-related quality of life, as assessed by the physical-component summary score of the RAND-36 Health Status Inventory (RAND SF-36) (range, 15 to 61, with higher scores indicating better quality of life), at the end of the treatment period at week 14, after the 2-week course of ceftriaxone and the 12-week course of the randomized study drug or placebo had been completed.
Results: Of the 281 patients who underwent randomization, 280 were included in the modified intention-to-treat analysis (86 patients in the doxycycline group, 96 in the clarithromycin–hydroxychloroquine group, and 98 in the placebo group).
The SF-36 physical-component summary score did not differ significantly among the three study groups at the end of the treatment period, with mean scores of 35.0 (95% confidence interval [CI], 33.5 to 36.5) in the doxycycline group, 35.6 (95% CI, 34.2 to 37.1) in the clarithromycin–hydroxychloroquine group, and 34.8 (95% CI, 33.4 to 36.2) in the placebo group (P=0.69; a difference of 0.2 [95% CI, –2.4 to 2.8] in the doxycycline group vs. the placebo group and a difference of 0.9 [95% CI, –1.6 to 3.3] in the clarithromycin–hydroxychloroquine group vs. the placebo group); the score also did not differ significantly among the groups at subsequent study visits (P=0.35).
In all study groups, the SF-36 physical-component summary score increased significantly from baseline to the end of the treatment period (P<0.001). The rates of adverse events were similar among the study groups. Four serious adverse events thought to be related to drug use occurred during the 2-week open-label ceftriaxone phase, and no serious drug-related adverse event occurred during the 12-week randomized phase.
Conclusions: In patients with persistent symptoms attributed to Lyme disease, longer-term antibiotic treatment did not have additional beneficial effects on health-related quality of life beyond those with shorter-term treatment. (Funded by the Netherlands Organization for Health Research and Development ZonMw; PLEASE ClinicalTrials.gov number, NCT01207739.)

 
https://www.dovepress.com/getfile.php?fileID=29668
Natural killer cells and single nucleotide polymorphisms of specific ion channels and receptor genes in myalgic encephalomyelitis/chronic fatigue syndrome
Authors Marshall-Gradisnik S, Huth T, Chacko A, Johnston S, Smith P, Staines D
Aim: The aim of this paper was to determine natural killer (NK) cytotoxic activity and if single nucleotide polymorphisms (SNPs) and genotypes in transient receptor potential (TRP) ion channels and acetylcholine receptors (AChRs) were present in isolated NK cells from previously identified myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) patients.
Subjects and methods: A total of 39 ME/CFS patients (51.69±2 years
old) and 30 unfatigued controls (47.60±2.39 years old) were included in this study. Patients were defined according to the 1994 Centers for Disease Control and Prevention criteria. Flow cytometry protocols were used to examine NK cytotoxic activity.
A total of 678 SNPs from isolated NK cells were examined for 21 mammalian TRP ion channel genes and for nine mammalian AChR genes via the Agena Bioscience iPlex Gold assay. SNP association and genotype was determined using analysis of variance and Plink software.
Results: ME/CFS patients had a significant reduction in NK percentage lysis of target cells (17%±4.68%) compared with the unfatigued control group (31%±6.78%). Of the 678 SNPs examined, eleven SNPs for TRP ion channel genes (TRPC4, TRPC2, TRPM3, and TRPM8) were identified in the ME/CFS group. Five of these SNPs were associated with TRPM3, while the remainder were associated with TRPM8, TRPC2, and TRPC4 (P<0.05).
Fourteen SNPs were associated with nicotinic and muscarinic AChR genes: six with CHRNA3, while the remainder were associated with CHRNA2, CHRNB4, CHRNA5, and CHRNE (P<0.05). There were sixteen genotypes identified from SNPs in TRP ion channels and AChRs for TRPM3 (n=5), TRPM8 (n=2), TRPC4 (n=3), TRPC2 (n=1), CHRNE (n=1), CHRNA2 (n=2), CHRNA3 (n=1), and CHRNB4 (n=1) (P<0.05).
Conclusion: We identified a number of SNPs and genotypes for TRP ion channels and AChRs from isolated NK cells in patients with ME/CFS, suggesting these SNPs and genotypes may be involved in changes in NK cell function and the development of ME/CFS pathology.
These anomalies suggest a role for dysregulation of Ca2+ in AChR and TRP ion channel signaling in the pathomechanism of ME/CFS.

 
J Clin Pathol doi:10.1136/jclinpath-2015-203502
Laboratory assessment of vitamin B12 status

1. Dominic J Harrington1,2

+ Author Affiliations
<>1.<>2.Correspondence to Dr Dominic J Harrington, The Nutristasis Unit, 4th Floor North Wing (Viapath), St Thomas' Hospital NHS Foundation Trust, Westminster Bridge Road, London SE1 7EH; UK; Dominic.Harrington@viapath.co.uk

• Received 8 January 2016
• Revised 19 April 2016
• Accepted 20 April 2016
• Published Online First 11 May 2016
• Abstract
  The detection and correction of vitamin B12 (B12) deficiency prevents megaloblastic anaemia and potentially irreversible neuropathy and neuropsychiatric changes. B12 status is commonly estimated using the abundance of the vitamin in serum, with ∼148 pmol/L (200 ng/L) typically set as the threshold for diagnosing deficiency. Serum B12 assays measure the sum of haptocorrin-bound and transcobalamin-bound (known as holotranscobalamin) B12. It is only holotranscobalamin that is taken up by cells to meet metabolic demand. Although receiver operator characteristic curves show holotranscobalamin measurement to be a moderately more reliable marker of B12 status than serum B12, both assays have an indeterminate range. Biochemical evidence of metabolic abnormalities consistent with B12 insufficiency is frequently detected despite an apparently sufficient abundance of the vitamin. Laboratory B12 status markers that reflect cellular utilisation rather than abundance are available. Two forms of B12 act as coenzymes for two different reactions. Methionine synthase requires methylcobalamin for the remethylation of methionine from homocysteine. A homocysteine concentration >20 µmol/L may suggest B12 deficiency in folate-replete patients. In the second B12-dependent reaction, methylmalonyl-CoA mutase uses adenosylcobalamin to convert methylmalonyl-CoA to succinyl-CoA. In B12 deficiency excess methylmalonyl-CoA is hydrolysed to methylmalonic acid. A serum concentration >280 nmol/L may suggest suboptimal status in young patients with normal renal function. No single laboratory marker is suitable for the assessment of B12 status in all patients. Sequential assay selection algorithms or the combination of multiple markers into a single diagnostic indicator are both approaches that can be used to mitigate inherent limitations of each marker when used independently.
  
   
  Vitamin B12 May Slow Brain Aging
  Liam Davenport
  | May 11, 2016
   
  Individuals with increased levels of circulating homocysteine have faster rates of brain changes associated with aging than other people, whereas higher levels of vitamin B12 are associated with slower rates of brain aging, new research suggests.
  Babak Hooshmand, MD, PhD, Center for Alzheimer Research–Aging Research Center, Karolinska Institutet, Stockholm, Sweden, and colleagues found that total brain volume losses were lower in individuals with higher baseline vitamin B12 levels, whereas the opposite was true of those with increased homocysteine levels.
  "Vitamin B12 and tHcy [total homocysteine] might be independent predictors of markers of brain aging in elderly individuals without dementia," the investigators write.
  They add, "[I]f the association is causal, supplementation with B vitamins may be effective for prevention of brain damage due to increased levels of total homocysteine. Adequately timed and powered randomized clinical trials are needed to determine efficient treatment guidelines."
  The research was published online April 27 in JAMA Psychiatry.
  Homocysteine and Brain Tissue Loss
  The researchers examined data on 501 participants aged 60 years and older from the Swedish National Study on Aging and Care, in Kungsholmen. All participants were free of dementia at baseline. Of these, 299 underwent repeated structural brain MRI between 2001 and 2009.
  At baseline and at each follow-up, participants underwent a thorough clinical examination, an interview, and assessment. Data on sociodemographic characteristics, medical history, drug use, and cognitive function were collected.
  Venous blood samples were collected at baseline, from which circulating levels of vitamin B12, red blood cell folate, and sulfur amino acids were determined. These were correlated with changes in brain tissue volumes and total white matter hyperintensity (WMH) over 6 years.
  Between baseline and the 6-year follow-up, the mean total brain tissue (TBT) volume decreased from 74.3% to 71.6% of the total cranial volume (P < .001), whereas the mean WMH volume increased from 0.0004% to 0.0007% (P < .001).
  Multiadjusted linear mixed model analysis revealed that increased baseline levels of vitamin B12 and holotranscobalamin (the biologically active fraction of B12) were associated with a decreased rate of TBT volume loss, at respective beta values of 0.048 (P < .001) and 0.040 (P = .002) for each standard deviation increase.
  Furthermore, the researchers found that each standard deviation increase in total homocysteine levels was linked to more rapid rates of TBT volume loss, at a beta value of -0.035 (P = .02).
  Increases in total homocysteine levels were also associated with increases in the progression of WMH in individuals with a systolic blood pressure >140 mmHg, at 0.000019 per standard deviation increase (P = .047).
  The results suggested that there was no association between markers of brain aging and levels of red blood folate and other sulfur amino acid.
  Modest Effect
  Commenting on the findings for Medscape Medical News, E. Sherwood Brown, MD, PhD, professor of psychiatry and director of the Psychoneuroendocrine Research Program at the University of Texas Southwestern Medical Center, Dallas, described the study as "interesting," with the "main plus" being the large sample size.
  Dr Brown noted that although similar studies have been published, "the longitudinal aspect of looking at the vitamin levels as a predictor of later changes is somewhat novel...and might offer some insights into ways to maybe prevent cognitive decline or decline in brain volume or even dementia."
  Dr Brown emphasized that although the researchers took into account a range of variables related to vitamin B12 and homocysteine, "it's very hard to know whether it's the levels of them per se or whether they're somehow a marker for some other lifestyle health factors that are really the culprit here, and that's certainly a legitimate limitation."
  In future studies, Dr Brown would like to see cognitive data along with the brain structural data to identify clinical correlates for the findings, as well as multiple measures of the vitamin and homocysteine levels.
  "I think the other cautionary note to throw in there is, even though the relationships were highly significant...the effect you're seeing is always pretty modest. I think you'd have to put all this in the context of one of probably many factors that might influence the degree of brain aging over time," he concluded.
  B12 Trial Warranted
  Dr Hooshmand agreed with Dr Brown that it would have been valuable to have multiple vitamin B12 and homocysteine assessments for the current analysis.
  "It is ideal if we have brain measures three times over 6 years, but the better situation is also to have vitamin B12 three times over 6 years," he said, adding that the team plans on taking multiple vitamin measurements in future studies.
  Nevertheless, he believes that the finding of an association between vitamin B12 levels and brain volume loss suggests that a randomized controlled trial of vitamin B12 supplementation is warranted to determine whether it could prevent brain aging.
  "But not everyone will benefit from supplementation," Dr Hooshmand told Medscape Medical News. "Those who have low levels of these vitamins, those who have clinical signs of vitamin B12 deficiency...those are the people who will benefit from receiving the supplements."
  He also pointed to the single-center, randomized VITACOG study, in which 271 individuals older than 70 years who had mild cognitive impairment received supplementation with high-dose folic acid and vitamins B6 and B12.
  "They lost less brain compared to people who had normal homocysteine and normal vitamin levels, meaning that those with high levels of homocysteine or with clinical or biochemical vitamin deficiency can benefit from supplementation," said Dr Hooshmand.
  Funding was provided by the Swedish Ministry of Health and Social Affairs, the Stockholm County Council, and the Stockholm municipality. The study was supported by grants from the Academy of Finland, Lipididiet, the Swedish Research Council, the Swedish Council for Working Life and Social Research, the Karolinska Institutet, the Axa Research Fund, the Alzheimer’s Research and Prevention Foundation, the Salama bint Hamdan Al Nahyan Foundation, the Alzheimer Foundation, Hjärnfonden, the Norwegian Research Council, the Charles Wolfson Charitable Trust, private foundations, and the Erityisvaltionosuus. Several authors have numerous ties with industry, which are listed in the original article. Dr Brown has disclosed no relevant financial relationships.
  JAMA Psychiatry. Published online April 27, 2016. Abstract
   
  
   
  Excessive Folate, B12 in Pregnancy Dramatically Ups Autism Risk
  Pam Harrison
  | May 12, 2016
   
  BALTIMORE ― Excessive levels of plasma folate and vitamin B12 during pregnancy have been linked to a dramatic increase in autism risk in offspring, new research shows.
  Investigators at Johns Hopkins University, Baltimore, found that when maternal plasma folate levels and vitamin B12 levels are >59 nmol/L and >600 pmol/L, respectively, autism risk is increased more than 17-fold.
  The findings were presented at the International Meeting for Autism Research (IMFAR) 2016.
  "When we looked at the vitamin supplementation evidence, we saw what our colleagues see ― that indeed, women who took vitamin supplementation during pregnancy had a lower risk of autism in their children and that is very consistent with the literature," principal investigator Daniele Fallin, PhD, director, Wendy Klag Center for Autism and Developmental Disabilities, John Hopkins Bloomberg School of Public Health, said during a press briefing.  "But when we looked at women who had excessively high levels of folate, we saw that very high levels of folate in the mother were responsible for about a twofold increased risk for autism in their child [P = .007], and when we looked at B12, women who had excessively high levels of B12 had a threefold increased risk for their child to have autism [P = .001], while women who had extreme levels of both folate and vitamin B12 had a 17.6 times greater risk of having their child diagnosed with an ASD [autism spectrum disorder] later on [P < .001]," she added.
  "So for now, the public health message is, supplementation is good, but there may be a subset of women whose levels are extremely high, and these extreme levels may be harmful."
  Led by Ramkripa Raghavan, MPH, investigators analyzed data from 1391 mother-child pairs enrolled in the Boston Birth Cohort, an ongoing, longitudinal study that includes a predominantly low- income, minority population.
  The study included children born between 1998 and 2013 who were followed from birth through childhood. At the time of delivery, maternal serum folate and vitamin B12 levels were analyzed. Mothers were asked whether they took a multivitamin supplement during pregnancy and, if so, how often.
  A total of 107 infants were diagnosed with autism, Asperger syndrome, and/or pervasive developmental disorder not otherwise specified and were categorized as having ASD.
  Investigators noted that levels of both nutrients varied from deficiency levels of plasma folate (<13.5 nmol/L) and vitamin B12 (<200 pmol/L) to excessive levels of plasma folate (>59 nmol/L) and vitamin B12 (>600 pmol/L).
  Dr Fallin said that the team was not able to determine whether excessive plasma folate and vitamin B12 levels corresponded to a certain level of intake of both supplements during pregnancy.
  "In our study, we were not able to connect precise vitamin use and later folate and B12 levels in these mothers. But, generally speaking, it's important to appreciate that levels of folate in blood are not just a function of supplement intake. They are also a function of diet and a genetic makeup that can change dramatically how easily a person retains or clears folate," she said.
  She acknowledged that it is important to establish what constitutes a safe and effective intake of supplements for women during pregnancy.
  A Balanced Approach
  Geraldine Dawson, MD, president of the International Society for Autism Research and professor of psychiatry and behavioral science at Duke University School of Medicine, Durham, North Carolina, told Medscape Medical News that it has long been known that diet and vitamin supplementation are very important for fetal brain development.
  "Now we're also seeing that it's also important for lowering the risk that your child will have autism," she added.
  Future research will help to identify exactly what levels of vitamins pregnant women need to take, she said.
  "But I think the new finding here is that we've been focusing on the need for supplementation of vitamin B and also folate, but now we're also seeing that we don't want to take too much ― that if you have very high levels of these nutrients, that this is not optimal," Dr Dawson said.
  "So the next step is to define what the right level is, but I think the message so far is to take moderate levels of supplements and not to overdo it, but certainly don't 'under-do' it, either."
  Dr Fallin has disclosed no relevant financial relationships.
  International Meeting for Autism Research (IMFAR) 2016: Abstract 149.004, to be presented May 13, 2016.
   
  Rheumatology International
  pp 1-11   First online: 07 April 2016The effects of long- and short-term interdisciplinary treatment approaches in women with fibromyalgia: a randomized controlled trial
  • Ilknur SaralAffiliated withDepartment of Physical Medicine and Rehabilitation, Istanbul Faculty of Medicine, Istanbul UniversityDepartment of Physical Medicine and Rehabilitation, Faculty of Medicine, Istanbul Medipol University
  • , Dilsad SindelAffiliated withDepartment of Physical Medicine and Rehabilitation, Istanbul Faculty of Medicine, Istanbul University
  • , Sina EsmaeilzadehAffiliated withDepartment of Physical Medicine and Rehabilitation, Istanbul Faculty of Medicine, Istanbul University Email author 
  • , Hanife Ozlem Sertel-BerkAffiliated withDepartment of Clinical Psychology, Faculty of Letters, Istanbul University
  • , Aydan OralAffiliated withDepartment of Physical Medicine and Rehabilitation, Istanbul Faculty of Medicine, Istanbul UniversityAbstract
  We investigated the effects of long- and short-term interdisciplinary treatment approaches for reducing symptoms and improving health-related quality of life (HRQoL) and physical functions of patients with fibromyalgia and compared the effects of two different interdisciplinary treatment approaches. We conducted a prospective, randomized, controlled trial involving 66 women with fibromyalgia eligible for the study at a university hospital setting. The patients were randomized into three groups (allocation ratio 1:1:1) using a computer-generated random numbers: a long-term interdisciplinary treatment group (LG, n = 22) that participated in 10 sessions (3-h once-weekly session for 10 weeks) of cognitive behavioral therapy (CBT) together with exercise training and other fibromyalgia related educational programs (two full days); a short-term interdisciplinary treatment group (SG, n = 22) that received two full days of educational, exercise, and CBT programs; and a control group (CG, n = 22). The patients were evaluated at baseline and 6 months after treatment using the visual analog scale (pain, fatigue, and sleep), Fibromyalgia Impact Questionnaire, Beck Depression Inventory, Short Form-36, tender point numbers, and pressure algometry as primary outcomes. The statistical analysis was confined to the ‘per-protocol’ set. No blinding was performed. The number of patients analyzed was 21 in the LG, 19 in the SG, and 19 in the CG. The intensity of pain (p < 0.001), severity of fatigue (p = 0.048), number of tender points (p = 0.002), and pressure pain threshold (p = 0.012) decreased significantly in both the LG and SG groups compared with controls. Moreover, physical functions (p = 0.017) and physical components of the HRQoL (p = 0.036) improved significantly in the intervention groups compared with the controls. However, there was no significant difference between intervention groups and the control group at the end of study in terms of quality of sleep (p = 0.055), severity of depressive symptoms (p = 0.696), and mental components of the HRQoL (p = 0.229). Finally, with the exception of the severity of fatigue and physical components of the HRQoL, there was no obvious significant difference between the efficacies of the two treatment approaches when compared with controls; the long-term treatment was found more effective in reducing pain than the short-term. Both, long- and short-term interdisciplinary treatments were effective in reducing the severity of some symptoms and disease activity in patients with fibromyalgia. The short-term program well meets the needs of women with fibromyalgia particularly in relation to pain and health status as measured using FIQ; however, a long-term program may be beneficial in reducing fatigue and improving physical function to a higher extent.KeywordsFibromyalgia Treatment Multidisciplinary Interdisciplinary Multicomponent Cognitive behavioral therapy
  
  

Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function:  The AREDS2 Randomized Clinical Trial
Emily Y. Chew, MD1; Traci E. Clemons, PhD2; Elvira Agrón, MA1; Lenore J. Launer, PhD3; Francine Grodstein, ScD4,5; Paul S. Bernstein, MD, PhD6 ; for the Age-Related Eye Disease Study 2 (AREDS2) Research Group
[+-] Author Affiliations
1Division of Epidemiology and Clinical Applications, Clinical Trials Branch, National Eye Institute/National Institutes of Health, Bethesda, Maryland
2The EMMES Corporation, Rockville, Maryland
3Neuroepidemiology Section, National Institute on Aging/National Institutes of Health, Bethesda, Maryland
4Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
5Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
6Moran Eye Center, University of Utah, Salt Lake City
JAMA. 2015;314(8):791-801. doi:10.1001/jama.2015.9677.
ABSTRACT
Importance  Observational data have suggested that high dietary intake of saturated fat and low intake of vegetables may be associated with increased risk of Alzheimer disease.
Objective  To test the effects of oral supplementation with nutrients on cognitive function.
Design, Setting, and Participants  In a double-masked randomized clinical trial (the Age-Related Eye Disease Study 2 [AREDS2]), retinal specialists in 82 US academic and community medical centers enrolled and observed participants who were at risk for developing late age-related macular degeneration (AMD) from October 2006 to December 2012. In addition to annual eye examinations, several validated cognitive function tests were administered via telephone by trained personnel at baseline and every 2 years during the 5-year study.
Interventions  Long-chain polyunsaturated fatty acids (LCPUFAs) (1 g) and/or lutein (10 mg)/zeaxanthin (2 mg) vs placebo were tested in a factorial design. All participants were also given varying combinations of vitamins C, E, beta carotene, and zinc.
Main Outcomes and Measures  The main outcome was the yearly change in composite scores determined from a battery of cognitive function tests from baseline. The analyses, which were adjusted for baseline age, sex, race, history of hypertension, education, cognitive score, and depression score, evaluated the differences in the composite score between the treated vs untreated groups. The composite score provided an overall score for the battery, ranging from −22 to 17, with higher scores representing better function.
Results  A total of 89% (3741/4203) of AREDS2 participants consented to the ancillary cognitive function study and 93.6% (3501/3741) underwent cognitive function testing. The mean (SD) age of the participants was 72.7 (7.7) years and 57.5% were women. There were no statistically significant differences in change of scores for participants randomized to receive supplements vs those who were not. The yearly change in the composite cognitive function score was −0.19 (99% CI, −0.25 to −0.13) for participants randomized to receive LCPUFAs vs −0.18 (99% CI, −0.24 to −0.12) for those randomized to no LCPUFAs (difference in yearly change, −0.03 [99% CI, −0.20 to 0.13]; P = .63). Similarly, the yearly change in the composite cognitive function score was −0.18 (99% CI, −0.24 to −0.11) for participants randomized to receive lutein/zeaxanthin vs −0.19 (99% CI, −0.25 to −0.13) for those randomized to not receive lutein/zeaxanthin (difference in yearly change, 0.03 [99% CI, −0.14 to 0.19]; P = .66). Analyses were also conducted to assess for potential interactions between LCPUFAs and lutein/zeaxanthin and none were found to be significant.
Conclusions and Relevance  Among older persons with AMD, oral supplementation with LCPUFAs or lutein/zeaxanthin had no statistically significant effect on cognitive function.

 
CYTOKINE
Vol 78 Feb 2016
Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome

• Abdolamir Landia, , , David Broadhurstb, Suzanne D. Vernonc, D. Lorne J. Tyrrella, Michael Houghtona, ,
• Abstract
• Recently, differences in the levels of various chemokines and cytokines were reported in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as compared with controls. Moreover, the analyte profile differed between chronic ME/CFS patients of long duration versus patients with disease of less than 3 years. In the current study, we measured the plasma levels of 34 cytokines, chemokines and growth factors in 100 chronic ME/CFS patients of long duration and in 79 gender and age-matched controls. We observed highly significant reductions in the concentration of circulating interleukin (IL)-16, IL-7, and Vascular Endothelial Growth Factor A (VEGF-A) in ME/CFS patients. All three biomarkers were significantly correlated in a multivariate cluster analysis. In addition, we identified significant reductions in the concentrations of fractalkine (CX3CL1) and monokine-induced-by-IFN-γ (MIG; CXCL9) along with increases in the concentrations of eotaxin 2 (CCL24) in ME/CFS patients. Our data recapitulates previous data from another USA ME/CFS cohort in which circulating levels of IL-7 were reduced. Also, a reduced level of VEGF-A was reported previously in sera of patients with Gulf War Illness as well as in cerebral spinal fluid samples from a different cohort of USA ME/CFS patients. To our knowledge, we are the first to test for levels of IL-16 in ME/CFS patients. In combination with previous data, our work suggests that the clustered reduction of IL-7, IL-16 and VEGF-A may have physiological relevance to ME/CFS disease. This profile is ME/CFS-specific since measurement of the same analytes present in chronic infectious and autoimmune liver diseases, where persistent fatigue is also a major symptom, failed to demonstrate the same changes. Further studies of other ME/CFS and overlapping disease cohorts are warranted in future.

 
Lyme disease: time for a new approach?

• BMJ 2015; 351 doi: http://dx.doi.org/10.1136/bmj.h6520 (Published 03 December 2015) Cite this as: BMJ 2015;351:h6520

Liesbeth Borgermans, professor, Christian Perronne, professor, Ran Balicer, professor , Ozren Polasek, professor
Valerie Obsomer, ecological and environmental risk expert6
<>1.2.3.4.5.6.liesbeth.borgermans@vub.ac.be
Many more questions than answers
Lyme disease is the most common vector borne disease in North America and Europe, with 300 000 new cases in the United States1 and an estimated 100 000 new cases in Europe each year.2 These numbers are likely to be underestimates because case reporting is inconsistent3 and many infections go undiagnosed.4 Climate change may have contributed to a rapid increase in tick borne diseases, with migratory birds disseminating infected ticks.5
Our common understanding of Lyme disease is that a tick bite is followed by the development of a classic rash pattern (erythema migrans). When treated early with a relatively short course of antibiotics, most patients have good outcomes.6 But the standard two tier testing for Lyme disease is inaccurate in the early stages.

 
http://www.ncbi.nlm.nih.gov/pubmed/26623235
Borderline Intracranial Hypertension Manifesting as Chronic Fatigue Syndrome Treated by Venous Sinus Stenting.
Higgins N, Pickard J, Lever A.
Abstract
Chronic fatigue syndrome and cases of idiopathic intracranial hypertension without signs of raised intracranial pressure can be impossible to distinguish without direct measurement of intracranial pressure. Moreover, lumbar puncture, the usual method of measuring intracranial pressure, can produce a similar respite from symptoms in patients with chronic fatigue as it does in idiopathic intracranial hypertension.
This suggests a connection between them, with chronic fatigue syndrome representing a forme fruste variant of idiopathic intracranial hypertension. If this were the case, then treatments available for idiopathic intracranial hypertension might be appropriate for chronic fatigue.
We describe a 49-year-old woman with a long and debilitating history of chronic fatigue syndrome who was targeted for investigation of intracranial pressure because of headache, then diagnosed with borderline idiopathic intracranial hypertension after lumbar puncture and cerebrospinal fluid drainage.
Further investigation showed narrowings at the anterior ends of the transverse sinuses, typical of those seen in idiopathic intracranial hypertension and associated with pressure gradients.
Stenting of both transverse sinuses brought about a life-changing remission of symptoms with no regression in 2 years of follow-up. This result invites study of an alternative approach to the investigation and management of chronic fatigue.

 
http://www.researchgate.net/publication/283476227_Psychogenic_expla...
Psychogenic Explanations of Physical Illness: Time to Examine the Evidence
Carolyn E. Wilshire and Tony Ward, Victoria University of Wellington, Wellington, New Zealand
In some patients with chronic physical complaints, detailed examination fails to identify a well-recognized underlying disease process. In this situation, the physician may suspect a psychological cause. This review critically evaluates the evidence for this causal claim, focusing on complaints presenting as neurological disorders.
There were four main conclusions.
First, patients with these complaints frequently exhibit psychopathology, but not consistently more often than patients with a comparable “organic” diagnosis, so a causal role cannot be inferred.
Second, these patients report a high incidence of adverse life experiences, but again, this evidence is insufficient to infer causation:A psychogenic diagnosis is likely to prompt careful reexamination of negative past experiences, thereby introducing a recall bias.
Third, although psychogenic illnesses are believed to be more responsive to psychological interventions than comparable “organic” illnesses, there is currently no evidence to support this claim.
Finally, recent evidence suggests that biological and physical factors play a much greater causal role in these illnesses than previously believed. We conclude that there is currently little evidential support for psychogenic theories of illness in the neurological domain. Future research needs to take a wider view concerning the etiology of these illnesses.

 
http://www.ncbi.nlm.nih.gov/pubmed/26615570
Cytokine. 2015 Nov 23;78:27-36. doi: 10.1016/j.cyto.2015.11.018. [Epub ahead of print]
Reductions in circulating levels of IL-16, IL-7 and VEGF-A in myalgic encephalomyelitis/chronic fatigue syndrome.
Landi A, Broadhurst D, Vernon SD, Tyrrell DL, Houghton M.
Abstract
Recently, differences in the levels of various chemokines and cytokines were reported in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as compared with controls. Moreover, the analyte profile differed between chronic ME/CFS patients of long duration versus patients with disease of less than 3years. In the current study, we measured the plasma levels of 34 cytokines, chemokines and growth factors in 100 chronic ME/CFS patients of long duration and in 79 gender and age-matched controls.
We observed highly significant reductions in the concentration of circulating interleukin (IL)-16, IL-7, and Vascular Endothelial Growth Factor A (VEGF-A) in ME/CFS patients. All three biomarkers were significantly correlated in a multivariate cluster analysis.
In addition, we identified significant reductions in the concentrations of fractalkine (CX3CL1) and monokine-induced-by-IFN-γ (MIG; CXCL9) along with increases in the concentrations of eotaxin 2 (CCL24) in ME/CFS patients.
Our data recapitulates previous data from another USA ME/CFS cohort in which circulating levels of IL-7 were reduced. Also, a reduced level of VEGF-A was reported previously in sera of patients with Gulf War Illness as well as in cerebral spinal fluid samples from a different cohort of USA ME/CFS patients. To our knowledge, we are the first to test for levels of IL-16 in ME/CFS patients. In combination with previous data, our work suggests that the clustered reduction of IL-7, IL-16 and VEGF-A may have physiological relevance to ME/CFS disease.
This profile is ME/CFS-specific since measurement of the same analytes present in chronic infectious and autoimmune liver diseases, where persistent fatigue is also a major symptom, failed to demonstrate the same changes. Further studies of other ME/CFS and overlapping disease cohorts are warranted in future.
Copyright © 2015 Elsevier Ltd. All rights reserved.

 
fulltext- http://www.biomedcentral.com/1472-6955/14/64
Fatigue in adults with post-infectious fatigue syndrome: a qualitative content analysis
Eva Stormorken, Leonard A. Jason and Marit Kirkevold
Abstract
Background: Fatigue is a major problem among individuals with post-infectious fatigue syndrome (PIFS), also known as chronic fatigue syndrome or myalgic encephalomyelitis. It is a complex phenomenon that varies across illnesses. From a nursing perspective, knowledge and understanding of fatigue in this illness is limited. Nurses lack confidence in caring for these patients and devalue their professional role. The aim of this study was to explore in-depth the experiences of fatigue among individuals with PIFS. A detailed description of the phenomenon of fatigue is presented. Increased knowledge would likely contribute to more confident nurses and improved nursing care.
Methods: A qualitative study with open interviews was employed.
In-depth interviews with patients were fully transcribed and underwent a qualitative content analysis. A maximum variation sample of 26 affected adults between 26–59 years old was recruited from a population diagnosed at a fatigue outpatient clinic.
Results: The fatigue was a post-exertional, multidimensional, fluctuating phenomenon with varying degrees of severity and several distinct characteristics and was accompanied by concomitant symptoms.
Fatigue was perceived to be an all-pervasive complex experience that substantially reduced the ability to function personally or professionally. A range of trigger mechanisms evoked or worsened the fatigue, but the affected were not always aware of what triggered it. 
There was an excessive increase in fatigue in response to even minor activities. An increase in fatigue resulted in the exacerbation of other concomitant symptoms. The term fatigue does not capture the participants’ experiences, which are accompanied by a considerable symptom burden that contributes to the illness experience and the severe disability.
Conclusions: Although some aspects of the fatigue experience have been reported previously, more were added in our study, such as the dimension of awakening fatigue and the characteristic beyond time, when time passes unnoticed. We also identified trigger mechanisms such as emotional, neurological, social, financial, and pressure on oneself or from others. This in-depth exploration of fatigue in PIFS provides an overview of the dimensions, characteristics, and trigger mechanisms of fatigue, thus making better clinical observations, early recognition, improved communication with patients and more appropriate nursing interventions possible.

 
http://www.ncbi.nlm.nih.gov/pubmed/26613325
Rev Environ Health. 2015 Dec 1;30(4):223-249. doi: 10.1515/reveh-2015-0026.
Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians.
Bested AC, Marshall LM.
Abstract
This review was written from the viewpoint of the treating clinician to educate health care professionals and the public about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). It includes: the clinical definition of ME/CFS with emphasis on how to diagnose ME/CFS; the etiology, pathophysiology, management approach, long-term prognosis and economic cost of ME/CFS.After reading this review, you will be better able to diagnose and treat your patients with ME/CFS using the tools and information provided. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic medical condition characterized by symptom clusters that include: pathological fatigue and malaise that is worse after exertion, cognitive dysfunction, immune dysfunction, unrefreshing sleep, pain, autonomic dysfunction, neuroendocrine and immune symptoms.
ME/CFS is common, often severely disabling and costly. The Institute of Medicine (IOM) reviewed the ME/CFS literature and estimates that between 836,000 and 2.5 million Americans have ME/CFS at a cost of between 17 and 24 billion dollars annually in the US. The IOM suggested a new name for ME/CFS and called it Systemic Exertion Intolerance Disease (SEID). SEID's diagnostic criteria are less specific and do not exclude psychiatric disorders in the criteria.
The 2010 Canadian Community Health Survey discovered that 29% of patients with ME/CFS had unmet health care needs and 20% had food insecurity - lack of access to sufficient healthy foods. ME/CFS can be severely disabling and cause patients to be bedridden.
Yet most patients (80%) struggle to get a diagnosis because doctors have not been taught how to diagnose or treat ME/CFS in medical schools or in their post-graduate educational training. Consequently, the patients with ME/CFS suffer. They are not diagnosed with ME/CFS and are not treated accordingly. Instead of compassionate care from their doctors, they are often ridiculed by the very people from whom they seek help.
The precise etiology of ME/CFS remains unknown, but recent advances and research discoveries are beginning to shed light on the enigma of this disease including the following contributors: infectious, genetic, immune, cognitive including sleep, metabolic and biochemical abnormalities. Management of patients with ME/CFS is supportive symptomatic treatment with a patient centered care approach that begins with the symptoms that are most troublesome for the patient.
Pacing of activities with strategic rest periods is, in our opinion, the most important coping strategy patients can learn to better manage their illness and stop their post-exertional fatigue and malaise. 
Pacing allows patients to regain the ability to plan activities and begin to make slow incremental improvements in functionality.
PMID: 26613325 [PubMed - as supplied by publisher]

 
SLEEP MEDICINE
December 2015Volume 24, Pages 1–12
Herbal medicine for insomnia: A systematic review and meta-analysis
Matthew J. Leach
Amy T. Page
Affiliations

• Western Australian Centre for Rural Health, University of Western Australia, Australia

DOI: http://dx.doi.org/10.1016/j.smrv.2014.12.003
Publication History
Published Online: December 17, 2014Accepted: December 9, 2014; Received in revised form: December 9, 2014; Received: April 6, 2014;
.Summary
Insomnia is a prevalent sleep disorder that can profoundly impact a person's health and wellbeing. Herbal medicine represents one of the most frequently used complementary and alternative treatments of insomnia. However, the safety and efficacy of herbal medicine for the treatment of this disorder is currently uncertain. In order to ascertain the evidence base for herbal medicine for insomnia, we systematically searched seventeen electronic databases and the reference lists of included studies for relevant randomised controlled trials (RCTs). Fourteen RCTs, involving a total of 1602 participants with insomnia, met the inclusion criteria. Four distinct orally administered herbal monopreparations were identified (i.e., valerian, chamomile, kava and wuling). There was no statistically significant difference between any herbal medicine and placebo, or any herbal medicine and active control, for any of the thirteen measures of clinical efficacy. As for safety, a similar or smaller number of adverse events per person were reported with kava, chamomile and wuling when compared with placebo. By contrast, a greater number of events per person were reported with valerian. While there is insufficient evidence to support the use of herbal medicine for insomnia, there is a clear need for further research in this area.
Keywords:
Chamomile, Complementary and alternative medicine, Herbal medicine, Insomnia, Sleep disorders, Kava, Systematic review, Valerian, Wuling

 
Journal of Clin Pathol doi:10.1136/jclinpath-2015-203455
The role of parvovirus B19 in the pathogenesis of autoimmunity and autoimmune disease

1. Jonathan R Kerr

1. Correspondence to Professor Jonathan R Kerr, Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Quinta de Mutis, Bogotá 111221, Colombia; jonathan@ssl-mail.com

• Received 13 October 2015
• Accepted 6 November 2015
• Published Online First 7 December 2015

Abstract
Human parvovirus B19 is a single-stranded DNA virus which preferentially targets the erythroblasts in the bone marrow. B19 infection commonly causes erythema infectiosum, arthralgia, fetal death, transient aplastic crisis in patients with shortened red cell survival, and persistent infection in people who are immunocompromised. Less common clinical manifestations include atypical skin rashes, neurological syndromes, cardiac syndromes, and various cytopenias. B19 infection has also been associated with development of a variety of different autoimmune diseases, including rheumatological, neurological, neuromuscular, cardiovascular, haematological, nephrological and metabolic. Production of a variety of autoantibodies has been demonstrated to occur during B19 infection and these have been shown to be key to the pathogenesis of the particular disease process in a significant number of cases, for example, production of rheumatoid factor in cases of B19-associated rheumatoid arthritis and production of anti-glutamic acid decarboxylase (GAD) in patients with B19-associated type 1 diabetes mellitus. B19 infection has also been associated with the development of multiple autoimmune diseases in 12 individuals. Documented mechanisms in B19-associated autoimmunity include molecular mimicry (IgG antibody to B19 proteins has been shown to cross react with a variety of recognised human autoantigens, including collagen II, keratin, angiotensin II type 1 receptor, myelin basic protein, cardiolipin, and platelet membrane glycoprotein IIb/IIIa), B19-induced apoptosis with presentation of self-antigens to T lymphocytes, and the phospholipase activity of the B19 unique VP1 protein.

 
Current Neuropharmacology, 2015, 13, 701-734 701
Myalgic Encephalomyelitis: Symptoms and Biomarkers
Leonard A. Jasona,*, Marcie L. Zinn1 and Mark A. Zinn2
Department of Psychology, Center for Community Research, DePaul University, Chicago, Illinois,
United States
 
Abstract: Myalgic Encephalomyelitis (ME) continues to cause significant morbidity worldwide with
an estimated one million cases in the United States. Hurdles to establishing consensus to achieve
accurate evaluation of patients with ME continue, fueled by poor agreement about case definitions,
slow progress in development of standardized diagnostic approaches, and issues surrounding research
priorities. Because there are other medical problems, such as early MS and Parkinson’s Disease,
which have some similar clinical presentations, it is critical to accurately diagnose ME to make a
differential diagnosis. In this article, we explore and summarize advances in the physiological and
neurological approaches to understanding, diagnosing, and treating ME. We identify key areas and approaches to
elucidate the core and secondary symptom clusters in ME so as to provide some practical suggestions in evaluation of ME
for clinicians and researchers. This review, therefore, represents a synthesis of key discussions in the literature, and has
important implications for a better understanding of ME, its biological markers, and diagnostic criteria. There is a clear
need for more longitudinal studies in this area with larger data sets, which correct for multiple testing.

 
Vaccine
Volume 33, Issue 46, 17 November 2015, Pages 6173–6177
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine

• Per Magnusa, , , Nina Gunnesa, Kari Tveitob, Inger Johanne Bakkena, Sara Ghaderia, Camilla Stoltenberga, Mady Hornigc, W. Ian Lipkinc, Lill Trogstada, Siri E. Håberga

• a Norwegian Institute of Public Health, 4404 Nydalen, 0403 Oslo, Norway
• b Journal of the Norwegian Medical Association, Oslo, Norway
• c Center for Infection and Immunity, Columbia University, NY, NY, USA

Received 10 June 2015, Revised 22 September 2015, Accepted 6 October 2015, Available online 17 October 2015

Abstract
Background
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated to infections and it has been suggested that vaccination can trigger the disease. However, little is known about the specific association between clinically manifest influenza/influenza vaccine and CFS/ME. As part of a registry surveillance of adverse effects after mass vaccination in Norway during the 2009 influenza A (H1N1) pandemic, we had the opportunity to estimate and contrast the risk of CFS/ME after infection and vaccination.
Methods
Using the unique personal identification number assigned to everybody who is registered as resident in Norway, we followed the complete Norwegian population as of October 1, 2009, through national registries of vaccination, communicable diseases, primary health, and specialist health care until December 31, 2012. Hazard ratios (HRs) of CFS/ME, as diagnosed in the specialist health care services (diagnostic code G93.3 in the International Classification of Diseases, Version 10), after influenza infection and/or vaccination were estimated using Cox proportional-hazards regression.
Results
The incidence rate of CFS/ME was 2.08 per 100,000 person-months at risk. The adjusted HR of CFS/ME after pandemic vaccination was 0.97 (95% confidence interval [CI]: 0.91–1.04), while it was 2.04 (95% CI: 1.78–2.33) after being diagnosed with influenza infection during the peak pandemic period.
Conclusions
Pandemic influenza A (H1N1) infection was associated with a more than two-fold increased risk of CFS/ME. We found no indication of increased risk of CFS/ME after vaccination. Our findings are consistent with a model whereby symptomatic infection, rather than antigenic stimulation may trigger CFS/ME.
Corresponding author. Tel.: +47 92683119.
Copyright © 2015 Elsevier Ltd. All rights reserved.

 
Reuters Health Information
Ticks Carrying Lyme Disease in Almost Half of U.S. CountiesBy Lisa Rapaport
| January 19, 2016
 
 (Reuters Health) - Ticks that can spread Lyme disease now live in almost half of U.S. counties, according to a new study from the Centers for Disease Control and Prevention.
Varieties of the blacklegged tick that may carry Borrelia burgdorferi responsible for Lyme disease are present in 45% of counties nationwide, compared with just 30% in 1998, researchers found.
"It's important for people to be aware that there may be ticks in areas where they haven't seen them previously so that they can take steps to help protect themselves and their families," lead study author Rebecca Eisen, a research biologist at the CDC, said by email.
Since the late 1990s, the number of reported Lyme disease cases in the U.S. has more than tripled, Eisen and colleagues report online January 18 in the Journal of Medical Entomology.
Lyme disease is spread by the blacklegged tick, Ixodes scapularis, also known as deer ticks, and the western blacklegged tick, Ixodes pacificus. These ticks are typically found in wooded and grassy areas.
Common symptoms of Lyme disease can include fever, headache, and fatigue, all of which can be easily confused with the flu. Some patients, but not all, develop a characteristic bull's eye rash soon after the tick bite.
If caught early, Lyme disease can be treated with antibiotics. But untreated Lyme disease can lead to lasting cognitive problems, joint and muscle pain and mood disorders.
To assess changes in the tick population, researchers analyzed data reported by counties using the same surveillance methods from 1998.
They found deer ticks in 1,420 out of 3,110 counties in the continental U.S., or about 46% of counties, and found western blacklegged ticks in 111 counties, or about 4%. Combined, this is a 45% increase from 1998 when ticks were reported in 1,058 counties.
Deer ticks are now established in 842 counties across 35 states, compared with 396 counties in 32 states in 1998. These ticks used to be concentrated in northeastern states but have moved west and south.
Western blacklegged ticks are now established in 95 counties across six states, up from 90 counties in 1998. These ticks remain concentrated in Pacific coast states.
Outside of the U.S., ticks carry the disease in forested areas of Asia, northwestern, central and eastern Europe, according to the World Health Organization.
Even though the tick population is spreading, the risk of catching Lyme disease isn't the same everywhere the ticks live, because the number of ticks infected with Lyme bacteria varies, as do the odds that infected ticks may bite people, Eisen noted.
To minimize the risk of catching Lyme disease from ticks, people can spray skin and clothing with insect repellants such as DEET or lemon permethrin, said Dr. Keith Berndtson of the Center for Research on Biotoxin Associated Illness in Pocomoke, Maryland. Long sleeves and pants legs tucked into socks can also keep ticks away, and light-colored fabrics can make the ticks easier to spot.
After a day outdoors, tossing all clothes in the dryer for about 20 minutes can kill most ticks. People should also have a friend or family member check their body for ticks, and check any pets. Saving ticks for testing can also help assess whether the bugs carried bacteria that can lead to Lyme disease, Berndtson, who wasn't involve in the study, added by email.
Environmental and climate changes may be helping ticks to expand their territory in the U.S., noted Dr. Bobbi Pritt, director of clinical parasitology at the Mayo Clinic in Rochester, Minnesota.
"Warmer temperatures, increases in rainfall, and milder winters can favor tick survival," Pritt, who wasn't involved in the study, said by email. "These factors can also favor survival and expansion of the mammals and birds that the ticks feed on."
SOURCE: http://bit.ly/1OslYEC
J Med Entomol 2016.

fulltext- http://downloads.hindawi.com/journals/jar/aip/328971.pdf
Understanding muscle dysfunction in Chronic Fatigue Syndrome
Gina Rutherford1 MSc, Philip Manning1 PhD, Julia L Newton MD, PhD 1,2
1Institute of cellular medicine, Newcastle University, Newcastle UK.
2 Newcastle hospitals NHS foundation trust, UK NIHR biomedical research centre in ageing and age related disease, Newcastle University, Newcastle UK
Abstract
Introduction: Chronic fatigue syndrome/ Myalgic Encephalomyelitis (CFS/ME) is a debilitating disorder of unknown aetiology and is characterised by severe disabling fatigue in the absence of an alternative diagnosis.
Historically, there has been a tendency to draw psychological explanations for the origin of fatigue, however this model is at odds with findings that fatigue and accompanying symptoms may be explained by central and peripheral pathophysiological mechanisms, including effects of the immune, oxidative, mitochondrial and neuronal pathways.
For example, patient descriptions of their fatigue regularly cite difficulty in maintaining muscle activity due to perceived lack of energy. This narrative review examines the literature for evidence of biochemical dysfunction in CFS/ME at the skeletal muscle level.
Methods: This narrative review examines literature following searches of PUB MED, MEDLINE and Google scholar, using key words such as (e.g.
CFS,ME, Immune, autoimmune, mitochondria, muscle, acidosis).
Results: Studies show evidence for skeletal muscle bio-chemical abnormality in CFS/ME patients. Following a low-level repeat exercise protocol CFS/ME patients exhibited a significantly greater muscular acidosis in addition to a slowed time to recovery from acidosis. There is also evidence for impaired AMPK activation following electrical pulse stimulation in CFS/ME patient myotube samples.
Discussion: Bio-energetic peripheral muscle dysfunction is evident in CFS/ME, with a tendency towards an over-utilisation of the lactate dehydrogenase pathway during low-level exercise, in addition to delayed acid clearance post-exercise. AMPK activation is impaired in CFS/ME myotube samples following electrical pulse stimulation.
Potentially, these bio-chemical abnormalities may lead to the perception of severe muscular fatigue in CFS/ME

 
http://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1124520?jo...
Case definitions integrating empiric and consensus perspectives for myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS)
Leonard A. Jason, Stephanie McManimen, Madison Sunnquist, Abigail Brown, Jacob Furst, Julia L. Newton & Elin Bolle Strand
Abstract
Background: There has been considerable controversy regarding how to name and define the illnesses known as myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS).
The Institute of Medicine (IOM) report has proposed new clinical criteria and a new name for this illness, but aspects of these recommendations have been scrutinized by patients and scientists.
Purpose: It is possible that both empiric and consensus approaches could be used to help settle some of these diagnostic challenges.
Using patient samples collected in the USA, Great Britain, and Norway (N = 556), the current study attempted to categorize patients using more general as well as more restricted case definitions.
Results: Overall, the outcomes suggest that there might be four groupings of patients, with the broadest category involving those with chronic fatigue (N = 62), defined by six or more months of fatigue which cannot be explained by medical or psychiatric conditions.
A second category involves those patients who have chronic fatigue that can be explained by a medical or psychiatric condition (N = 47). A third category involves more specific criteria that have been posited both by the IOM report, Canadian Clinical Case criteria, ME-ICC criteria and a more empiric approach.
These efforts have specified domains of substantial reductions of activity, post-exertional malaise, neurocognitive impairment, and sleep dysfunction (N = 346). Patients with these characteristics were more functionally impaired than those meeting just chronic fatigue criteria, p  < .05.
Finally, those meeting even more restrictive ME criteria proposed by Ramsay, identified a smaller and even more impaired group, p < .05.
Conclusion: It is important that scientists world-wide develop consensus on how to identify and classify patients using clinical and research criteria, and ultimately develop subtypes within such categories.

 
http://jpet.aspetjournals.org/content/early/2016/01/13/jpet.115.230...
Substance P, Hemokinin-1, CRH, TNF and IL-6 are increased in serum of patients with Fibromyalgia Syndrome and may serve both as biomarkers and targets for treatment
Irene Tsilioni, Irwin J Russell, Julia M Stewart, Rae M Gleason, and Theoharis C Theoharides
1 Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiol;
2 Fibromyalgia Research and Consulting, Arthritis and Osteoporosis Center of South Texas, San Antonio,;
3 National Fibromyalgia and Chronic Pain Association, Logan, UT, USA
Abstract
Fibromyalgia Syndrome (FMS) is a chronic, idiopathic condition of widespread musculoskeletal pain, affecting more women than men. Even though clinical and laboratory studies have provided evidence of altered central pain pathways, the lack of definitive pathogenesis or objective diagnostic markers has hampered development of effective treatments.
Here we report for the first time that the neuropeptides corticotropin-releasing hormone (CRH), substance P (SP) and its structurally related Hemokinin-1 (HK-1) were significantly (p=0.026, p<0.0001 and p=0.002, respectively) elevated (0.82±0.57 ng/mL, 0.39±0.18 ng/mL and 7.98±3.12 ng/mL, respectively) in the serum of patients with FMS as compared to healthy controls (0.49±0.26 ng/mL, 0.12±0.1 ng/mL and 5.71±1.08 ng/mL, respectively).
Moreover, SP and HK-1 levels were positively correlated (Pearson’s r=0.45, p=0.002).
The serum concentrations of the inflammatory cytokines IL-6 and TNF were also significantly (p=0.029 and p=0.006, respectively) higher (2.97±2.35 pg/mL and 0.92±0.31 pg/mL, respectively) in the FMS group as compared to healthy subjects (1.79±0.62 pg/mL and 0.69±0.16 pg/mL, respectively).
In contrast, serum IL-31 and IL-33 levels were significantly lower (p=0.0001 and p=0.044, respectively) in the FMS patients (849.5±1005 pg/mL and 923.2±1284 pg/mL, respectively) in comparison to healthy controls (1281±806.4 pg/mL and 3149±4073 pg/mL, respectively).
Our results indicate that neuro-inflammation may contribute to the symptoms of FMS patients, especially since we had previously shown that CRH and SP are known to stimulate IL-6 and TNF release from mast cells. Treatment directed at preventing the secretion on antagonizing these elevated neuroimmune markers may be useful in the management of FMS patients.
The American Society for Pharmacology and Experimental Therapeutics

 
http://www.ncbi.nlm.nih.gov/pubmed/26745400
J Rehabil Res Dev. 2015;52(7):805-814. doi: 10.1682/JRRD.2014.11.0293.
Reduced gait automaticity in female patients with chronic fatigue syndrome: Case-control study.
Eyskens JB1, Nijs J, Wouters K, Moorkens G.
Abstract
Patients with chronic fatigue syndrome (CFS) report difficulties walking for a prolonged period of time. This study compares gait automaticity between women with CFS and nondisabled controls.
The "stops walking with eyes closed with secondary cognitive task" test is based on the classic "stops walking while talking" test but compares walking with eyes closed while performing a secondary cognitive task in a female CFS population (n = 34) and in female nondisabled controls (n = 38).
When initiating gate, 23.5% of patients with CFS looked toward the ground compared with only 2.6% of nondisabled controls.
After 7 m, subjects were asked to close their eyes, and after another 7 m, they were asked, "How much is 100 minus 7?" Of the patients with CFS, 55.9% stopped walking compared with 5.3% of nondisabled controls.
Less automated walking was observed in patients with CFS than in nondisabled controls (p < 0.001). The test-retest reliability is moderate for global stopping.
This simple test observed reduced gait automaticity in patients with CFS for the first time. Dual tasking could be helpful to address the functional limitations found in this particular study.

 
http://www.ncbi.nlm.nih.gov/pubmed/26717948
Neuroimaging of Central Sensitivity Syndromes: Key Insights from the Scientific Literature.
Walitt B1, Ceko M, Gracely J, Gracely RH.
Abstract
Central sensitivity syndromes are characterized by distressing symptoms, such as pain and fatigue, in the absence of clinically obvious pathology. The scientific underpinnings of these disorders are not currently known. Modern neuroimaging techniques promise new insights into mechanisms mediating these postulated syndromes.
We review the results of neuroimaging applied to five central sensitivity syndromes: fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, temporomandibular joint disorder, and vulvodynia syndrome. Neuroimaging studies of basal metabolism, anatomic constitution, molecular constituents, evoked neural activity, and treatment effect are compared across all of these syndromes.
Evoked sensory paradigms reveal sensory augmentation to both painful and non-painful stimulation. This is a transformative observation for these syndromes, which were historically considered to be completely of hysterical or feigned in origin.
However, whether sensory augmentation represents the cause of these syndromes, a predisposing factor, an endophenotype, or an epiphenomenon cannot be discerned from the current literature.
Further, the result from cross-sectional neuroimaging studies of basal activity, anatomy, and molecular constituency are extremely heterogeneous within and between the syndromes.
A defining neuroimaging "signature" cannot be discerned for any of the particular syndromes or for an over-arching central sensitization mechanism common to all of the syndromes. Several issues confound initial attempts to meaningfully measure treatment effects in these syndromes.
At this time, the existence of "central sensitivity syndromes" is based more soundly on clinical and epidemiological evidence. A coherent picture of a "central sensitization" mechanism that bridges across all of these syndromes does not emerge from the existing scientific evidence.
PMID:26717948 [PubMed - as supplied by publisher]

 
fulltext- http://journals.plos.org/plosone/article?id=10.1371/journal.pone.01...
PLoS One. 2015 Dec 22;10(12):e0143970. doi:
10.1371/journal.pone.0143970. eCollection 2015.
A Transcriptional Signature of Fatigue Derived from Patients with Primary Sjögren's Syndrome.
James K, Al-Ali S, Tarn J, Cockell SJ, Gillespie CS, Hindmarsh V, Locke J, Mitchell S, Lendrem D, Bowman S, Price E, Pease CT, Emery P, Lanyon P, Hunter JA, Gupta M, Bombardieri M, Sutcliffe N, Pitzalis C, McLaren J, Cooper A, Regan M, Giles I, Isenberg D, Saravanan V, Coady D, Dasgupta B, McHugh N, Young-Min S, Moots R, Gendi N, Akil M, Griffiths B; UK Primary Sjögren’s Syndrome registry, Wipat A, Newton J, Jones DE, Isaacs J, Hallinan J, Ng WF.
Abstract
BACKGROUND: Fatigue is a debilitating condition with a significant impact on patients' quality of life. Fatigue is frequently reported by patients suffering from primary Sjögren's Syndrome (pSS), a chronic autoimmune condition characterised by dryness of the eyes and the mouth. However, although fatigue is common in pSS, it does not manifest in all sufferers, providing an excellent model with which to explore the potential underpinning biological mechanisms.
METHODS: Whole blood samples from 133 fully-phenotyped pSS patients stratified for the presence of fatigue, collected by the UK primary Sjögren's Syndrome Registry, were used for whole genome microarray.
The resulting data were analysed both on a gene by gene basis and using pre-defined groups of genes. Finally, gene set enrichment analysis (GSEA) was used as a feature selection technique for input into a support vector machine (SVM) classifier. Classification was assessed using area under curve (AUC) of receiver operator characteristic and standard error of Wilcoxon statistic, SE(W).
RESULTS: Although no genes were individually found to be associated with fatigue, 19 metabolic pathways were enriched in the high fatigue patient group using GSEA. Analysis revealed that these enrichments arose from the presence of a subset of 55 genes. A radial kernel SVM classifier with this subset of genes as input displayed significantly improved performance over classifiers using all pathway genes as input. The classifiers had AUCs of 0.866 (SE(W) 0.002) and 0.525
(SE(W) 0.006), respectively.
CONCLUSIONS: Systematic analysis of gene expression data from pSS patients discordant for fatigue identified 55 genes which are predictive of fatigue level using SVM classification. This list represents the first step in understanding the underlying pathophysiological mechanisms of fatigue in patients with pSS.

 
http://www.sciencedirect.com/science/article/pii/S0730725X15003033
Abnormal resting state functional connectivity in patients with chronic fatigue syndrome: An arterial spin-labeling fMRI study
Jeff Boissoneault, Janelle Letzen, Song Lai, Andrew O'Shea, Jason Craggs, Mike Robinson, Roland Staud
Abstract
Background: Myalgic encephalomyelitis/chronic fatigue syndrome
(ME/CFS) is a debilitating disorder characterized by severe fatigue and neurocognitive dysfunction. Recent work from our laboratory and others utilizing arterial spin labeling functional magnetic resonance imaging (ASL) indicated that ME/CFS patients have lower resting state regional cerebral blood flow (rCBF) in several brain areas associated with memory, cognitive, affective, and motor function. This hypoperfusion may underlie ME/CFS pathogenesis and may result in alterations of functional relationships between brain regions. The current report used ASL to compare functional connectivity of regions implicated in ME/CFS between patients and healthy controls (HC).
Methods: Participants were 17 ME/CFS patients (Mage = 48.88 years, SD = 12) fulfilling the 1994 CDC criteria and 17 age/sex matched HC (Mage = 49.82 years, SD = 11.32). All participants underwent T1-weighted structural MRI as well as a 6-min pseudo-continuous arterial spin labeling (pCASL) sequence, which quantifies CBF by magnetically labeling blood as it enters the brain. Imaging data were preprocessed using SPM 12 and ASL tbx, and seed-to-voxel functional connectivity analysis was conducted using the CONN toolbox. All effects noted below are significant at p < 0.05 with cluster-wise FDR correction for multiple comparisons.
Results: ME/CFS patients demonstrated greater functional connectivity relative to HC in bilateral superior frontal gyrus, ACC, precuneus, and right angular gyrus to regions including precuneus, right postcentral gyrus, supplementary motor area, posterior cingulate gyrus, and thalamus. In contrast, HC patients had greater functional connectivity than ME/CFS in ACC, left parahippocampal gyrus, and bilateral pallidum to regions including right insula, right precentral gyrus, and hippocampus. Connectivity of the left parahippocampal gyrus correlated strongly with overall clinical fatigue of ME/CFS patients.
Conclusion: This is the first ASL based connectivity analysis of patients with ME/CFS. Our results demonstrate altered functional connectivity of several regions associated with cognitive, affective, memory, and higher cognitive function in ME/CFS patients. Connectivity to memory related brain areas (para-hippocampal gyrus) was correlated with clinical fatigue ratings, providing supporting evidence that brain network abnormalities may contribute to ME/CFS pathogenesis.

 
http://onlinelibrary.wiley.com/doi/10.1111/nmo.12741/abstract
Genome-wide DNA methylation profiling of peripheral blood mononuclear cells in irritable bowel syndrome
S. Mahurkar, C. Polytarchou, D. Iliopoulos, C. Pothoulakis, E.A. Mayer and L. Chang
Abstract
Background: Irritable bowel syndrome (IBS) is a stress-sensitive disorder. Environmental factors including stress can trigger epigenetic changes, which have not been well-studied in IBS. We performed a pilot study investigating genome-wide DNA methylation of IBS patients and healthy controls (HCs) to identify potential epigenetic markers and associated pathways. Additionally, we investigated relationships of epigenetic changes in selected genes with clinical traits.
Methods: Twenty-seven IBS patients (59% women; 10 IBS-diarrhea, 8 IBS-constipation, 9 IBS-mixed) and 23 age- and sex-matched HCs were examined. DNA methylation from peripheral blood mononuclear cells
(PBMCs) was measured using HM450 BeadChip, and representative methylation differences were confirmed by bisulphite sequencing. Gene expression was measured using quantitative PCR. Gastrointestinal (GI) and non-GI symptoms were measured using validated questionnaires.
Associations were tested using non-parametric methods.
Key Results: Genome-wide DNA methylation profiling of IBS patients compared with HCs identified 133 differentially methylated positions
(DMPs) (mean difference ≥10%; p < 0.05). These genes were associated with gene ontology terms including glutathione metabolism related to oxidative stress and neuropeptide hormone activity. Validation by sequencing confirmed differential methylation of subcommissural organ (SCO)-Spondin (SSPO), glutathione-S-transferases mu 5 (GSTM5), and tubulin polymerization promoting protein genes. Methylation of two promoter CpGs in GSTM5 was associated with epigenetic silencing.
Epigenetic changes in SSPO gene were positively correlated with hospital anxiety and depression scores in IBS patients (r > 0.4 and false discovery rate <0.05).
Conclusions & Inferences: This study is the first to comprehensively explore the methylome of IBS patients. We identified DMPs in novel candidate genes which could provide new insights into disease mechanisms; however, these preliminary findings warrant confirmation in larger, independent studies.

 
http://solvecfs.org/wp-content/uploads/2015/12/Chronicle_Winter2015...
The SolveCFSChronical, Winter 2015
Breaking News:  The $5.4 million in Centers for Disease Control funding for ME/CFS has been restored in its entirety! This is a huge win for the entire ME/CFS community and one that has taken many months of dedicated effort to achieve. 
Had the funding not been restored, the CDC’s multi-year multi-site study on ME/CFS would not have been completed. Given the state of the budget discussions, this was a very real possibility that fortunately did not come to pass. 

Additionally, a potentially very significant development has occurred with the National Institutes of Health, which received a $2 billion increase in funding in the new budget. The entire budget package will be formally voted on by Congress this Friday and is expected to pass. This additional NIH funding bodes well for ME/CFS, given that we have heard from our contacts in the past that they are unable to take research funds already dedicated to diseases and reappropriate them to ME/CFS. This substantial additional funding opens a wealth of possibilities for funding our disease. 
Significant Breakthrough for ME/CFS at the NIH
On Oct. 29, the National Institutes of Health announced that it is taking several major steps to advance research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. NIH is launching a research project at the NIH Clinical Center to intensely study individuals with ME/CFS and will also be funding external research on the disease to a degree that will be “substantially greater” than our disease has received in the past, according to NIH Director Dr. Francis S. Collins.
Additionally, NIH announced that the leadership role for ME/CFS research, which was assigned to the Office of Research on Women’s Health, has now been assigned to the National Institute of Neurological Disorders and Stroke (NINDS). NINDS will lead a multi-institute ME/CFS research effort and a re-invigorated Trans-NIH ME/CFS Research Working Group. This move marks a very positive elevation of the status of our disease within NIH. NINDS Director Dr.
Walter Koroshetz will chair the Working Group, along with Vicky Holets Whittemore, PhD, the NIH representative to the U.S. Department of Health and Human Services’ Chronic Fatigue Syndrome Advisory Committee (CFSAC), on which Solve ME/CFS Initiative President Carol Head serves.

 
fulltext- http://journals.plos.org/plosone/article?id=10.1371/journal.pone.01...
Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Sanjay K. Shukla, Dane Cook, Jacob Meyer, Suzanne D. Vernon, Thao Le, Derek Clevidence, Charles E. Robertson, Steven J. Schrodi, Steven Yale, Daniel N. Frank
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by intense and debilitating fatigue not due to physical activity that has persisted for at least 6 months, post-exertional malaise, unrefreshing sleep, and accompanied by a number of secondary symptoms, including sore throat, memory and concentration impairment, headache, and muscle/joint pain.
In patients with post-exertional malaise, significant worsening of symptoms occurs following physical exertion and exercise challenge serves as a useful method for identifying biomarkers for exertion intolerance.
Evidence suggests that intestinal dysbiosis and systemic responses to gut microorganisms may play a role in the symptomology of ME/CFS. As such, we hypothesized that post-exertion worsening of ME/CFS symptoms could be due to increased bacterial translocation from the intestine into the systemic circulation.
To test this hypothesis, we collected symptom reports and blood and stool samples from ten clinically characterized ME/CFS patients and ten matched healthy controls before and 15 minutes, 48 hours, and 72 hours after a maximal exercise challenge. Microbiomes of blood and stool samples were examined.Stool sample microbiomes differed between ME/CFS patients and healthy controls in the abundance of several major bacterial phyla.
Following maximal exercise challenge, there was an increase in relative abundance of 6 of the 9 major bacterial phyla/genera in ME/CFS patients from baseline to 72 hours post-exercise compared to only 2 of the 9 phyla/genera in controls (p = 0.005).
There was also a significant difference in clearance of specific bacterial phyla from blood following exercise with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls.
These results provide evidence for a systemic effect of an altered gut microbiome in ME/CFS patients compared to controls. Upon exercise challenge, there were significant changes in the abundance of major bacterial phyla in the gut in ME/CFS patients not observed in healthy controls. In addition, compared to controls clearance of bacteria from the blood was delayed in ME/CFS patients following exercise.
These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients that may account for the profound post-exertional malaise experienced by ME/CFS patients.

 
http://onlinelibrary.wiley.com/doi/10.1111/cei.12749/abstract
Clin Exp Immunol. 2015 Dec 8. doi: 10.1111/cei.12749. [Epub ahead of print]
Extended B-cell phenotype in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A cross-sectional study.
Mensah F, Bansal A, Berkovitz S, Sharma A, Reddy V, Leandro MJ, Cambridge G.
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a heterogeneous condition of unknown etiology characterized by multiple symptoms including fatigue, post-exertional malaise and cognitive impairment, lasting for at least 6 months.
Recently, two clinical trials of B-cell depletion therapy with rituximab (anti-CD20) reported convincing improvement in symptoms. A possible but undefined role for B-cells has therefore been proposed. Studies of the relative percentages of B-cell subsets in patients with ME/CFS have not revealed any reproducible differences from healthy controls (HC).
In order to explore whether more subtle alterations in B-cell subsets related to B-cell differentiation exist in ME/CFS patients we used flow cytometry to immunophenotype CD19+ B-cells. The panel utilized IgD, CD27 and CD38 (classical B-cell subsets) together with additional markers.
A total of 38 patients fulfilling Canadian, Centre for Disease Control, and Fukuda ME/CFS criteria and 32 age/sex-matched HC were included.
We found no difference in percentages of classical subsets between ME/CFS patients and HC. However, we observed an increase in frequency (p<0.01) and expression (MFI; p=0.03) of CD24 on total B-cells, confined to IgD+ subsets.
Within memory subsets, a higher frequency of CD21+ CD38- B-cells (>20%) was associated with the presence of ME/CFS (Odds ratio: 3.47 (1.15-10.46); p=0.03) compared with HC and there was a negative correlation with disease duration.
In conclusion, we identified possible changes in B-cell phenotype in patients with ME/CFS. These may reflect altered B-cell function and if confirmed in other patient cohorts, could provide a platform for studies based on clinical course or responsiveness to rituximab-therapy.
This article is protected by copyright. All rights reserved. © 2015 British Society for Immunology.

 
fulltext: http://www.jneuro.com/neurology-neuroscience/evaluation-of-antivira...
Evaluation of Antiviral Antibodies against Epstein-Barr Virus and Neurotransmitters in Patients with Fibromyalgia
Reshkova V, Kalinova D and Milanov I
Abstract
Fibromyalgia (FM) is characterized by chronic widespread pain lasting for a minimum of three months, and pain at mechanical pressure in at least 11 of the 18 tender points. The cause of fibromyalgia is unknown. Several hypotheses have been developed including "central sensitization".
This theory proposes that fibromyalgia patients have a lower threshold for pain because of increased reactivity of painsensitive neurons in the spinal cord or brain. Some researchers supposed that different neurotransmitters (serotonin, catecholamine) could be involved in the pathophysiology of fibromyalgia-associated symptoms.
The connection of FM to different viral infections has been proposed. Epstein Barr Virus (EBV) has been considered a possible cause of FM because of similarity of symptoms, but so far, the connection has not been proven.
The objective of this study was to determine the prevalence of antibodies (Abs) IgM and IgG against EBV, and respectively the presence of a viral infection in a group of patients with FM. We also analysed the association between the titter of the antiviral antibodies, some neurotransmitters (serotonin, noradrenaline and adrenaline) and different clinical symptoms.
The obtained results revealed that high EBV IgG concentrations in the serum of patients with FM correlated with pain intensity and associated clinical symptoms. This is consistent with the fact that FM is connected to the immune response to certain infectious agents (e.g. EBV, CMV).

 
Mol Neurobiol
DOI 10.1007/s12035-015-9262-7
The Putative Role of Viruses, Bacteria, and Chronic Fungal
Biotoxin Exposure in the Genesis of Intractable Fatigue
Accompanied by Cognitive and Physical Disability
Gerwyn Morris1 & Michael Berk2,3 & Ken Walder4 & Michael Maes2,5
Received: 24 December 2014 /Accepted: 28 May 2015
# Springer Science+Business Media New York 2015
 
Abstract Patients who present with severe intractable apparently idiopathic fatigue accompanied by profound physical and or cognitive disability present a significant therapeutic challenge. The effect of psychological counseling is limited,with significant but very slight improvements in psychometric measures of fatigue and disability but no improvement on scientific measures of physical impairment compared to controls.Similarly, exercise regimes either produce significant,but practically unimportant, benefit or provoke symptom exacerbation.
 
Many such patients are afforded the exclusionary,non-specific diagnosis of chronic fatigue syndrome if rudimentary testing fails to discover the cause of their symptoms.More sophisticated investigations often reveal the presence of a range of pathogens capable of establishing life-long infections with sophisticated immune evasion strategies, including Parvoviruses, HHV6, variants of Epstein-Barr, Cytomegalovirus, Mycoplasma, and Borrelia burgdorferi. Other patients have a history of chronic fungal or other biotoxin exposure.
 
Herein, we explain the epigenetic factors that may render such individuals susceptible to the chronic pathology induced by such agents, how such agents induce pathology, and, indeed,how such pathology can persist and even amplify even when infections have cleared or when biotoxin exposure has ceased.The presence of active, reactivated, or even latent Herpes virus could be a potential source of intractable fatigue accompanied by profound physical and or cognitive disability in some patients,and the same may be true of persistent Parvovirus B12 and mycoplasma infection. A history of chronic mold exposure is a feasible explanation for such symptoms, as is the presence of B. burgdorferi. The complex tropism, life cycles,
genetic variability, and low titer of many of these pathogens makes their detection in blood a challenge. Examination of lymphoid tissue or CSF in such circumstances may be warranted.
 
Keywords Immune . Inflammation . Oxidative stress .Toll-like receptor . Cognition . Depression . Chronic fatigue syndrome . Neurology . Psychiatry

http://www.ncbi.nlm.nih.gov/pubmed/26271272
Scand J Rheumatol. 2015 Aug 14:1-8. [Epub ahead of print]
 Endogenous event-related potentials in patients with primary Sjögren's syndrome without central nervous system involvement. 
Dziadkowiak E, Sebastian A, Wiland P, Waliszewska-Prosół M, Wieczorek M, Zagrajek M, Ejma M.
Abstract
OBJECTIVES: Endogenous cognitive event-related potentials (CERPs) reflect higher-level processing of sensory information and can be used to evaluate cognitive functions. The aim of this paper was to determine whether there are any abnormalities in the electrophysiological parameters of CERPs in patients with primary Sjögren's syndrome (pSS) but without symptoms of central nervous system (CNS) involvement or mental disorder. The analysis of CERP parameters was then correlated with the clinical status of the patients and with some of the immunological parameters in the patient group.
METHOD: Thirty consecutive patients with pSS (29 females, one male) were included in the study. All the patients underwent CERP examination.
RESULTS: There was a significant prolongation of the latency of P300 and N200 potentials in patients with pSS. Abnormalities in electrophysiological parameters of CERPs correlated with the duration of the disease, salivary gland abnormalities, and elevated erythrocyte sedimentation rate (ESR) values. Patients with coexisting chronic fatigue syndrome (CFS) had larger P300 amplitudes. There were no statistically significant changes in the electrophysiological parameters of CERPs in patients with pSS dependent on the presence of peripheral nervous system (PNS) lesions, skin changes, arthritis, abnormalities in white blood cells and the immune system or the levels of blood lipids.
CONCLUSIONS: The results of the study suggest the presence of a minor cognitive dysfunction in patients with pSS without symptoms of CNS involvement or mental disorder. Cognitive dysfunction correlated with the disease duration time and the severity of inflammatory changes (salivary gland abnormalities and inflammatory markers in the blood).
Further and larger longitudinal studies are necessary for confirmation of this correlation.
PMID:26271272 [PubMed - as supplied by publisher]

 
http://www.ncbi.nlm.nih.gov/pubmed/26272057
Clin Rheumatol. 2015 Aug 15. [Epub ahead of print]
The prevalence of severe fatigue in rheumatic diseases: an international study. 
Overman CL, Kool MB, Da Silva JA, Geenen R.
Abstract
Fatigue is a common, disabling, and difficult-to-manage problem in rheumatic diseases. Prevalence estimates of fatigue within rheumatic diseases vary considerably. Data on the prevalence of severe fatigue across multiple rheumatic diseases using a similar instrument is missing. Our aim was to provide an overview of the prevalence of severe fatigue across a broad range of rheumatic diseases and to examine its association with clinical and demographic variables. 
Online questionnaires were filled out by an international sample of 6120 patients (88 % female, mean age 47) encompassing 30 different rheumatic diseases.
Fatigue was measured with the RAND(SF)-36 Vitality scale. A score of ≤35 was taken as representing severe fatigue (90 % sensitivity and 81 % specificity for chronic fatigue syndrome).
Severe fatigue was present in 41 to 57 % of patients with a single inflammatory rheumatic disease such as rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjögren's syndrome, psoriatic arthritis, and scleroderma. Severe fatigue was least prevalent in patients with osteoarthritis (35 %) and most prevalent in patients with fibromyalgia (82 %).
In logistic regression analysis, severe fatigue was associated with having fibromyalgia, having multiple rheumatic diseases without fibromyalgia, younger age, lower education, and language (French: highest prevalence; Dutch: lowest prevalence).
In conclusion, one out of every two patients with a rheumatic disease is severely fatigued. As severe fatigue is detrimental to the patient, the near environment, and society at large, unraveling the underlying mechanisms of fatigue and developing optimal treatment should be top priorities in rheumatologic research and practice.
PMID:26272057 [PubMed - as supplied by publisher]

 
http://link.springer.com/content/pdf/10.1186%2Fs12967-015-0628-4.pdf
J Transl Med. 2015 Aug 14;13(1):264. doi: 10.1186/s12967-015-0628-4.
Polymorphism in COMT is associated with IgG3 subclass level and susceptibility to infection in patients with chronic fatigue syndrome. 
Löbel M, Mooslechner AA, Bauer S, Günther S, Letsch A, Hanitsch LG, Grabowski P, Meisel C, Volk HD, Scheibenbogen C.
Abstract
BACKGROUND: Chronic fatigue syndrome (CFS) is considered as a neuroimmunological disease but the etiology and pathophysiology is poorly understood. Patients suffer from sustained exhaustion, cognitive impairment and an increased sensitivity to pain and sensory stimuli. A subset of patients has frequent respiratory tract infections (RRTI).
Dysregulation of the sympathetic nervous system and an association with genetic variations in the catechol-O-methyltransferase (COMT) and glucocorticoid receptor genes influencing sympathetic and glucocorticoid metabolism were reported in CFS. Here, we analyzed the prevalence of SNPs of COMT and glucocorticoid receptor-associated genes in CFS patients and correlated them to immunoglobulin levels and susceptibility to RRTI.
METHODS: We analyzed blood cells of 74 CFS patients and 76 healthy controls for polymorphisms in COMT, FKBP5 and CRHR1 by allelic discrimination PCR. Serum immunoglobulins were determined by immunoturbidimetric technique, cortisol levels by ECLIA.
RESULTS: Contrary to previous reports, we found no difference between CFS patients and healthy controls in the prevalence of SNPs for COMT, FKBP5 and CRHR1. In patients with the Met/Met variant of COMT rs4680 we observed enhanced cortisol levels providing evidence for its functional relevance.
Both enhanced IgE and diminished IgG3 levels and an increased susceptibility to RRTI were observed in CFS patients with the Met/Met variant. Such an association was not observed in 68 non-CFS patients with RRTI.
CONCLUSION: Our results indicate a relationship of COMT polymorphism rs4680 with immune dysregulation in CFS providing a potential link for the association between stress and infection susceptibility in CFS.
PMID:26272340 [PubMed - in process]

 
http://www.ncbi.nlm.nih.gov/pubmed/26272528
J Psychosom Res. 2015 Jul 17. pii: S0022-3999(15)00492-4. doi:
10.1016/j.jpsychores.2015.07.005. [Epub ahead of print]
A comparison of patients with Q fever fatigue syndrome and patients with chronic fatigue syndrome with a focus on inflammatory markers and possible fatigue perpetuating cognitions and behaviour. 
Keijmel SP, Saxe J, van der Meer JW, Nikolaus S, Netea MG, Bleijenberg G, Bleeker-Rovers CP, Knoop H.
Abstract
OBJECTIVE: Comparison of Q fever fatigue syndrome (QFS) and chronic fatigue syndrome (CFS) patients, with a focus on markers of inflammation and fatigue-related cognitive-behavioural variables.
METHODS: Data from two independent prospective studies on QFS (n=117) and CFS (n=173), respectively, were pooled and analyzed.
RESULTS: QFS patients were less often female, had a higher BMI, and had less often received treatment for depression before the onset of symptoms. After controlling for symptom duration and correcting for differences in diagnostic criteria for QFS and CFS with respect to the level of impairment and the presence of additional symptoms, differences in the proportion of females and BMI remained significant.
After correction, QFS patients were also significantly older. In all analyses QFS patients were as fatigued and distressed as CFS patients, but reported less additional symptoms. QFS patients had stronger somatic attributions, and higher levels of physical activity. No differences were found with regard to inflammatory markers and in other fatigue-related cognitive-behavioural variables. The relationship between cognitive-behavioural variables and fatigue, previously established in CFS, could not be confirmed in QFS patients with the exception of the negative relationship between physical activity and fatigue.
CONCLUSION: Differences and similarities between QFS and CFS patients were found. Although the relationship between perpetuating factors and fatigue previously established in CFS could not be confirmed in QFS patients, the considerable overlap in fatigue-related cognitive-behavioural variables and the relationship found between physical activity and fatigue may suggest that behavioural interventions could reduce fatigue severity in QFS patients.
Copyright © 2015 Elsevier Inc. All rights reserved

 
 http://www.biomehe edcentral.com/1471-2377/15/137
Testing the efficacy of web-based cognitive behavioural therapy for adult patients with chronic fatigue syndrome (CBIT): study protocol for a randomized controlled trial
Anthonie Janse, Margreet Worm-Smeitink, José Bussel-Lagarde, Gijs Bleijenberg, Stephanie Nikolaus and Hans Knoop
BMC Neurology 2015, 15:137 doi:10.1186/s12883-015-0392-3
Abstract
Background: Cognitive behavioural therapy (CBT) is an effective treatment for fatigue and disabilities in patients with chronic fatigue syndrome (CFS). However, treatment capacity is limited. 
Providing web-based CBT and tailoring the amount of contact with the therapist to the individual needs of the patient may increase the efficiency of the intervention. Web-based CBT for adolescents with CFS has proven to be effective in reducing fatigue and increasing school attendance.
In the proposed study the efficacy of a web-based CBT intervention for adult patients with CFS will be explored. Two different formats of web-based CBT will be tested. In the first format named protocol driven feedback, patients report on their progress and receive feedback from a therapist according to a preset schedule.
In the second format named support on demand, feedback and support of the therapist is only given when patients ask for it. The primary objective of the study is to determine the efficacy of a web-based CBT intervention on fatigue severity.
Method/Design: A randomized clinical trial will be conducted. Two-hundred-forty adults who have been diagnosed with CFS according to the US Centers for Disease Control and Prevention (CDC) consensus criteria will be recruited and randomized to one of three conditions: web-based CBT with protocol driven feedback, web-based CBT with support on demand, or wait list.
Feedback will be delivered by therapists specialized in CBT for CFS. Each of the web-based CBT interventions will be compared to a wait list condition with respect to its effect on the primary outcome measure; fatigue severity. 
Secondary outcome measures are level of disability, physical functioning, psychological distress, and the proportion of patients with clinical significant improvement in fatigue severity. Outcomes will be assessed at baseline and six months post randomization. The web-based CBT formats will be compared with respect to the time therapists need to deliver the intervention.
Discussion: As far as we know this is the first randomized controlled trial (RCT) that evaluates the efficacy of a web-based CBT intervention for adult patients with CFS.
Trial registration
NTR4013
 

 
http://www.ncbi.nlm.nih.gov/pubmed/26242228
Am J Clin Dermatol. 2015 Aug 5. [Epub ahead of print]
The Dermatological Manifestations of Postural Tachycardia Syndrome: A Review with Illustrated Cases.
Huang H, Hohler AD.
Abstract
Postural tachycardia syndrome (POTS) is a syndrome of excessive tachycardia with orthostatic challenge, and relief of such symptoms with recumbence.
There are several proposed subtypes of the syndrome, each with unique pathophysiology. Numerous symptoms such as excessive tachycardia, lightheadedness, blurry vision, weakness, fatigue, palpitations, chest pain, and tremulousness are associated with orthostatic intolerance.
Other co-morbid conditions associated with POTS are not clearly attributable to orthostatic intolerance. These include chronic headache, fibromyalgia, functional gastrointestinal or bladder disorders, cognitive impairment, and sleep disturbances. 
Dermatological manifestations of POTS are also common and wide ranging, from livedo reticularis to Raynaud's phenomenon, from cutaneous flushing to erythromelalgia.
Here, we provide three illustrative cases of POTS with dermatological manifestations. We discuss the potential pathophysiology underlying such dermatological manifestations, and how such mechanisms could in turn help guide development of management.
PMID:26242228 [PubMed - as supplied by publisher]

Reflections on the Institute of Medicine’s
systemic exertion intolerance disease
Leonard A. Jason, Madison Sunnquist, Abigail Brown, Stephanie McManimen, Jacob Furst
Center for Community Research, DePaul University, Chicago, Illinois, United States
 
 Abstract
The Institute of Medicine (IOM) in the United States has recently proposed that the term systemic exertion
intolerance disease (SEID) replace chronic fatigue syndrome. In addition, the IOM proposed a new
case definition for SEID, which includes substantial reductions or impairments in the ability to engage
in pre‑illness activities, unrefreshing sleep, postexertional malaise, and either cognitive impairment or
orthostatic intolerance. Unfortunately, these recommendations for a name change were not vetted with
patient and professional audiences, and the new criteria were not evaluated with data sets of patients
and controls. A recent poll suggests that the majority of patients reject this new name. In addition, studies
have found that prevalence rates will dramatically increase with the new criteria, particularly due to
the ambiguity revolving around exclusionary illnesses. Findings suggest that the new criteria select more
patients who have less impairment and fewer symptoms than several other criteria. The implications of
these findings are discussed in the current review.

 
Cognitive dysfunction in adolescents with chronic
fatigue: a cross-sectional study
Dag Sulheim,1,2 Even Fagermoen,3,4 Øyvind Stople Sivertsen,5 Anette Winger,6
Vegard Bruun Wyller,1,7,8 Merete Glenne Øie9,10
▸ Additional material is published online only. To view please visit the journal online (http://dx.doi
  /10.1136/archdischild-2014-   06764).
For numbered affiliations see end of article.
Correspondence to
Dr Dag Sulheim, Department
of Paediatrics, Innlandet
Hospital Trust, Anders
Sandvigsgate 17, Lillehammer
N-2609, Norway;
dag.sulheim@medisin.uio.no
Received 11 May 2014 Revised 25 February 2015 Accepted 26 February 2015 Published Online First 19 March 2015
To cite: Sulheim D, Fagermoen E, Sivertsen ØS,et al. Arch Dis Child 2015;100:838–844.
 
ABSTRACT
 
Objective To compare cognitive function in adolescents with chronic fatigue with cognitive function
in healthy controls (HC). Study design Cross-sectional study. Setting Paediatric department at Oslo University
Hospital, Norway.
Participants 120 adolescents with chronic fatigue (average age 15.4 years; range 12–18) and 39 HC
(average age 15.2 years; range 12–18).
 
Methods The adolescents completed a neurocognitive test battery measuring processing speed, working
memory, cognitive inhibition, cognitive flexibility, verbal learning and verbal memory, and questionnaires
addressing demographic data, depression symptoms, anxiety traits, fatigue and sleep problems. Parents
completed the Behaviour Rating Inventory of Executive Function (BRIEF), which measures the everyday executive functions of children.
 
Results Adolescents with chronic fatigue had impaired cognitive function compared to HC regarding processing
speed (mean difference 3.3, 95% CI 1.1 to 5.5, p=0.003), working memory (−2.4, −3.7 to −1.1,
p<0.001), cognitive inhibition response time (6.2, 0.8 to 11.7, p=0.025) and verbal learning (−1.7, −3.2 to
−0.3, p=0.022).
 The BRIEF results indicated that everyday executive functions were significantly worse in the chronic fatigue group compared to the HC (11.2, 8.2 to 14.3, p<0.001). Group differences remained largely unaffected when adjusted for symptoms of depression, anxiety traits and sleep problems.
 
Conclusions Adolescents with chronic fatigue had impaired cognitive function of clinical relevance, measured by objective cognitive tests, in comparison to HC. Working memory and processing speed may represent core difficulties.

 
Brain, Behavior, and Immunity
 Plasma cytokine expression in adolescent chronic fatigue syndrome
Vegard Bruun Wyller a,b,c,⇑, Øystein Sørensen d, Dag Sulheim a,e, Even Fagermoen f,g, Thor Ueland h,i,
Tom Eirik Mollnes j,k,l
a Dept. of Paediatrics, Oslo University Hospital, Norway
b Division of Medicine and Laboratory Sciences, Medical Faculty, University of Oslo, Norway
c Dept. of Paediatrics, Akershus University Hospital, Nordbyhagen, Norway
d Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo, Norway
e Dept. of Paediatrics, Lillehammer County Hospital, Norway
f Institute of Clinical Medicine, Medical Faculty, University of Oslo, Norway
g Dept. of Anesthesiology and Critical Care, Oslo University Hospital, Norway
h Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet, and Faculty of Medicine, K.G. Jebsen IRC, University of Oslo, Oslo, Norway
i K.G. Jebsen TREC, University of Tromsø, Norway
j Department of Immunology, Oslo University Hospital, and K.G. Jebsen IRC, University of Oslo, Norway
k Research Laboratory, Nordland Hospital, Bodø, and Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, Norway
l Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway
a r t i c l e i n f o
Article history:
Received 25 September 2014
Received in revised form 18 December 2014
Accepted 23 December 2014
Available online 31 December 2014
Keywords:
Chronic fatigue syndrome
Adolescent
Inflammation
Cytokine
a b s t r a c t
Chronic fatigue syndrome (CFS) is a prevalent and disabling condition among adolescents. The pathophysiology
is poorly understood, but low-grade systemic inflammation has been suggested as an important
component. This study compared circulating levels of individual cytokines and parameters of
cytokine networks in a large set of adolescent CFS patients and healthy controls, and explored associations
between cytokines and symptoms in the CFS group.
CFS patients (12–18 years old) were recruited nation-wide to a single referral center as part of the Nor-
CAPITAL project (ClinicalTrials ID: NCT01040429). A broad case definition of CFS was applied, requiring
three months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying
symptoms were necessary. Thus, the case definition was broader than the Fukuda-criteria of CFS.
Healthy controls having comparable distribution of gender and age were recruited from local schools.
Twenty-seven plasma cytokines, including interleukins, chemokines and growth factors were assayed
using multiplex technology. The results were subjected to network analyses using the ARACNE algorithm.
Symptoms were charted by a questionnaire, and patients were subgrouped according to the Fukuda-criteria.
A total of 120 CFS patients and 68 healthy controls were included. CFS patients had higher scores for
fatigue (p < 0.001) and inflammatory symptoms (p < 0.001) than healthy controls. All cytokine levels
and cytokine network parameters were similar, and none of the differences were statistically different
across the two groups, also when adjusting for adherence to the Fukuda criteria of CFS. Within the CFS
group, there were no associations between aggregate cytokine network parameters and symptom scores.
Adolescent CFS patients are burdened by symptoms that might suggest low-grade systemic inflammation,
but plasma levels of individual cytokines as well as cytokine network measures were not different
from healthy controls, and there were no associations between symptoms and cytokine expression in the
CFS group. Low-grade systemic inflammation does not appear to be a central part of adolescent CFS
pathophysiology.
_ 2014 Elsevier Inc. All rights reserved.

 
Activity Pacing Self-Management in Chronic Fatigue Syndrome: A Randomized Controlled Trial
Daphne Kos; Inge van Eupen; Jill Meirte; Deborah Van Cauwenbergh; Greta Moorkens; Mira Meeus; Jo Nijs
Activity Pacing Self-Management in Chronic Fatigue Syndrome: A Randomized Controlled Trial
American Journal of Occupational Therapy, September 2015, Vol. 69, 6905290020p1-6905290020p11. doi:10.5014/ajot.2015.016287
© 2015 American Occupational Therapy Association

Abstract
OBJECTIVE. The objective of this study was to evaluate the effectiveness of an activity pacing self-management (APSM) intervention in improving performance of daily life activities in women with chronic fatigue syndrome (CFS).
METHOD. A total of 33 women with CFS (age 41.1 ± 11.2 yr) were randomly allocated to APSM (experimental group; n = 16) or relaxation (control group; n = 17). Main outcome measures included the Canadian Occupational Performance Measure (COPM; primary) and Checklist Individual Strength (CIS).
RESULTS. COPM scores changed significantly over time in both groups (p = .03). The change in Satisfaction scores showed a significant difference in favor only of APSM (effect size = 0.74 [0.11, 1.4]). CIS scores decreased significantly in the experimental group only (p < .01).
CONCLUSION. APSM was found to be feasible and effective in optimizing participation in desired daily life activities in women with CFS. Replication in a larger sample with long-term follow-up is required.

 
Int J Clin Exp Med 2015;8(7):11064-11074
www.ijcem.com /ISSN:1940-5901/IJCEM0010510
Original Article
A prospective, proof-of-concept investigation of
KPAX002 in chronic fatigue syndrome
Jon D Kaiser1,2
1Department of Medicine, University of California San Francisco Medical School, San Francisco, CA, USA; 2Medical
Director, K-PAX Pharmaceuticals, Inc., Mill Valley, CA, USA
Received May 21, 2015; Accepted July 11, 2015; Epub July 15, 2015; Published July 30, 2015
Abstract: Stimulant drugs and various micronutrient interventions have previously been studied in chronic fatigue
syndrome (CFS) but they have never been studied in combination. This proof of concept investigation seeks to
examine the clinical effects and safety profile of KPAX002 (a combination of methylphenidate hydrochloride and
mitochondrial support nutrients) in patients with CFS. Fifteen patients diagnosed with CFS by 1994 Fukuda criteria
were recruited and treated with KPAX002 to explore a potential synergistic effect of this combination. Fatigue and
concentration disturbance symptoms were measured at baseline, 4 weeks, and 12 weeks using two clinically validated
tools: Checklist Individual Strength (CIS) and Visual Analog Scale (VAS). The primary outcome objective was a
decrease in the total CIS score of ≥25% in at least 50% of the subjects. The mean total CIS score decreased by 36.4
points (34%) at 12 weeks (P<0.0001), corresponding to a ≥25% decrease in 87% of the participants. Treatment
with KPAX002 was well tolerated and significantly improved fatigue and concentration disturbance symptoms in
greater than 50% of patients with CFS. These results were statistically significant. This combination treatment is
worthy of additional investigation.

 
http://www.omicsonline.org/open-access/low-nk-cell-activity-in-chro...
Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity
David Strayer, Victoria Scott and William Carter
Abstract
Background: Natural killer (NK) cells act as an immune surveillance against invading pathogens and tumors. NK cell cytotoxicity (NKCC) has been reported to be decreased in patients with CFS.
Methods: The objective of this review was to conduct an analysis of available publications that reported NKCC data in CFS in order to evaluate any relationships to case definitions used to define CFS and symptom severity.
Results: Of 17 studies that evaluated NKCC in patients with CFS, defined using the CDC 1988 and/or 1994 case definition (CD), 88%
(15/17) concluded that NKCC was decreased in CFS patients compared to normal controls. The NKCC decrease was seen using two established methods, 51Cr release (11/13) and flow cytometry (4/4). The mean percent decrease in NKCC using the CDC 1988 CD (66.3%) was significantly greater than that using the CDC 1994 CD (49.7%) (p<0.01).
This result is consistent with that of six publications showing a greater decrease in NKCC associated with increased CFS symptom severity based on the lower symptom requirement for the CDC 1994 vs. 1988 CD. In contrast, there was no significant difference in the mean percent decrease in NKCC seen comparing the CDC 1994 CD defined population using the 51Cr release (48.3%) vs. flow cytometry (50.7%) assays (p>0.5).
Finally, seven studies investigating the ability of various agents to augment NKCC in patients with CFS showed increases of NKCC with both in vitro exposure (4/5) and in vivo exposure using randomized trials (2/2).
Conclusions: Low NKCC is commonly seen in CFS and is associated with increase symptom severity.

 
http://www.ncbi.nlm.nih.gov/pubmed/26354426
Clin Rheumatol. 2015 Sep 10. [Epub ahead of print]
HPV vaccination syndrome. A questionnaire-based study.
Martínez-Lavín M, Martínez-Martínez LA, Reyes-Loyola P.
Abstract
Isolated cases and small series have described the development of complex regional pain syndrome, postural orthostatic tachycardia, and fibromyalgia after human papillomavirus (HPV) vaccination. These illnesses are difficult to diagnose and have overlapping clinical features.
Small fiber neuropathy and dysautonomia may play a major role in the pathogenesis of these entities. We used the following validated questionnaires to appraise the chronic illness that might appear after HPV vaccination: The 2010 American College of Rheumatology Fibromyalgia Diagnostic Criteria, COMPASS 31 dysautonomia questionnaire, and S-LANSS neuropathic pain form.
These questionnaires and a "present illness" survey were e-mailed to persons who had the onset of a chronic ailment soon after HPV vaccination. Forty-five filled questionnaires from individuals living in 13 different countries were collected in a month's period. Mean (±SD) age at vaccination time was 14 ± 5 years. Twenty-nine percent of the cases had immediate (within 24 h) post-vaccination illness onset. The most common presenting complaints were musculoskeletal pain (66 %), fatigue (57 %), headache (57 %), dizziness/vertigo (43 %), and paresthesias/allodynia (36 %).
Fifty-three percent of affected individuals fulfill the fibromyalgia criteria. COMPASS-31 score was 43 ± 21, implying advanced autonomic dysfunction. Eighty-three percent of the patients who had ongoing pain displayed S-LANSS values >12, suggesting a neuropathic component in their pain experience.
After a mean period of 4.2 ± 2.5 years post-vaccination, 93 % of patients continue to have incapacitating symptoms and remain unable to attend school or work.
In conclusion, a disabling syndrome of chronic neuropathic pain, fatigue, and autonomic dysfunction may appear after HPV vaccination.

 
http://www.ncbi.nlm.nih.gov/pubmed/26359713
J Psychosom Res. 2015 Sep 2. pii: S0022-3999(15)00521-8. doi:
10.1016/j.jpsychores.2015.08.008. [Epub ahead of print]
Capturing the post-exertional exacerbation of fatigue following physical and cognitive challenge in patients with chronic fatigue syndrome.
Keech A1, Sandler CX2, Vollmer-Conna U3, Cvejic E3, Lloyd AR4, Barry BK5.
Abstract
OBJECTIVE: To design and validate an instrument to capture the characteristic post-exertional exacerbation of fatigue in patients with chronic fatigue syndrome (CFS).
METHODS: Firstly, patients with CFS (N=19) participated in five focus group discussions to jointly explore the nature of fatigue and dynamic changes after activity, and inform development of a self-report instrument - the Fatigue and Energy Scale (FES). The psychometric properties of the FES were then examined in two case-control challenge
studies: a physically-demanding challenge (moderate-intensity aerobic exercise; N=10 patients), and a cognitively-demanding challenge (simulated driving; N=11 patients). Finally, ecological validity was evaluated by recording in association with tasks of daily living (N=9).
RESULTS: Common descriptors for fatigue included 'exhaustion', 'tiredness', 'drained of energy', 'heaviness in the limbs', and 'foggy in the head'. Based on the qualitative data, fatigue was conceptualised as consisting of 'physical' and 'cognitive' dimensions.
Analysis of the psychometric properties of the FES showed good sensitivity to the changing symptoms during a post-exertional exacerbation of fatigue following both physical exercise and driving simulation challenges, as well as tasks of daily living.
CONCLUSION: The 'fatigue' experienced by patients with CFS covers both physical and cognitive components. The FES captured the phenomenon of a post-exertional exacerbation of fatigue commonly reported by patients with CFS. The characteristics of the symptom response to physical and cognitive challenges were similar. Both the FES and the challenge paradigms offer key tools to reliably investigate biological correlates of the dynamic changes in fatigue.
Copyright © 2015. Published by Elsevier Inc.

 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475466/
J Urol. 2015 Jul;194(1):118-26. doi: 10.1016/j.juro.2015.02.082. 
 Brain White Matter Abnormalities in Female Interstitial Cystitis/Bladder Pain Syndrome: A MAPP Network Neuroimaging Study.
Farmer MA1, Huang L, Martucci K, Yang CC, Maravilla KR, Harris RE, Clauw DJ, Mackey S, Ellingson BM, Mayer EA, Schaeffer AJ, Apkarian AV; MAPP Research Network.
Abstract
PURPOSE: Several chronic pain conditions may be distinguished by condition specific brain anatomical and functional abnormalities on imaging, which are suggestive of underlying disease processes. We present what is to our knowledge the first characterization of interstitial cystitis/bladder pain syndrome associated white matter
(axonal) abnormalities based on multicenter neuroimaging from the MAPP Research Network.
MATERIALS AND METHODS: We assessed 34 women with interstitial cystitis/bladder pain syndrome and 32 healthy controls using questionnaires on pain, mood and daily function. White matter microstructure was evaluated by diffusion tensor imaging to model directional water flow along axons or fractional anisotropy. Regions correlating with clinical parameters were further examined for gender and syndrome dependence.
RESULTS: Women with interstitial cystitis/bladder pain syndrome showed numerous white matter abnormalities that correlated with pain severity, urinary symptoms and impaired quality of life. Interstitial cystitis/bladder pain syndrome was characterized by decreased fractional anisotropy in aspects of the right anterior thalamic radiation, the left forceps major and the right longitudinal fasciculus. Increased fractional anisotropy was detected in the right superior and bilateral inferior longitudinal fasciculi.
CONCLUSIONS: To our knowledge we report the first characterization of brain white matter abnormalities in women with interstitial cystitis/bladder pain syndrome. Regional decreases and increases in white matter integrity across multiple axonal tracts were associated with symptom severity. Given that white matter abnormalities closely correlated with hallmark symptoms of interstitial cystitis/bladder pain syndrome, including bladder pain and urinary symptoms, brain anatomical alterations suggest that there are neuropathological contributions to chronic urological pelvic pain.
Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

 
http://www.ncbi.nlm.nih.gov/pubmed/26334394
Eur J Pediatr. 2015 Sep 3. [Epub ahead of print]
The impact of chronic fatigue syndrome on cognitive functioning in adolescents.
Nijhof LN, Nijhof SL, Bleijenberg G, Stellato RK, Kimpen JL, Pol HE, van de Putte EM.
Abstract
Chronic fatigue syndrome (CFS) is characterized by persistent fatigue and severe disability. Most adolescent patients report attention and concentration problems, with subsequent poor performance at school. 
This study investigated the impact of CFS on intellectual capacity by (1) assessing discrepancies between current intelligence quotient (IQ) and school level and (2) exploring differences in current IQ and pre-CFS school performance, compared with healthy individuals. Current data was cross-sectionally gathered and compared with retrospective pre-CFS school performance data.
Fifty-nine CFS adolescents and 40 controls were evaluated on performance on age-appropriate intelligence tests and school level. Current IQ scores of CFS adolescents were lower than expected on the basis of their school level.
Furthermore, there was a difference in intelligence performance across time when current IQ scores were compared with pre-CFS cognitive achievement.
Healthy controls did not show any discrepancies.
CONCLUSION: According to their pre-CFS intelligence assessments, CFS patients started with appropriate secondary school levels at the age of 12. Our data suggest that CFS may be accompanied by a decline in general cognitive functioning.
Given the critical age for intellectual development, we recommend a timely diagnosis followed by appropriate treatment of CFS in adolescents. What is Known: • Adolescent chronic fatigue syndrome (CFS) is a debilitating condition with major impact on social and intellectual development. • Most patients report concentration problems, with subsequent poor performance at school. 
Little is known about the influence of CFS on intellectual performances. What is New: • IQ scores of CFS adolescents are lower than the IQ scores of healthy peers with an equivalent school level. • There is a decrease in intelligence performance across time when current IQ scores are compared with pre-CFS cognitive achievement. 
Healthy controls do not show any discrepancies between their current IQ, school level and previous cognitive functioning. This suggest that adolescent CFS may be accompanied by a decline in general cognitive functioning.
PMID:26334394 [PubMed - as supplied by publisher]

 
http://www.ncbi.nlm.nih.gov/pubmed/26335989
J Pain. 2015 Aug 31. pii: S1526-5900(15)00838-X. doi:
10.1016/j.jpain.2015.08.004. [Epub ahead of print]
Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-blind, Placebo-controlled Trial. 
Natelson BH1, Vu D2, Mao X3, Weiduschat N3, Togo F4, Lange G2, Blate M2, Kang G3, Coplan JD5, Shungu DC3.
Abstract
Milnacipran, a serotonin/norepinephrine reuptake inhibitor (SNRI), is FDA-approved for the treatment of fibromyalgia (FM). This report presents the results of a randomized, double-blind, placebo-controlled trial of milnacipran conducted to test the hypotheses that (a) similar to patients with chronic fatigue syndrome, FM patients have elevated ventricular lactate at baseline; (b) 8 weeks of treatment with milnacipran will lower ventricular lactate levels compared to both baseline and to placebo; and (c) treatment with milnacipran will improve attention and executive function in the Attention Network Test compared to placebo.
In addition, we examined the results for potential associations between ventricular lactate and pain. Baseline ventricular lactate measured by proton magnetic resonance spectroscopic imaging (1H MRSI) was found to be higher in FM than in healthy controls [F(1,37) = 22.11; p < 0.0001, partial η2 = 0.37]. 
Milnacipran reduced pain in FM relative to placebo but had no effect on cognitive processing. At study end, ventricular lactate in the milnacipran-treated group decreased significantly compared to baseline and to placebo [F1,18 = 8.18, p = 0.01, partial η2 = 0.31].
A significantly larger proportion of milnacipran-treated patients showed decreases in both ventricular lactate and in pain than placebo [p = 0.03]. These results suggest that 1H MRSI measurements of lactate may serve as a potential biomarker for therapeutic response in FM and that milnacipran may act, at least in part, by targeting the brain response to glial activation and neuroinflammation.
PERSPECTIVE: Patients treated with milnacipran showed decreases in both pain and ventricular lactate compared to those treated with placebo, but, even after treatment, levels of ventricular lactate remained higher than in controls. The hypothesized mechanism for these decreases is via drug-induced reductions of a central inflammatory state.
Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

 
http://www.ncbi.nlm.nih.gov/pubmed/26399744
Brain Behav Immun. 2015 Sep 20. pii: S0889-1591(15)30020-9. doi: 10.1016/j.bbi.2015.09.013.
Antibodies to ß adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome.
Loebel M, Grabowski P, Heidecke H, Bauer S, Hanitsch LG, Wittke K, Meisel C, Reinke P, Volk HD, Fluge Ø, Mella O, Scheibenbogen C.
Abstract
Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in CFS point to an autoimmune disease directed against neurotransmitter receptors. Autoantibodies against G-protein coupled receptors were shown to play a pathogenic role in several autoimmune diseases.
Here, serum samples from a patient cohort from Berlin (n= 268) and from Bergen with pre- and post-treatment samples from 25 patients treated within the KTS-2 rituximab trial were analysed for IgG against human α and ß adrenergic, muscarinic (M) 1-5 acetylcholine, dopamine, serotonin, angiotensin, and endothelin receptors by ELISA and compared to a healthy control cohort (n=108). 
Antibodies against ß2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls. In contrast, levels of antibodies against α adrenergic, dopamine, serotonin, angiotensin, and endothelin receptors were not different between patients and controls. 
A high correlation was found between levels of autoantibodies and elevated IgG1-3 subclasses, but not with IgG4. Further patients with high ß2 antibodies had significantly more frequently activated HLA-DR+ T cells and more frequently thyreoperoxidase and anti-nuclear antibodies. In patients receiving rituximab maintenance treatment achieving prolonged B-cell depletion, elevated ß2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder.
We provide evidence that 29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and ß adrenergic receptors which are potential biomarkers for response to B-cell depleting therapy.
The association of autoantibodies with immune markers suggests that they activate B and T cells expressing ß adrenergic and M acetylcholine receptors. Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS.
Copyright © 2015. Published by Elsevier Inc.

 
http://onlinelibrary.wiley.com/doi/10.1111/nmo.12670/abstract
Increased serum levels of lipopolysaccharide and antiflagellin antibodies in patients with diarrhea-predominant irritable bowel syndrome
A. Dlugosz, P. Nowak, M. D'Amato, G. Mohammadian Kermani, J. Nyström, S. Abdurahman and G. Lindberg
Abstract
Background: Innate immune responses to conserved microbial products such as lipopolysaccharide (LPS) and flagellin are likely important in microbial–host interactions and intestinal homeostasis. We hypothesized that bacterial translocation and activation of mucosal immunity against common microbial antigens might be involved in the development of irritable bowel syndrome (IBS). We therefore compared serum levels of LPS, soluble CD14 (sCD14), and flagellin antibodies between patients with different subtypes of IBS and healthy controls.
Methods: We analyzed serum obtained from 88 patients (74 females) aged
19(43)–73 years and 106 healthy volunteers (77 females) aged 19(38)–62 years. Diarrhea-predominant IBS (D-IBS) was present in 32 patients (36%), 23 patients (26%) had constipation-predominant IBS (C-IBS), and
33 patients (38%) had A-IBS. We used ELISA for sCD14 and antiflagellin immunoglobulin G and limulus amebocyte assay for LPS. Abdominal symptoms and psychiatric comorbidities were assessed using validated questionnaires.
Key Results: We found a significantly higher serum level of LPS in patients with D-IBS compared to controls (p = 0.0155). The level of antibodies to flagellin was higher in patients with IBS than in controls (mainly driven by higher levels in D-IBS, p = 0.0018). The levels of sCD14 were lower in D-IBS patients compared to controls (p = 0.0498). We found a weak, but significant correlation between the levels of antiflagellin antibodies and anxiety among IBS patients (ρ = 0.38; p = 0.0045).
Conclusions & Inferences: Our results support the concept that immune reactivity to luminal antigens may have a role in the development of D-IBS. The serum level of antiflagellin antibodies was found to correlate with patients’ self-reported anxiety score.

 
http://www.sciforschenonline.org/journals/drug/JDRD-1-103.php
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): Characteristics of Responders to Rintatolimod
David R Strayer, Bruce C Stouch, Staci R Stevens, Lucinda Bateman, Charles W Lapp, Daniel L Peterson, William A Carter, William M Mitchell
Abstract
Background: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a debilitating disease of unknown pathogenesis consisting of a variety of flu-like symptoms including severe fatigue. Initial analysis of the use of rintatolimod (Poly I: Poly C12U), a selective TLR3 agonist, in a Phase III, double-blind, randomized, placebo-controlled trial of CFS/ME demonstrated statistical significance (p<0.05) in the reduction of fatigue as measured by exercise tolerance (ET) as the primary endpoint using a modified Bruce protocol with reduced physical exertion in patients with severe CFS/ME as defined by a Karnofsky performance score (KPS) of 40-60.
Methods and Findings: In order to better identify responders to rintatolimod, primary and secondary endpoints have been reexamined post hoc as a function of a pre-specified study baseline ET duration
>9 minutes. Analysis of improvement in exercise performance at the ≥ 25% and ≥ 50% levels using ET at 40 weeks compared to baseline was performed for the intent-to-treat (ITT) population (n=208) using the pre-specified baseline exercise stratum (baseline ET duration >9 minutes).
For this subset of patients (n=126), 33% (n=20), and 12% (n=8) of rintatolimod vs. placebo patients, respectively, improved ET duration by ≥ 25% (p=0.004) while 23% (n=14) compared to 4.5% (n=3) of rintatolimod vs. placebo patients, respectively improved ET duration by ≥ 50% (p=0.003). This corresponds to increases of ≥ 186 and ≥ 373 seconds for patients receiving rintatolimod, respectively, at ≥ 25% and ≥ 50% improvement responses.
A frequency distribution analysis of ≥ 25% improvement, <25% change, and ≥ 25% deterioration in ET from baseline at 40 weeks for the baseline >9 minutes cohort showed net improvement to be 18.3% for the rintatolimod cohort vs. 4.6% deterioration for placebo (p=0.015). A continuous responder analysis using 5% increments from ≥ 25% to ≥ 50% provided a robust clinical enhancement in ET effect in the rintatolimod cohorts as compared to placebo.
The KPS and Vitality (SF-36 subscale) quality of life secondary endpoints demonstrated similar clinically significant improvements for the rintatolimod cohort as a function of the same ET dichotomization. Rintatolimod was generally well-tolerated in this CFS/ME population.
Conclusions: Using a modified Bruce ET protocol with reduced physical exertion allowed clear identification of patient responders to rintatolimod with severe CFS/ME syndrome. Rintatolimod produced significant enhancement in ET and quality of life indicators in patients able to complete >9 minutes in a modified Bruce ET test. 
Rintatolimod also reduced deterioration in ET compared to placebo in patients with the poorest initial ET. Exercise endurance >9 minutes in a Bruce protocol modified for patients with CFS/ME provides a method to identify patients most likely to respond to rintatolimod.

 
http://www.translational-medicine.com/content/pdf/s12967-015-0653-3...
Longitudinal analysis of immune abnormalities in varying severities of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients
Sharni Lee Hardcastle*, Ekua Weba Brenu, Samantha Johnston, Thao Nguyen, Teilah Huth, Sandra Ramos, Donald Staines and Sonya Marshall‑Gradisnik
Abstract 
Background: Research has identified immunological abnormalities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), a heterogeneous illness with an unknown cause and absence of diagnostic test. There have been no CFS/ME studies examining innate and adaptive immune cells longitudinally in patients with varying severities. This is the first study to investigate immune cells over 6 months while also examining CFS/ME patients of varying symptom severity.
Methods: Participants were grouped into 18 healthy controls, 12 moderate and 12 severe CFS/ME patients and flow cytometry was used to examine cell parameters at 0 and 6 months.
Results: Over time, iNKT CD62L expression significantly increased in moderate CFS/ME patients and CD56bright NK receptors differed in severe CFS/ME. Naïve CD8+T cells, CD8−CD4− and CD56−CD16− iNKT phenotypes, γδ2T cells and effector memory subsets were significantly increased in severe CFS/ME patients at 6 months. Severe CFS/ME patients were significantly reduced in CD56brightCD16dim NKG2D, CD56dimCD16− KIR2DL2/DL3, CD94−CD11a− γδ1T cells and CD62L+CD11a− γδ1T cells at 6 months.
Conclusions: Severe CFS/ME patients differed from controls and moderate CFS/ME patients over time and expressed significant alterations in iNKT cell phenotypes, CD8+T cell markers, NK cell receptors and γδT cells at 6 months. This highlights the importance of further assessing these potential immune biomarkers longitudinally in both moderate and severe CFS/ME patients.

 
The effect of dietary glutamate on fibromyalgia and irritable bowel symptoms.
1.  Holton, K, Taren D, Thomson C, Bennett R, Jones K.  The effect of dietary glutamate on fibromyalgia and irritable bowel symptoms. Clin and Exper Rheumatology. 2012 Vol 30 No. 6. Suppl 74.
A key neurotransmitter in central sensitization is glutamate; which is the most ubiquitous excitatory neurotransmitter in mammals.  In animal models, experimentally high glutamate levels have been shown to overexcite a neuron to the point of death.”1
Research shows a relationship between consumption of dietary glutamate and increased symptoms of fibromyalgia (FM) and irritable bowel syndrome (IBS). Study subjects maintained a daily symptom checklist throughout a four-week diet and two-week double-blind placebo-controlled crossover challenge. Significant decreases in symptoms were seen in participants who received the placebo rather than the dietary glutamate.

Fifty-seven people diagnosed with both FM and IBS participated in a 4-week diet that omitted dietary additive excitotoxins, including monosodium glutamate (MSG) and aspartame.  The subjects received a group diet training session prior to the study and had access to professional dietary counseling throughout the study.  They also maintained food/symptom journals during weeks one and four, and also Monday through Wednesday of the second part of the study.

Thirty-seven people completed the four-week diet and were eligible for the next portion of the study.  Of those patients, 84% reported more than 30% of their symptoms were resolved.  Eight participants reported fewer than 12 symptoms by the end of the four-week diet and on average 11 symptoms remitted in the subjects.
 
The second part of the study included a double-blind placebo-controlled challenge with MSG. The subjects received MSG or placebo for three consecutive days each week. Each subject tracked their symptoms daily on a checklist, which consisted of 28 symptoms of FM, IBS, and four ‘Chinese Restaurant Syndrome’ symptoms.  All fibromyalgia symptoms were reported more frequently during the MSG challenge in the second part of the study. Severe fatigue was reported by 70 percent of the participants receiving MSG while only 30 percent of those receiving the placebo reported this side effect.  All IBS symptoms were reported more frequently during the MSG challenge, except for straining during BM which remained the same as reported by 30 percent of the subjects. Significant differences were seen in abdominal pain and diarrhea between the MSG and non-MSG groups.  Only 9% of those receiving the placebo reported these symptoms, while 32% of MSG recipients reported abdominal pain and diarrhea.

Conclusion:  Patients whose symptoms improved during the (first part of the study) four-week diet saw the symptoms return when they received MSG in the second part of the study.  Clinically significant symptom improvement was reported by 84% of the participants who completed the four-week diet and suggests a diet free of excitotoxin is not only feasible for individuals, but that it improves symptoms of FM/IBS. This indicates excitotoxins may evoke symptoms in some FM/IBS patients.
 
1.  Holton, K, Taren D, Thomson C, Bennett R, Jones K.  The effect of dietary glutamate on fibromyalgia and irritable bowel symptoms. Clin and Exper Rheumatology. 2012 Vol 30 No. 6. Suppl 74.
Copyright © 2015 National Fibromyalgia & Chronic Pain Association. All Rights Reserved. Designed by JoomlArt.com.Joomla! is Free Software released under the GNU

 
Brain White Matter Abnormalities in Female Interstitial Cystitis/Bladder Pain Syndrome: A MAPP Network Neuroimaging Study.Farmer MA1, Huang L1, Martucci K2, Yang CC3, Maravilla KR4, Harris RE5, Clauw DJ5, Mackey S2, Ellingson BM6, Mayer EA6, Schaeffer AJ7, Apkarian AV8; MAPP Research Network.
Author information

• 1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
• 2Division of Pain Medicine, Departments of Anesthesiology, Perioperative and Pain Medicine, Stanford University Medical Center, Stanford, California.
• 3Department of Urology, University of Washington, Seattle, Washington.
• 4Department of Radiology, University of Washington, Seattle, Washington.
• 5Department of Anesthesiology and Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, Michigan.
• 6Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California.
• 7Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
• 8Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Department of Surgery and Anesthesia, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Electronic address: a-apkarian@northwestern.edu.

AbstractPURPOSE:
Several chronic pain conditions may be distinguished by condition specific brain anatomical and functional abnormalities on imaging, which are suggestive of underlying disease processes. We present what is to our knowledge the first characterization of interstitial cystitis/bladder pain syndrome associated white matter (axonal) abnormalities based on multicenter neuroimaging from the MAPP Research Network.
MATERIALS AND METHODS:
We assessed 34 women with interstitial cystitis/bladder pain syndrome and 32 healthy controls using questionnaires on pain, mood and daily function. White matter microstructure was evaluated by diffusion tensor imaging to model directional water flow along axons or fractional anisotropy. Regions correlating with clinical parameters were further examined for gender and syndrome dependence.
RESULTS:
Women with interstitial cystitis/bladder pain syndrome showed numerous white matter abnormalities that correlated with pain severity, urinary symptoms and impaired quality of life. Interstitial cystitis/bladder pain syndrome was characterized by decreased fractional anisotropy in aspects of the right anterior thalamic radiation, the left forceps major and the right longitudinal fasciculus. Increased fractional anisotropy was detected in the right superior and bilateral inferior longitudinal fasciculi.
CONCLUSIONS:
To our knowledge we report the first characterization of brain white matter abnormalities in women with interstitial cystitis/bladder pain syndrome. Regional decreases and increases in white matter integrity across multiple axonal tracts were associated with symptom severity. Given that white matter abnormalities closely correlated with hallmark symptoms of interstitial cystitis/bladder pain syndrome, including bladder pain and urinary symptoms, brain anatomical alterations suggest that there are neuropathological contributions to chronic urological pelvic pain.
Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Sleep MedicineReceived: April 22, 2015; Received in revised form: July 17, 2015; Accepted: July 23, 2015; Published Online: August 19, 2015
Publication stage: In Press Accepted Manuscript
The effect of sleep deprivation on pain perception in healthy subjects: a meta-analysis
Marlene Schrimpfx

• Department of Psychotherapy and Biopsychosocial Health, Danube-University Krems, Dr. Karl Dorrek Straße 30, A-3500 Krems, Austria

,
Peter Geislerx
Peter Geisler
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Affiliations

• Department of Psychiatry and Psychotherapy, University Hospital Regensburg, Universitätsstraße 84, 93053 Regensburg, Germany

,
Christoph Piehx
Christoph Pieh
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Affiliations

• Department of Psychotherapy and Biopsychosocial Health, Danube-University Krems, Dr. Karl Dorrek Straße 30, A-3500 Krems, Austria

• Department of Psychosomatic Medicine, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany

• Karl Landsteiner University of Health Sciences, Dr.-Karl-Dorrek-Straße 30, 3500 Krems, Austria

Correspondence

• Corresponding Author: Univ.-Prof. Dr. med. univ. , Danube University Krems, Faculty of Health and Medicine, Department of Psychotherapy and Biopsychosocial Health, Dr. Karl Dorrek Straße 30, A-3500 Krems an der Donau, Austria, Tel.: +432732-893/2530

 

Highlights• Sleep deprivation has a medium effect (SMD=0.62) on pain perception.
• The calculated effect-size is comparable with effect-sizes achieved through pain treatment.
• Sleep deprivation affects self-reported pain as well as pain threshold.
AbstractBackgroundThere is strong evidence indicating an interaction between sleep and pain. However, the size of this effect, as well as the clinical relevance is unclear. This meta-analysis was therefore conducted to quantify the effect of sleep deprivation on pain perception.
MethodsA systematic literature search was conducted using the electronic databases PubMed, Cochrane, Psyndex, Psycinfo and Scopus. By conducting a random effect model, we calculated the pooled standardized mean differences (SMDs) of sleep deprivation on pain perception. Studies that investigated any kind of sleep deprivation in conjunction with a pain measurement were included. In cases of several pain measurements within a study, we calculated the average effect size of all measures.
ResultsWe identified five eligible studies (N=190) for the between-group analysis and 10 studies (N=266) for the within-group analysis. Sleep deprivation showed a medium effect in the between group analysis (SMD=0.62; CI95: 0.12, 1.12; z=2.43; p=.015) and a large effect in the within-group analysis (SMD=1.49; CI95: 0.82, 2.17; z=4.35; p<.0001). The test for heterogeneity was not significant in the between-group analysis (Q=5.29; df=4; p=.2584), but was significant in the within-group analysis (Q=53.49; df=9; p<.0001).
ConclusionThis meta-analysis confirms a medium effect (SMD=0.62) of sleep deprivation on pain perception. As this meta-analysis is based on experimental studies in healthy subjects, the clinical relevance should be clarified.
Keywords:
sleep deprivation, pain perception, meta-analysis, reciprocal relation

 
Journal of PainVolume 16, Issue 9, Pages 852–861Long-Term Outcome of the Management of Chronic Neuropathic Pain: A Prospective Observational Study
A. John Clark
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Affiliations

• Department of Anesthesiology, Dalhousie University, Halifax, Nova Scotia, Canada

• Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada

,
Received: March 16, 2015; Received in revised form: May 16, 2015; Accepted: May 29, 2015; Published Online: June 13, 2015
DOI: http://dx.doi.org/10.1016/j.jpain.2015.05.011
AbstractThis prospective observational cohort study addressed the long-term clinical effectiveness of the management of chronic neuropathic noncancer pain at 7 Canadian tertiary pain centers. Patients were treated according to standard guidelines and were followed at 3, 6, 12, 18, and 24 months. Standard outcome measures for pain, mood, quality of life, and overall treatment satisfaction were administered, with the primary outcome measure designated as the composite of 30% reduction in average pain intensity and 1-point decrease in the mean Interference Scale Score (0–10) of the Brief Pain Inventory at 12 months relative to baseline. Of 789 patients recruited, mean age was 53.5 ± 14.2 years (55% female) and mean duration of pain was 4.88 ± 5.82 years. Mean average pain intensity (0–10) at baseline was 6.1 ± 1.9. All standard outcome measures showed statistically significant improvement at 12 months relative to baseline (P < .001). However, only 23.7% attained clinically significant improvement in pain and function at 12 months as the primary outcome measure. Univariable analyses showed poorer outcomes at 12-month follow-up with longer duration of pain (P = .002), greater cigarette use (P = .01), more disability compensation (P = .001), and higher opioid doses at baseline and at 12 months (P < .02). Our present treatment modalities provide significant long-term benefit in only about a quarter of patients with neuropathic pain managed at tertiary care pain clinics. Opioid therapy may not be beneficial for the long term.
PerspectiveEvidence-based treatment of chronic neuropathic pain provides long-term benefit in only about one-quarter of patients seen in tertiary care centers. Opioid therapy may not be beneficial
 
Pain:
August 2015 - Volume 156 - Issue 8 - p 1433–1439
doi: 10.1097/j.pain.0000000000000131
Research Paper
Sleep and pain sensitivity in adults
Sivertsen, Børgea,b,c,*; Lallukka, Tead,e; Petrie, Keith J.f; Steingrímsdóttir, Ólöf Annag; Stubhaug, Audunh,i; Nielsen, Christopher Siverta
 
Abstract
Abstract: Sleep problems and pain are major public health concerns, but the nature of the association between the 2 conditions is inadequately studied. The aim of this study was to determine whether a range of sleep measures is associated with experimental increased pain sensitivity. A cross-sectional large population-based study from 2007 to 2008, the Tromsø 6 study, provided data from 10,412 participants (age: mean [SD], 58 [13] years; 54% women). Self-reported sleep measures provided information on sleep duration, sleep onset latency (SOL), and sleep efficiency, as well as frequency and severity of insomnia. The main outcome measure was pain sensitivity tests, including assessment of cold-pressor pain tolerance. We found that all sleep parameters, except sleep duration, were significantly associated with reduced pain tolerance. Both the frequency and severity of insomnia, in addition to SOL and sleep efficiency, were associated with pain sensitivity in a dose–response manner. Adjusting for demographics and psychological distress reduced the strengths of the hazard ratios, but most associations remained significant in the fully adjusted models. There was also a synergistic interaction effect on pain tolerance when combining insomnia and chronic pain. We conclude that sleep problems significantly increase the risk for reduced pain tolerance. Because comorbid sleep problems and pain have been linked to elevated disability, the need to improve sleep among patients with chronic pain, and vice versa, should be an important agenda for future research.
© 2015 International Association for the Study of Pain
 
http://www.ncbi.nlm.nih.gov/pubmed/26429318
Hum Immunol. 2015 Sep 28. pii: S0198-8859(15)00465-6. doi:
10.1016/j.humimm.2015.09.028. [Epub ahead of print]
Frequent IgG subclass and mannose binding lectin deficiency in patients with CFS.
Guenther S, Loebel M, Mooslechner AA, Knops M, Hanitsch LG, Grabowski P, Wittke K, Meisel C, Unterwalder N, Volk HD, Scheibenbogen C.
Abstract
Chronic fatigue syndrome (CFS) is a severe disease characterized by various symptoms of immune dysfunction. CFS onset is typically with an infection and many patients suffer from frequently recurrent viral or bacterial infections. Immunoglobulin and mannose binding lectin (MBL) deficiency are frequent causes for increased susceptibility to infections.
In this study we retrospectively analysed 300 patients with CFS for immunoglobulin and MBL levels, and B-cell subset frequencies. 25% of the CFS patients had decreased serum levels of at least one antibody class or subclass with IgG3 and IgG4 subclass deficiencies as most common phenotypes. However, we found elevated immunoglobulin levels with an excess of IgM and IgG2 in particular in another 25% of patients.
No major alteration in numbers of B cells and B-cell subsets was seen. Deficiency of MBL was found in 15% of the CFS patients in contrast to 6% in a historical control group. In a 2nd cohort of 168 patients similar frequencies of IgG subclass and MBL deficiency were found.
Thus, humoral immune defects are frequent in CFS patients and are associated with infections of the respiratory tract.

http://www.tandfonline.com/doi/abs/10.1080/21641846.2015.1091152?jo...
Autonomic function in chronic fatigue syndrome with and without painful temporomandibular disorder
Lucy J. Robinsona, Justin Durham, Laura L. MacLachlan & Julia L. Newton
Abstract
Background: Chronic fatigue syndrome (CFS) is heterogeneous in nature, yet no clear subclassifications currently exist. There is evidence of dysautonomia in almost 90% of patients and CFS is often co-morbid with conditions associated with autonomic nervous system (ANS) dysfunction, such as temporomandibular disorders (TMD). The present study examined the point prevalence of TMD in a sample of people with CFS and explored whether co-morbidity between the conditions is associated with greater ANS dysfunction than CFS alone.
Method: Fifty-one patients and 10 controls underwent screening for TMD. They completed a self-report measure of ANS function (COMPASS-31) and objective assessment of heart rate variability during rest and standing (derived using spectral analysis). Frequency densities in the high-frequency (HF) and low-frequency (LF) band were calculated.
Results: Patients with CFS were divided into those who screened positive for TMD (n = 16, 31%; CFS + TMD) and those who did not (n  = 35, 69%; CFS − TMD). Both CFS groups had significantly higher self-rated ANS dysfunction than controls. CFS + TMD scored higher than CFS − TMD on the orthostatic and vasomotor subscales. The CFS + TMD group had significantly higher HF and significantly lower LF at rest than the other two groups. In discriminant function analysis, self-report orthostatic intolerance and HF units correctly classified 75% of participants.
Conclusions: Almost one-third of CFS patients screened positive for TMD and this was associated with greater evidence of parasympathetic dysfunction. The presence of TMD shows potential as an effective screen for patients with CFS showing an autonomic profile and could help identify subgroups to target for treatment.

 
fulltext- http://www.trialsjournal.com/content/16/1/439
Trials. 2015 Oct 5;16(1):439. doi: 10.1186/s13063-015-0971-z.
Cytokine inhibition in chronic fatigue syndrome patients: study protocol for a randomized controlled trial. 
Roerink ME, Knoop H, Bredie SJ, Heijnen M, Joosten LA, Netea MG, Dinarello CA, van der Meer JW.
Abstract
BACKGROUND: Chronic fatigue syndrome (CFS) is a medically unexplained syndrome for which no somatic or pharmacological treatment has been proven effective. Dysfunction of the cytokine network has been suspected to play a role in the pathophysiology of CFS. The disturbances of the cytokine network detected in CFS patients are highly variable, in part due to the lack of adequate controls in many studies. Furthermore, all studies have been performed on peripheral venous blood of patients. As cytokines mainly act in tissues, for example, the brain, the information that can be derived from peripheral blood cells is limited. The information regarding the possible role of cytokines in the pathophysiology could come from intervention studies in which the activities of relevant cytokines are reduced, for example, reducing interleukin-1, interleukin-6 or tumor necrosis factor. In this study, the clinical usefulness of anakinra, an IL-1 antagonist, will be assessed in patients with CFS.
METHODS/DESIGN: A randomized placebo-controlled, double-blind trial will be conducted. Fifty adult female patients meeting the Centers for Disease Control (CDC) criteria for CFS and without psychiatric co-morbidity will be included. After inclusion, patients will be randomized between treatment with anakinra (recombinant human
interleukin-1 receptor antagonist) or placebo. Each group will be treated for 4 weeks. Outcome measures will be assessed at baseline, after 4 weeks of intervention, and 6 months after baseline assessment.
The primary outcome measure will be fatigue severity at 4 weeks, measured with the validated Checklist of Individual Strength (CIS).
Secondary outcome measures are functional impairment, physical and social functioning, psychological distress, pain severity, presence of accompanying symptoms, and cytokine and cortisol concentrations.
DISCUSSION: This is the first randomized placebo-controlled trial that will evaluate the effect of interference with IL-1 on the experience of fatigue in patients with CFS. The results of this study may expand treatment options for patients with CFS, for whom graded exercise therapy and cognitive behavioral therapy are the only evidence-based interventions that exist at this moment.
TRIAL REGISTRATION: Clinicaltrials.gov: NCT02108210 .Clinicaltrials.gov registration date: 8 April 2014. EudraCT: 2013-005466-19.
PMID:26438161 [PubMed - in process]

 
http://www.ncbi.nlm.nih.gov/pubmed/26431138
Pain Physician. 2015 Sep-Oct;18(5):E841-E852.
Associations Between Cognitive Performance and Pain in Chronic Fatigue Syndrome: Comorbidity with Fibromyalgia Does Matter. 
Ickmans K, Meeus M, De Kooning M, Lambrecht L, Pattyn N, Nijs J.
Abstract
BACKGROUND: In addition to the frequently reported pain comp laints, performance-based cognitive capabilities in patients with chronic fatigue syndrome (CFS) with and without comorbid fibromyalgia (FM) are significantly worse than those of healthy controls. In various chronic pain populations, cognitive impairments are known to be related to pain severity. However, to the best of our knowledge, the association between cognitive performance and experimental pain measurements has never been examined in CFS patients.
OBJECTIVES: This study aimed to examine the association between cognitive performance and self-reported as well as experimental pain measurements in CFS patients with and without FM.
STUDY DESIGN: Observational study.
SETTING: The present study took place at the Vrije Universiteit Brussel and the University of Antwerp.
METHODS: Forty-eight (18 CFS-only and 30 CFS+FM) patients and 30 healthy controls were studied. Participants first completed 3 performance-based cognitive tests designed to assess selective and sustained attention, cognitive inhibition, and working memory capacity. Seven days later, experimental pain measurements (pressure pain thresholds [PPT], temporal summation [TS], and conditioned pain modulation [CPM]) took place and participants were asked to fill out 3 questionnaires to assess self-reported pain, fatigue, and depressive symptoms.
RESULTS: In the CFS+FM group, the capacity of pain inhibition was significantly associated with cognitive inhibition. Self-reported pain was significantly associated with simple reaction time in CFS-only patients. The CFS+FM but not the CFS-only group showed a significantly lower PPT and enhanced TS compared with controls.
LIMITATIONS: The cross-sectional nature of this study does not allow for inferences of causation.
CONCLUSIONS: The results underline disease heterogeneity in CFS by indicating that a measure of endogenous pain inhibition might be a significant predictor of cognitive functioning in CFS patients with FM, while self-reported pain appears more appropriate to predict cognitive functioning in CFS patients without FM.
PMID:26431138 [PubMed - as supplied by publisher]

 
fulltext- http://www.sciencedirect.com/science/article/pii/S0010945215003329
Recent Research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment
Roberta F. White, PhD (Chair, Professor), Lea Steele, PhD, (Veterans Health Research Program), James P. O’Callaghan, PhD, (Head, CDC Distinguished Consultant), Kimberly Sullivan, PhD, (Associate Scientific Director), James H. Binns, (Past Chair), Beatrice A. Golomb, MD, PhD, (Associate Professor of Internal Medicine), Floyd E. Bloom, MD, (Professor Emeritus), James A. Bunker, Fiona Crawford, PhD, (President), Joel C. Graves, DMin, (Captain, U.S. Army, Retired), Anthony Hardie, Nancy Klimas, MD, PhD
Abstract
Veterans of the 1991 Gulf War (GW) are a unique population of veterans who returned from theatre with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25-32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities.
Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theatre, including organophosphates, carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out.
This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008).
We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. 
Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been called “toxic wounds” by veterans. This type of injury requires further study and concentrated treatment research efforts that may also benefit other occupational groups with similar exposure-related illnesses.

 
fulltext- http://hic.sagepub.com/content/3/3/2324709615607908.full
Mitochondrial Myopathy in Follow-up of a Patient With Chronic Fatigue Syndrome
Fernando Galán, AOPT, Isabel de Lavera, PhD, David Cotán, PhD, José A.
Sánchez-Alcázar, AOPT
Journal of Investigative Medicine High Impact Case Reports 
Abstract
Introduction. Symptoms of mitochondrial diseases and chronic fatigue syndrome (CFS) frequently overlap and can easily be mistaken.
Methods. We report the case of a patient diagnosed with CFS and during follow-up was finally diagnosed with mitochondrial myopathy by histochemical study of muscle biopsy, spectrophotometric analysis of the complexes of the mitochondrial respiratory chain, and genetic studies.
Results. The results revealed 3% fiber-ragged blue and a severe deficiency of complexes I and IV and several mtDNA variants. Mother, sisters, and nephews showed similar symptoms, which strongly suggests a possible maternal inheritance. The patient and his family responded to treatment with high doses of riboflavin and thiamine with a remarkable and sustained fatigue and muscle symptoms improvement.
Conclusions. This case illustrates that initial symptoms of mitochondrial disease in adults can easily be mistaken with CFS, and in these patients a regular reassessment and monitoring of symptoms is recommended to reconfirm or change the diagnosis.

 

http://www.ncbi.nlm.nih.gov/pubmed/26454487
A new case definition of Neuro-Inflammatory and Oxidative Fatigue (NIOF), a neuroprogressive disorder, formerly known as chronic fatigue syndrome or Myalgic Encephalomyelitis: results of multivariate pattern recognition methods and external validation by neuro-immune biomarkers. 
Maes M.
Abstract
BACKGROUND: Chronic fatigue syndrome (CFS) or Myalgic Encephalomyelitis (ME) is characterized by neuro-psychiatric (e.g. depression, irritability, sleep disorders, autonomic symptoms and neurocognitive defects) and physio-somatic (fatigue, a flu-like malaise, hyperalgesia, irritable bowel, muscle pain and tension) symptoms. New ME/CFS case definitions based on consensus criteria among experts are largely inadequate, e.g. those of the US Institute of Medicine .
OBJECTIVES: The aim of the present study was to delineate a new case definition of ME/CFS based on pattern recognition methods and using neuro-immune, inflammatory, oxidative and nitrosative stress
(neuro-IO&NS) biomarkers as external validating criteria.
METHODS: We measured the 12-item Fibromyalgia and Chronic Fatigue Syndrome Rating (FF) Scale in 196 subjects with CFS (CDC criteria) and 83 with chronic fatigue. The "Neuro-IO&NS" biomarkers were: IgM / IgA responses against LPS of gut commensal bacteria (leaky gut), IgM responses to O&NS modified neoepitopes, autoimmunity to serotonin, plasma interleukin-1 (IL-1) and serum neopterin.
RESULTS: Cluster analysis showed the presence of two well-separated clusters with highly significant differences in symptoms and biomarkers. The cluster with higher scores on all FF items was externally validated against all IO&NS biomarkers and therefore this diagnostic group was labeled "Neuro-IO&NS Fatigue" or "Neuro-Inflammatory and Oxidative Fatigue" (NIOF).
An algorithm was constructed which defined NIOF as chronic fatigue and 4 or more of the following 6 symptoms: muscle tension, memory disturbances, sleep disorders, irritable bowel, headache or a flu-like malaise.
There was a significant overlap between NIOF and CFS although NIOF criteria were much more restrictive. Factor analysis showed two factors, the first a fatigue-hyperalgesia (fibromyalgic complaints) and the second a fatigue-depression factor.
PMID:26454487 [PubMed - as supplied by publisher]

 
http://www.ncbi.nlm.nih.gov/pubmed/26449441
Brain Connect. 2015 Oct 9. [Epub ahead of print]
Abnormal Resting-State Functional Connectivity in Patients with Chronic Fatigue Syndrome: Results of Seed and Data-Driven Analyses. 
Gay C, Robinson ME, Lai S, O'Shea A, Craggs J, Price DD, Staud R.
Abstract
Although altered resting-state functional connectivity is a characteristic of many chronic pain conditions it has not yet been evaluated in patients with chronic fatigue. Our objective was to investigate the association between fatigue and altered resting-state functional connectivity in myalgic-encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Thirty-six female subjects, 19 ME/CFS and 17 healthy controls completed a fatigue inventory before undergoing functional magnetic-resonance imaging. Two methods, 1) data driven and 2) model-based, were used to estimate and compare the intra-regional functional connectivity between both groups during the resting state (RS).
The first approach using independent-component analysis was applied to investigate five RS-networks: the default mode network (DMN), salience network (SN), left and right fronto-parietal networks (LFPN, RFPN), and sensory-motor network (SMN).
The second approach used a-priori selected seed regions demonstrating abnormal regional cerebral blood-flow (rCBF) in ME/CFS patients at rest.
In ME/CFS patients, Method-1 identified decreased intrinsic connectivity among regions within the LFPN. Furthermore, the functional connectivity of the left anterior mid-cingulate with the SMN and the connectivity of the left posterior-cingulate cortex with the SN were significantly decreased.
For Method-2, five distinct clusters within the right parahippocampus and occipital lobes, demonstrating significant rCBF reductions in ME/CFS patients were used as seeds.
The parahippocampal seed and three occipital-lobe seeds showed altered functional connectivity with other brain regions. The degree of abnormal connectivity correlated with the level of self-reported fatigue.
Our results confirm altered RS functional connectivity in patients with ME/CFS which was significantly correlated with the severity of their chronic fatigue.

 
Early Menopause and Other Gynecologic Risk Indicators for Chronic Fatigue Syndrome in Women
Roumiana S. Boneva, MD, PhD; Jin-Mann S. Lin, PhD; Elizabeth R. Unger, PhD, MD
| Disclosures
Menopause. 2015;22(8):826-834. 
Abstract
Objective. This study aims to examine whether gynecologic conditions are associated with chronic fatigue syndrome (CFS).
Methods. This study includes a subset of 157 women from a population-based case-control study in Georgia, United States, conducted in 2004-2009. Gynecologic history was collected using a self-administered questionnaire. Crude odds ratios (ORs) with 95% CIs and ORs adjusted for body mass index and other covariates, where relevant, were estimated for gynecologic conditions between 84 CFS cases and 73 healthy controls.
Results. Cases and controls were of similar age. Women with CFS reported significantly more gynecologic conditions and surgical operations than controls: menopause status (61.9% vs 37.0%; OR, 2.37; 95% CI, 1.21-4.66), earlier mean age at menopause onset (37.6 vs 48.6 y; adjusted OR, 1.22; 95% CI, 1.09-1.36), excessive menstrual bleeding (73.8% vs 42.5%; adjusted OR, 3.33; 95% CI, 1.66-6.70), bleeding between periods (48.8% vs 23.3%; adjusted OR, 3.31; 95% CI, 1.60-6.86), endometriosis (29.8% vs 12.3%; adjusted OR, 3.67; 95% CI, 1.53-8.84), use of noncontraceptive hormonal preparations (57.1% vs 26.0%; adjusted OR, 2.95; 95% CI, 1.36-6.38), nonmenstrual pelvic pain (26.2% vs 2.7%; adjusted OR, 11.98; 95% CI, 2.57-55.81), and gynecologic surgical operation (65.5% vs 31.5%; adjusted OR, 3.33; 95% CI, 1.66-6.67), especially hysterectomy (54.8% vs 19.2%; adjusted OR, 3.23; 95% CI, 1.46-7.17). Hysterectomy and oophorectomy occurred at a significantly younger mean age in the CFS group than in controls and occurred before CFS onset in 71% of women with records of date of surgical operation and date of CFS onset.
Conclusions. Menstrual abnormalities, endometriosis, pelvic pain, hysterectomy, and early/surgical menopause are all associated with CFS. Clinicians should be aware of the association between common gynecologic problems and CFS in women. Further work is warranted to determine whether these conditions contribute to the development and/or perpetuation of CFS in some women.

 
http://www.scientificamerican.com/article/the-tantalizing-links-bet...
The Tantalizing Links between Gut Microbes and the Brain
Neuroscientists are probing the idea that intestinal microbiota might influence brain development and behavior
By Peter Andrey Smith and Nature magazine | October 24, 2015

Nearly a year has passed since Rebecca Knickmeyer first met the participants in her latest study on brain development. Knickmeyer, a neuroscientist at the University of North Carolina School of Medicine in Chapel Hill, expects to see how 30 newborns have grown into crawling, inquisitive one-year-olds, using a battery of behavioural and temperament tests. In one test, a child's mother might disappear from the testing suite and then reappear with a stranger. Another ratchets up the weirdness with some Halloween masks. Then, if all goes well, the kids should nap peacefully as a noisy magnetic resonance imaging machine scans their brains.
“We try to be prepared for everything,” Knickmeyer says. “We know exactly what to do if kids make a break for the door.”
Knickmeyer is excited to see something else from the children—their faecal microbiota, the array of bacteria, viruses and other microbes that inhabit their guts. Her project (affectionately known as 'the poop study') is part of a small but growing effort by neuroscientists to see whether the microbes that colonize the gut in infancy can alter brain development.
The project comes at a crucial juncture. A growing body of data, mostly from animals raised in sterile, germ-free conditions, shows that microbes in the gut influence behaviour and can alter brain physiology and neurochemistry.
In humans, the data are more limited. Researchers have drawn links between gastrointestinal pathology and psychiatric neurological conditions such as anxiety, depression, autism, schizophrenia and neurodegenerative disorders—but they are just links.
“In general, the problem of causality in microbiome studies is substantial,” says Rob Knight, a microbiologist at the University of California, San Diego. “It's very difficult to tell if microbial differences you see associated with diseases are causes or consequences.” There are many outstanding questions. Clues about the mechanisms by which gut bacteria might interact with the brain are starting to emerge, but no one knows how important these processes are in human development and health.

 
 
.fulltext- http://www.sciencedirect.com/science/article/pii/S1984006315000632
Sleep Science
Sleep quality and the treatment of intestinal microbiota imbalance in Chronic Fatigue Syndrome: A pilot study
Melinda L. Jackson, Henry Butt, Michelle Ball, Donald Lewis, Dorothy Bruck
Abstract
Chronic Fatigue Syndrome (CFS) is a multisystem illness, which may be associated with imbalances in gut microbiota. This study builds on recent evidence that sleep may be influenced by gut microbiota, by assessing whether changes to microbiota in a clinical population known to have both poor sleep and high rates of colonization with gram-positive faecal Streptococcus, can improve sleep.
Twenty-one CFS participants completed a 22- day open label trial. Faecal microbiota analysis was performed at baseline and at the end of the trial. 
Participants were administered erythromycin 400 mg b.d. for 6 days. Actigraphy and questionnaires were used to monitor sleep, symptoms and mood. Changes in patients who showed a clinically significant change in faecal Streptococcus after treatment (responders; defined as post-therapy distribution<6%) were compared to participants who did not respond to treatment.
In the seven responders, there was a significant increase in actigraphic total sleep time (p=0.028) from baseline to follow up, compared with non-responders. Improved vigour scores were associated with a lower Streptococcus count (ρ=−0.90, p=0.037). For both the responders and the whole group, poorer mood was associated with higher Lactobacillus.
Short term antibiotic treatment appears to be insufficient to effect sustainable changes in the gut ecosystem in most CFS participants. Some improvement in objective sleep parameters and mood were found in participants with reduced levels of gram-positive gut microbiota after antibiotic treatment, which is encouraging.
Further study of possible links between gut microorganisms and sleep and mood disturbances is warranted.

 
fulltext- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605442/
Int J Psychol Behav Sci. 2015;5(2):98-107.
A Cross Cultural Comparison of Disability and Symptomatology Associated with CFS.
Zdunek M, Jason LA, Evans M, Jantke R, Newton JL
Abstract
Few studies have compared symptomatology and functional differences experienced by patients with chronic fatigue syndrome (CFS) across cultures. The current study compared patients with CFS from the United States (US) to those from the United Kingdom (UK) across areas of functioning, symptomatology, and illness onset characteristics. 
Individuals in each sample met criteria for CFS as defined by Fukuda et al. (1994). These samples were compared on two measures of disability and impairment, the DePaul Symptom Questionnarie (DSQ) and the Medical outcomes study 36-item short-form health survey (SF-36). 
Results revealed that the UK sample was significantly more impaired in terms of mental health and role emotional functioning, as well as specific symptoms of pain, neurocognitive difficulties, and immune manifestations. In addition, the UK sample was more likely to be working rather than on disability.
Individuals in the US sample reported more difficulties falling asleep, more frequently reported experiencing a sudden illness onset (within 24 hours), and more often reported that the cause of illness was primarily due to physical causes.
These findings suggest that there may be important differences in illness characteristics across individuals with CFS in the US and the UK, and this has implications for the comparability of research findings across these two countries.

 
http://www.ncbi.nlm.nih.gov/pubmed/26475444
Vaccine. 2015 Oct 13. pii: S0264-410X(15)01433-4. doi: 10.1016/j.vaccine.2015.10.018. [Epub ahead of print]
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated with pandemic influenza infection, but not with an adjuvanted pandemic influenza vaccine. 
Magnus P1, Gunnes N2, Tveito K3, Bakken IJ2, Ghaderi S2, Stoltenberg C2, Hornig M4, Lipkin WI4, Trogstad L2, Håberg SE2.
Author information
1Norwegian Institute of Public Health, 4404 Nydalen, 0403 Oslo, Norway. Electronic address: per.magnus@fhi.no.
2Norwegian Institute of Public Health, 4404 Nydalen, 0403 Oslo, Norway.
3Journal of the Norwegian Medical Association, Oslo, Norway.
4Center for Infection and Immunity, Columbia University, NY, NY, USA.
Abstract
BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is associated to infections and it has been suggested that vaccination can trigger the disease. However, little is known about the specific association between clinically manifest influenza/influenza vaccine and CFS/ME. As part of a registry surveillance of adverse effects after mass vaccination in Norway during the 2009 influenza A (H1N1) pandemic, we had the opportunity to estimate and contrast the risk of CFS/ME after infection and vaccination.
METHODS: Using the unique personal identification number assigned to everybody who is registered as resident in Norway, we followed the complete Norwegian population as of October 1, 2009, through national registries of vaccination, communicable diseases, primary health, and specialist health care until December 31, 2012. Hazard ratios (HRs) of CFS/ME, as diagnosed in the specialist health care services (diagnostic code G93.3 in the International Classification of Diseases, Version 10), after influenza infection and/or vaccination were estimated using Cox proportional-hazards regression.
RESULTS: The incidence rate of CFS/ME was 2.08 per 100,000 person-months at risk. The adjusted HR of CFS/ME after pandemic vaccination was 0.97 (95% confidence interval [CI]: 0.91-1.04), while it was 2.04 (95% CI: 1.78-2.33) after being diagnosed with influenza infection during the peak pandemic period.
CONCLUSIONS: Pandemic influenza A (H1N1) infection was associated with a more than two-fold increased risk of CFS/ME. We found no indication of increased risk of CFS/ME after vaccination. Our findings are consistent with a model whereby symptomatic infection, rather than antigenic stimulation may trigger CFS/ME.
Copyright © 2015. Published by Elsevier Ltd.

 
Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial
Prof Michael Sharpe x
Michael Sharpe

• Centre for Psychiatry, Wolfson Institute of Preventive Medicine, Bart's and The London Medical School, Queen Mary University of London, London, UK

Published Online: 27 October 2015    Publication stage: In Press Corrected Proof
DOI: http://dx.doi.org/10.1016/S2215-0366(15)00317-X
© 2015 Elsevier Ltd. All rights reserved.
SummaryBackgroundThe PACE trial found that, when added to specialist medical care (SMC), cognitive behavioural therapy (CBT), or graded exercise therapy (GET) were superior to adaptive pacing therapy (APT) or SMC alone in improving fatigue and physical functioning in people with chronic fatigue syndrome 1 year after randomisation. In this pre-specified follow-up study, we aimed to assess additional treatments received after the trial and investigate long-term outcomes (at least 2 years after randomisation) within and between original treatment groups in those originally included in the PACE trial.
MethodsThe PACE trial was a parallel-group randomised controlled trial of patients meeting Oxford criteria for chronic fatigue syndrome who were recruited from six secondary care clinics in the UK between March 18, 2005, and Nov 28, 2008. Participants were randomly allocated to receive SMC alone or plus APT, CBT, or GET. Primary outcomes (were fatigue measured with Chalder fatigue questionnaire score and physical functioning with short form-36 subscale score, assessed 1 year after randomisation. In this long-term follow-up, we sent postal questionnaires to assess treatment received after the trial and outcomes a minimum of 2 years after randomisation. We assessed long-term differences in outcomes within and between originally randomised groups. The PACE trial is registered at http://isrctn.org, number ISRCTN54285094.
FindingsBetween May 8, 2008, and April 26, 2011, 481 (75%) participants from the PACE trial returned questionnaires. Median time from randomisation to return of long-term follow-up assessment was 31 months (IQR 30–32; range 24–53). 210 (44%) participants received additional treatment (mostly CBT or GET) after the trial; with participants originally assigned to SMC alone (73 [63%] of 115) or APT (60 [50%] of 119) more likely to seek treatment than those originally assigned to GET (41 [32%] of 127) or CBT (36 [31%] of 118; p<0·0001). Improvements in fatigue and physical functioning reported by participants originally assigned to CBT and GET were maintained (within-group comparison of fatigue and physical functioning, respectively, at long-term follow-up as compared with 1 year: CBT −2·2 [95% CI −3·7 to −0·6], 3·3 [0·02 to 6·7]; GET −1·3 [–2·7 to 0·1], 0·5 [–2·7 to 3·6]). Participants allocated to APT and to SMC alone in the trial improved over the follow-up period compared with 1 year (fatigue and physical functioning, respectively: APT −3·0 [–4·4 to −1·6], 8·5 [4·5 to 12·5]; SMC −3·9 [–5·3 to −2·6], 7·1 [4·0 to 10·3]). There was little evidence of differences in outcomes between the randomised treatment groups at long-term follow-up.
InterpretationThe beneficial effects of CBT and GET seen at 1 year were maintained at long-term follow-up a median of 2·5 years after randomisation. Outcomes with SMC alone or APT improved from the 1 year outcome and were similar to CBT and GET at long-term follow-up, but these data should be interpreted in the context of additional therapies having being given according to physician choice and patient preference after the 1 year trial final assessment. Future research should identify predictors of response to CBT and GET and also develop better treatments for those who respond to neither.
 
 
Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy
E-mail address: petro8888@aol.com
 Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious
disease
R.A. Underhill ⇑,1
a r t i c l e i n f o
Article history:
Received 12 July 2015
Accepted 11 October 2015
Available online xxxx
a b s t r a c t
The etiology of myalgic encephalomyelitis also known as chronic fatigue syndrome or ME/CFS has not
been established. Controversies exist over whether it is an organic disease or a psychological disorder
and even the existence of ME/CFS as a disease entity is sometimes denied. Suggested causal hypotheses
have included psychosomatic disorders, infectious agents, immune dysfunctions, autoimmunity, metabolic
disturbances, toxins and inherited genetic factors. Clinical, immunological and epidemiological evidence
supports the hypothesis that: ME/CFS is an infectious disease; the causal pathogen persists in
patients; the pathogen can be transmitted by casual contact; host factors determine susceptibility to
the illness; and there is a population of healthy carriers, who may be able to shed the pathogen. ME/
CFS is endemic globally as sporadic cases and occasional cluster outbreaks (epidemics). Cluster outbreaks
imply an infectious agent. An abrupt flu-like onset resembling an infectious illness occurs in outbreak
patients and many sporadic patients. Immune responses in sporadic patients resemble immune
responses in other infectious diseases. Contagion is shown by finding secondary cases in outbreaks,
and suggested by a higher prevalence of ME/CFS in sporadic patients’ genetically unrelated close contacts
(spouses/partners) than the community. Abortive cases, sub-clinical cases, and carrier state individuals
were found in outbreaks. The chronic phase of ME/CFS does not appear to be particularly infective.
Some healthy patient-contacts show immune responses similar to patients’ immune responses, suggesting
exposure to the same antigen (a pathogen). The chronicity of symptoms and of immune system
changes and the occurrence of secondary cases suggest persistence of a causal pathogen. Risk factors
which predispose to developing ME/CFS are: a close family member with ME/CFS; inherited genetic factors;
female gender; age; rest/activity; previous exposure to stress or toxins; various infectious diseases
preceding the onset of ME/CFS; and occupational exposure of health care professionals. The hypothesis
implies that ME/CFS patients should not donate blood or tissue and usual precautions should be taken
when handling patients’ blood and tissue. No known pathogen has been shown to cause ME/CFS.
Confirmation of the hypothesis requires identification of a causal pathogen. Research should focus on a
search for unknown and known pathogens. Finding a causal pathogen could assist with diagnosis; help
find a biomarker; enable the development of anti-microbial treatments; suggest preventive measures;
explain pathophysiological findings; and reassure patients about the validity of their symptoms.
_ 2015 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
0306-9877/_ 2015 The Author. Published by Elsevier Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
⇑ Address: 7 Avenue De La Mer, #506, Palm Coast, FL 32137, USA. Tel.: +1 386 283
4025.
E-mail address: petro8888@aol.com
1 Independent researcher.
Medical Hypotheses xxx (2015) xxx–xxx
Contents lists available at ScienceDirect

 
Original article | Published 4 December 2014, doi:10.4414/smw.2014.14061
Cite this as: Swiss Med Wkly. 2014;144:w14061
Is internet use unhealthy? A cross-sectional study of adolescent internet overuse
Joan-Carles Surísa, Christina Akrea, Claire Pigueta, Anne-Emmanuelle Ambresina, Grégoire Zimmermannc, André Berchtolda,b
a Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland
b Institute of Social Sciences, University of Lausanne, Lausanne, Switzerland
c Institute of Psychology, University of Lausanne, Lausanne, Switzerland
SummaryAbbreviations
aOR  adjusted odds ratio
IAT  internet addiction test
SES  socioeconomic status
OBJECTIVE: To assess whether problematic internet use is associated with somatic complaints and whether this association remains when checking for internet activity among a random sample of adolescents living in the canton of Vaud, Switzerland.
METHODS: Cross-sectional survey of 3,067 8th graders (50.3% females) divided into average (n = 2,708) and problematic (n = 359) Internet users and compared for somatic complaints (backache, overweight, headaches, musculoskeletal pain, sleep problems and sight problems) controlling for sociodemographic and internet-related variables. Logistic regressions were performed for each complaint and for all of them simultaneously controlling variables significant at the bivariate level.
RESULTS: At the multivariate level, when taken separately, problematic internet users were more likely to have a chronic condition (adjusted odds ratio [aOR] with 95% CI: 1.58 [1.11:2.23]) and to report back pain (aOR: 1.46 [1.04:2.05]), overweight (aOR: 1.74 [1.03:2.93]), musculoskeletal pain (aOR: 1.36 [1.00:1.84]) and sleep problems (aOR: 2.16 [1.62:2.88]). When considered in the full model, only sleep problems remained significant (aOR: 2.03 [1.50:2.74]).
CONCLUSIONS: Our results confirm that problematic internet users report health problems more frequently, with lack of sleep being the most strongly associated and seeming to act as mediator regarding the other ones. Clinicians should remember to screen for excessive internet use their patients complaining of sleep-related problems, back or musculoskeletal pain or overweight. Clinicians should advise parents to limit the amount of time their adolescent children can spend online for leisure activities. Furthermore, limiting the number of devices used to connect to the internet could help warrant enough sleeping time.
Key words: adolescence; internet use; health status; adolescent behaviour

 
Adolescent Sleep Patterns and Night-Time Technology Use: Results of the Australian Broadcasting Corporation's Big Sleep Survey

• Amanda L. Gamble,

Affiliation: NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), The University of Sydney, Sydney, NSW, Australia
⨯

• Angela L. D'Rozario,

Affiliations: NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), The University of Sydney, Sydney, NSW, Australia, Sleep and Circadian Research Group, Woolcock Institute of Medical Research, Sydney, NSW, Australia
⨯

• Delwyn J. Bartlett,

Affiliations: NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), The University of Sydney, Sydney, NSW, Australia, Sleep and Circadian Research Group, Woolcock Institute of Medical Research, Sydney, NSW, Australia
⨯

• Shaun Williams,

Affiliation: NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), The University of Sydney, Sydney, NSW, Australia
⨯

• Yu Sun Bin,

Affiliation: NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), The University of Sydney, Sydney, NSW, Australia
⨯

• Ronald R. Grunstein,

Affiliations: NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), The University of Sydney, Sydney, NSW, Australia, Sleep and Circadian Research Group, Woolcock Institute of Medical Research, Sydney, NSW, Australia, Department of Sleep and Respiratory Failure, Royal Prince Alfred Hospital, Sydney, NSW, Australia
⨯

• Nathaniel S. Marshall

* E-mail: nathaniel.marshall@sydney.edu.au
Affiliations: NHMRC Centre for Integrated Research and Understanding of Sleep (CIRUS), The University of Sydney, Sydney, NSW, Australia, Sleep and Circadian Research Group, Woolcock Institute of Medical Research, Sydney, NSW, Australia, Sydney Nursing School, The University of Sydney, Sydney, NSW, Australia
⨯
 one

• Published: November 12, 2014
• DOI: 10.1371/journal.pone.0111700

AbstractIntroductionElectronic devices in the bedroom are broadly linked with poor sleep in adolescents. This study investigated whether there is a dose-response relationship between use of electronic devices (computers, cellphones, televisions and radios) in bed prior to sleep and adolescent sleep patterns.
MethodsAdolescents aged 11–17 yrs (n = 1,184; 67.6% female) completed an Australia-wide internet survey that examined sleep patterns, sleepiness, sleep disorders, the presence of electronic devices in the bedroom and frequency of use in bed at night.
ResultsOver 70% of adolescents reported 2 or more electronic devices in their bedroom at night. Use of devices in bed a few nights per week or more was 46.8% cellphone, 38.5% computer, 23.2% TV, and 15.8% radio. Device use had dose-dependent associations with later sleep onset on weekdays (highest-dose computer adjOR  = 3.75: 99% CI  = 2.17–6.46; cellphone 2.29: 1.22–4.30) and weekends (computer 3.68: 2.14–6.32; cellphone 3.24: 1.70–6.19; TV 2.32: 1.30–4.14), and later waking on weekdays (computer 2.08: 1.25–3.44; TV 2.31: 1.33–4.02) and weekends (computer 1.99: 1.21–3.26; cellphone 2.33: 1.33–4.08; TV 2.04: 1.18–3.55). Only ‘almost every night’ computer use (: 2.43: 1.45–4.08) was associated with short weekday sleep duration, and only ‘almost every night’ cellphone use (2.23: 1.26–3.94) was associated with wake lag (waking later on weekends).
ConclusionsUse of computers, cell-phones and televisions at higher doses was associated with delayed sleep/wake schedules and wake lag, potentially impairing health and educational outcomes.

 
BMJ 2015 Oct 28;5(10):e008830. doi: 10.1136/bmjopen-2015-008830.
Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is different in children compared to in adults: a study of UK and Dutch clinical cohorts.Collin SM1, Nuevo R1, van de Putte EM2, Nijhof SL2, Crawley E1.
Author information

• 1Centre for Child & Adolescent Health, School of Social and Community Medicine, University of Bristol, Bristol, UK.
• 2Department of Paediatrics, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.

AbstractOBJECTIVE:
To investigate differences between young children, adolescents and adults with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).
STUDY DESIGN:
Comparison of clinical cohorts from 8 paediatric and 27 adult CFS/ME services in the UK and a paediatric randomised controlled trial from the Netherlands. Outcome measures include: fatigue (the UK-Chalder Fatigue Scale); Disability (the UK-SF-36 physical function subscale; the Netherlands-CHQ-CF87); school attendance, pain, anxiety and depression (the UK-Hospital Anxiety & Depression Scale, Spence Children's Anxiety Scale; the Netherlands-Spielberger State-Trait Anxiety Inventory for Children, Children's Depression Inventory); symptoms; time-to-assessment; and body mass index. We used multinomial regression to compare younger (aged <12 years) and older (aged 12-18 years) children with adults, and logistic regression to compare UK and Dutch adolescents.
RESULTS:
Younger children had a more equal gender balance compared to adolescents and adults. Adults had more disability and fatigue, and had been ill for longer. Younger children were less likely to have cognitive symptoms (OR 0.18 (95% CI 0.13 to 0.25)) and more likely to present with a sore throat (OR 1.42 (1.07 to 1.90). Adolescents were more likely to have headaches (81.1%, OR 1.56 (1.36% to 1.80%)) and less likely to have tender lymph nodes, palpitations, dizziness, general malaise and pain, compared to adults. Adolescents were more likely to have comorbid depression (OR 1.51 (1.33 to 1.72)) and less likely to have anxiety (OR 0.46 (0.41 to 0.53)) compared to adults.
CONCLUSIONS:
Paediatricians need to recognise that children with CFS/ME present differently from adults. Whether these differences reflect an underlying aetiopathology requires further investigation.
TRIAL REGISTRATION NUMBERS:
FITNET trial registration numbers are ISRCTN59878666 and NCT00893438. This paper includes secondary (post-results) analysis of data from this trial, but are unrelated to trial outcomes.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
KEYWORDS:
EPIDEMIOLOGY; PAEDIATRICS
PMID:
26510728
[PubMed - in process]

 
Sleepmedicine - Nov 2015Volume 16, Issue 11, Pages 1313–1320
The effect of sleep deprivation on pain perception in healthy subjects: a meta-analysis
Marlene Schrimpfx

• epartment of Psychiatry and Psychotherapy, University Hospital Regensburg, Universitätsstraße 84, 93053 Regensburg, Germany

,
Highlights

• •Sleep deprivation has a medium effect (SMD = 0.62) on pain perception.
• •The calculated effect size is comparable with effect sizes achieved through pain treatment.
• •Sleep deprivation affects self-reported pain as well as pain threshold.

AbstractBackgroundThere is strong evidence indicating an interaction between sleep and pain. However, the size of this effect, as well as the clinical relevance, is unclear. Therefore, this meta-analysis was conducted to quantify the effect of sleep deprivation on pain perception.
MethodsA systematic literature search was conducted using the electronic databases PubMed, Cochrane, Psyndex, Psycinfo, and Scopus. By conducting a random-effect model, the pooled standardized mean differences (SMDs) of sleep deprivation on pain perception was calculated. Studies that investigated any kind of sleep deprivation in conjunction with a pain measurement were included. In cases of several pain measurements within a study, the average effect size of all measures was calculated.
ResultsFive eligible studies (N = 190) for the between-group analysis and ten studies (N = 266) for the within-group analysis were identified. Sleep deprivation showed a medium effect in the between-group analysis (SMD = 0.62; CI95: 0.12, 1.12; z = 2.43; p = 0.015) and a large effect in the within-group analysis (SMD = 1.49; CI95: 0.82, 2.17; z = 4.35; p < 0.0001). The test for heterogeneity was not significant in the between-group analysis (Q = 5.29; df = 4; p = 0.2584), but it was significant in the within-group analysis (Q = 53.49; df = 9; p < 0.0001).
ConclusionThis meta-analysis confirms a medium effect (SMD = 0.62) of sleep deprivation on pain perception. As this meta-analysis is based on experimental studies in healthy subjects, the clinical relevance should be clarified.
Keywords:
Sleep deprivation, Pain perception, Meta-analysis, Reciprocal relation

 
http://www.ncbi.nlm.nih.gov/pubmed/26594619
Neuroimage Clin. 2015 Sep 10;9:355-68. doi:
10.1016/j.nicl.2015.09.001. eCollection 2015.
Less efficient and costly processes of frontal cortex in childhood chronic fatigue syndrome. 
Mizuno K, Tanaka M, Tanabe HC, Joudoi T, Kawatani J, Shigihara Y, Tomoda A, Miike T, Imai-Matsumura K, Sadato N, Watanabe Y.
Abstract
The ability to divide one's attention deteriorates in patients with childhood chronic fatigue syndrome (CCFS).
We conducted a study using a dual verbal task to assess allocation of attentional resources to two simultaneous activities (picking out vowels and reading for story comprehension) and functional magnetic resonance imaging. Patients exhibited a much larger area of activation, recruiting additional frontal areas.
The right middle frontal gyrus (MFG), which is included in the dorsolateral prefrontal cortex, of CCFS patients was specifically activated in both the single and dual tasks; this activation level was positively correlated with motivation scores for the tasks and accuracy of story comprehension. In addition, in patients, the dorsal anterior cingulate gyrus (dACC) and left MFG were activated only in the dual task, and activation levels of the dACC and left MFG were positively associated with the motivation and fatigue scores, respectively.
Patients with CCFS exhibited a wider area of activated frontal regions related to attentional resources in order to increase their poorer task performance with massive mental effort.
This is likely to be less efficient and costly in terms of energy requirements. It seems to be related to the pathophysiology of patients with CCFS and to cause a vicious cycle of further increases in fatigue.

 
http://pec.sagepub.com/content/early/2015/11/03/0301006615614467.ab...
Increased Vulnerability to Pattern-Related Visual Stress in Myalgic Encephalomyelitis
Rachel L. Wilson, Kevin B. Paterson, Claire V. Hutchinson⇑
College of Medicine, Biological Sciences and Psychology, University of Leicester, UK.
Abstract
The objective of this study was to determine vulnerability to pattern-related visual stress in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A total of 20 ME/CFS patients and 20 matched (age, gender) controls were recruited to the study.
Pattern-related visual stress was determined using the Pattern Glare Test. Participants viewed three patterns, the spatial frequencies (SF) of which were 0.3 (low-SF), 2.3 (mid-SF), and 9.4 (high-SF) cycles per degree (c/deg).
They reported the number of distortions they experienced when viewing each pattern. ME/CFS patients exhibited significantly higher pattern glare scores than controls for the mid-SF pattern. Mid-high SF differences were also significantly higher in patients than controls.
These findings provide evidence of altered visual perception in ME/CFS. Pattern-related visual stress may represent an identifiable clinical feature of ME/CFS that will prove useful in its diagnosis. However, further research is required to establish if these symptoms reflect ME/CFS-related changes in the functioning of sensory neural pathways.

 
 
National Institute of Health Report for ME/CFS Research!    What it Means for You
By Suzanne D. Vernon, PhD
In case you missed it, ME/CFS, the Institute of Medicine report and the NIH have been all over the news the past few weeks. The National Institutes of Health (NIH) announced that they are taking action to bolster research on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). NIH has taken their cue from the Institute of Medicine (IOM) that recommended new diagnostic criteria for ME/CFS in a report published in February 2015 [that] emphasized the need for safe and effective treatments since focusing on ME/CFS in 2012.
But perhaps the most persuasive influence on NIH and the other government agencies has come from the patients who have used technology to unite and make their voice heard. Social media, petitions, blogs (like occupycfs.com and healthrising.com) and websites (like MEAction.org) have made it impossible the government to ignore millions of people suffering with ME/CFS.
Perhaps all of the media coverage has left you wondering what this really means. Since Dr. Bateman was on the IOM committee that produced the landmark report and I worked for the government for almost 20 years, we thought we could help cut through the noise.
First, here is what’s happening at the NIH. A study will start at the NIH Clinical Center –the world’s largest research hospital – where only patients that participate in research on specific diseases are admitted. The details of the ME/CFS study have not yet been released but it looks like it will focus on ME/CFS patients that had a sudden, flu-like onset. The main objective will be to understand what is going on at the biological and molecular level when someone develops ME/CFS following an infection. 
This ME/CFS study is going to generate some long overdue BIG DATA! I intend to be among the first to submit a BIG DATA analysis proposal to NIH. 
It was also announced that the Trans-NIH ME/CFS Research Working Group will be chaired by the Director of the National Institute of Neurological Disorders and Stroke (NINDS), Walter J. Koroshetz, M.D.
This refreshed working group with new leadership will help reinvigorate, coordinate and support ME/CFS activities at NIH. .
For far too long, the ME/CFS community has been diminished and dismissed. . A handful of researchers and doctors, like my colleague Dr. Bateman, have worked tirelessly to make change happen; champions that at times have worked at great personal sacrifice to forge a better way for our ME/CFS patient community. I believe it is all beginning to pay off. The wheels of change move far too slowly on a federal level, but they are moving. We are building a better future for all those impacted by ME/CFS. It is an exciting time to be on this journey with you!

 
fulltext- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615236/
Int J Med Sci. 2015; 12(10): 764–772.
Published online 2015 Sep 5. doi: 10.7150/ijms.12399
PMCID: PMC4615236
Serum Immune Proteins in Moderate and Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients
Sharni Lee Hardcastle, Ekua Weba Brenu, Samantha Johnston, Thao Nguyen, Teilah Huth, Sandra Ramos, Donald Staines, and Sonya Marshall-Gradisnik
Abstract
Immunological dysregulation is present in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), with recent studies also highlighting the importance of examining symptom severity.
This research addressed this relationship between CFS/ME severity subgroups, assessing serum immunoglobulins and serum cytokines in severe and moderate CFS/ME patients. Participants included healthy controls (n= 22), moderately (n = 22) and severely (n=19) affected CFS/ME patients.
The 1994 Fukuda Criteria defined CFS/ME and severity scales confirmed mobile and housebound CFS/ME patients as moderate and severe respectively. IL-1β was significantly reduced in severe compared with moderate CFS/ME patients. IL-6 was significantly decreased in moderate CFS/ME patients compared with healthy controls and severe CFS/ME patients. RANTES was significantly increased in moderate CFS/ME patients compared to severe CFS/ME patients.
Serum IL-7 and IL-8 were significantly higher in the severe CFS/ME group compared with healthy controls and moderate CFS/ME patients. IFN-γ was significantly increased in severe CFS/ME patients compared with moderately affected patients.
This was the first study to show cytokine variation in moderate and severe CFS/ME patients, with significant differences shown between CFS/ME symptom severity groups.
This research suggests that distinguishing severity subgroups in CFS/ME research settings may allow for a more stringent analysis of the heterogeneous and otherwise inconsistent illness.

 
http://journals.cambridge.org/action/displayAbstract?fromPage=onlin...
Original Papers
Persistence of impaired health status of Q fever patients 4 years after the first Dutch outbreak
G. J. M. LIMONARD, J. B. PETERS, R. BESSELINK, C. A. R. GROOT, P. N.
R. DEKHUIJZEN, J. H. VERCOULEN and M. H. NABUURS-FRANSSEN
SUMMARY
A significant proportion of Q fever patients from the first Dutch Q fever outbreak in 2007 showed impairment in health status up to 1 year after infection. Interested in whether this decrease in health status persisted, we set out to determine the health status in the same cohort of patients, 4 years after primary infection and to compare health status scores at the individual patient level between 1 and 4 years follow-up.
Health status was assessed with the Nijmegen Clinical Screening Instrument (NCSI). Patients were serologically tested to exclude patients with possible, probable or proven chronic Q fever.
Results on the NCSI sub-domains at group level [2008 (n = 54) and 2011 (n = 46)] showed a persistent significant percentage of patients exhibiting clinically relevant (‘severe’) scores for all NCSI sub-domains.
After 4 years, undue fatigue was present in 46% and exactly half of all patients experienced a severely impaired general quality of life. Patients with NCSI scores available in both 2008 and 2011 (n = 37) showed no difference in all sub-domain scores, except for a small decrease in dyspnoea emotions in 2011.
In this group, a significant proportion of patients either improved or worsened in one or more sub-domains of health status.
We conclude that at the group level, health status of Q fever patients remained impaired 4 years after primary infection. At the individual patient level, health status may change.

 
BMC Nursing 2015, 14:64  doi:10.1186/s12912-015-0115-5
Fatigue in adults with post-infectious fatigue syndrome: a qualitative content analysis
Eva Stormorken1*, Leonard A. Jason2 and Marit Kirkevold1 *
Corresponding author: Eva Stormorken eva.stormorken@medisin.uio.no
Author Affiliations
1 Department of Nursing Science, Institute of Health and Society, University of Oslo, Blindern 0318, Oslo, Norway
2 Center for Community Research, DePaul University, 990 W. Fullerton Ave, Suite 3100, Chicago 60614, Illinois, USA
The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1472-6955/14/64
 

Published:
28 November 2015
AbstractBackground
Fatigue is a major problem among individuals with post-infectious fatigue syndrome (PIFS), also known as chronic fatigue syndrome or myalgic encephalomyelitis. It is a complex phenomenon that varies across illnesses. From a nursing perspective, knowledge and understanding of fatigue in this illness is limited. Nurses lack confidence in caring for these patients and devalue their professional role. The aim of this study was to explore in-depth the experiences of fatigue among individuals with PIFS. A detailed description of the phenomenon of fatigue is presented. Increased knowledge would likely contribute to more confident nurses and improved nursing care.
Methods
A qualitative study with open interviews was employed. In-depth interviews with patients were fully transcribed and underwent a qualitative content analysis. A maximum variation sample of 26 affected adults between 26–59 years old was recruited from a population diagnosed at a fatigue outpatient clinic.
Results
The fatigue was a post-exertional, multidimensional, fluctuating phenomenon with varying degrees of severity and several distinct characteristics and was accompanied by concomitant symptoms. Fatigue was perceived to be an all-pervasive complex experience that substantially reduced the ability to function personally or professionally. A range of trigger mechanisms evoked or worsened the fatigue, but the affected were not always aware of what triggered it. There was an excessive increase in fatigue in response to even minor activities. An increase in fatigue resulted in the exacerbation of other concomitant symptoms. The term fatigue does not capture the participants’ experiences, which are accompanied by a considerable symptom burden that contributes to the illness experience and the severe disability.
Conclusions
Although some aspects of the fatigue experience have been reported previously, more were added in our study, such as the dimension of awakening fatigue and the characteristic beyond time, when time passes unnoticed. We also identified trigger mechanisms such as emotional, neurological, social, financial, and pressure on oneself or from others. This in-depth exploration of fatigue in PIFS provides an overview of the dimensions, characteristics, and trigger mechanisms of fatigue, thus making better clinical observations, early recognition, improved communication with patients and more appropriate nursing interventions possible.