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
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.
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.
↵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.
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
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).
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.
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.
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
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.
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
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.
Attentional and interpretive bias towards illness-related information in chronic fatigue syndrome: A systematic review.
Hughes A, Hirsch C, Chalder T, Moss-Morris R.
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.
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.
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.
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
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.
Factors determining fatigue in the chronic fatigue syndrome: a path analysis.
Tobback E, Hanoulle I, Mariman A, Delesie L, Pevernagie D, Vogelaers D
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; firstname.lastname@example.org
Received 15 April 2016 Revised 10 June 2016 Accepted 14 June 2016 Published Online First 4 July 2016
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.
- 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.
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.
- 1The National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute, Griffith University, Parklands Drive, Southport, Mailbox 68, Gold Coast, 4222, Australia. email@example.com.
- 2School of Medical Science, Griffith University, Gold Coast, Australia. firstname.lastname@example.org.
- 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.
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.
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.
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.
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; email@example.com
Received 7 October 2015
Revised 12 January 2016
Accepted 13 January 2016
Published Online First 2 February 2016
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.Department of General Surgery and Surgical SpecialtiesUniversity of Modena and Reggio Emilia Medical School, Surgical ClinicModenaItaly
- 2.Department of PaediatricsASST Melegnano e MartesanaVizzolo PredabissiItaly
- 3.Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, National Research Council-Institute of Neuroscience, University Hospital L. SaccoUniversity of MilanoMilanItaly
09 August 2016
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.