Chiari malformations: principles of diagnosis and management
BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l1159 (Published 08 April 2019)Cite this as: BMJ 2019;365:l1159

1. Rory J Piper, academic clinical fellow and neurosurgical trainee1,  
2. Michael Pike, honorary consultant paediatric neurologist2,  
3. Richard Harrington, honorary senior clinical lecturer and general practitioner3,  
4. Shailendra A Magdum, consultant paediatric neurosurgeon1

What you need to know

• There are different types of Chiari malformation, but they generally share the feature of the hindbrain protruding through the foramen magnum and into the spinal canal
• Chiari 1 malformation (CM1) is more common and typically presents in childhood or early adulthood with a combination of pain (headache, neck pain, or back pain), fatigue, poor memory, and neurological symptoms. Up to a quarter of patients have no symptoms
• Suspect Chiari 2 malformation (CM2) in infants with myelomeningocele. It may be diagnosed antenatally on ultrasound scan. Around 1 in 5 children will have associated symptoms
• Refer patients with a confirmed or suspected diagnosis to a neurosurgeon for further investigations and management
• The key investigation is magnetic resonance imaging of the brain and whole spine. Lumbar puncture must not be performed in these patients
• Offer support for long term follow-up and management of symptoms. Surgery may be considered in patients with significant or progressive symptoms

Chiari malformations are a heterogeneous group of hindbrain anomalies. Six different malformations are described. Most common are Chiari 1 malformation (CM1) and Chiari 2 malformation (CM2, also termed “Arnold-Chiari malformation”) and are the focus of this review.
These are rare conditions, but symptoms may impair quality of life in both adults and children,1 causing disruption to work or education and social exclusion. The diagnosis is often delayed or missed as symptoms may be mistaken for other neurological conditions or attributed as psychogenic.2 Not enough information or explanation from healthcare professionals3 can aggravate patients’ fears on being diagnosed. Although some patients improve after surgery, others experience lifelong symptoms, progression of deficits, need for re-operation, and complications.
Non-specialists can play an important role in early diagnosis and referral, counselling, and supporting long term care for these patients. 
Front. Pediatr., 18 April 2019 | https://doi.org/10.3389/fped.2019.00131

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Advances in ME/CFS: Past, Present, and Future
Kenneth J. Friedman*  Retired, Plantation, FL, United States
The forerunner of what is today termed myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was described by the U.S. Public Health Service in 1934. At the present time, we still do not know its cause and/or how to detect it by routine clinical laboratory tests. In consequence, the pathological nature of ME/CFS has been overlooked and the disease has been stigmatized by being mislabeled as psychosomatic or somatoform illness. Such misperceptions of the disease have led to insufficient research exploration of the disease and minimal to absent patient care. A 2015 Institute of Medicine report on the illness declared ME/CFS a disease affecting up to 2.5 million Americans and chastised the U.S. government for doing little to research the disease and to support its patients. Clinicians who currently treat this disease declare it to be more devastating than HIV/AIDS. A comparison of the histories of the two diseases, an examination of the current status of the two diseases, and a listing of the accomplishments that would be needed for ME/CFS to achieve the same level of treatment and care as currently experienced by patients with HIV/AIDS is provided.
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A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
R. Esfandyarpour, A. Kashi, M. Nemat-Gorgani, J. Wilhelmy, and R. W. Davis
PNAS first published April 29, 2019 https://doi.org/10.1073/pnas.1901274116
Contributed by R. W. Davis, March 26, 2019 (sent for review February 5, 2019; reviewed by Javad Gatabi and David R. Hillyard)
Significance
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease which afflicts approximately 2 million people in the United States and many more around the globe. A combination of factors might trigger ME/CFS, and there is currently no well-established blood-based biomarker to diagnose it. Taking advantage of advancements in micro/nanofabrication, direct electrical detection of cellular and molecular properties, microfluidics, and artificial intelligence techniques, we developed a nanoelectronics blood-based assay that can potentially establish a diagnostic biomarker and a drug-screening platform for ME/CFS. Given the significance of this assay, we envision it has the potential to be widely employed in research laboratories and clinics in the future as an aid to physicians as well as to our colleagues in the ME/CFS research community.
Abstract
There is not currently a well-established, if any, biological test to diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The molecular aberrations observed in numerous studies of ME/CFS blood cells offer the opportunity to develop a diagnostic assay from blood samples. Here we developed a nanoelectronics assay designed as an ultrasensitive assay capable of directly measuring biomolecular interactions in real time, at low cost, and in a multiplex format. To pursue the goal of developing a reliable biomarker for ME/CFS and to demonstrate the utility of our platform for point-of-care diagnostics, we validated the array by testing patients with moderate to severe ME/CFS patients and healthy controls. The ME/CFS samples’ response to the hyperosmotic stressor observed as a unique characteristic of the impedance pattern and dramatically different from the response observed among the control samples. We believe the observed robust impedance modulation difference of the samples in response to hyperosmotic stress can potentially provide us with a unique indicator of ME/CFS. Moreover, using supervised machine learning algorithms, we developed a classifier for ME/CFS patients capable of identifying new patients, required for a robust diagnostic tool.
Mol Med 2019 Apr 23;25(1):14. doi: 10.1186/s10020-019-0083-4.

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Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis patients.
Cabanas H1,2,3, Muraki K4,5, Balinas C6,7,5, Eaton-Fitch N6,7,5, Staines D6,7,5, Marshall-Gradisnik S
Abstract
BACKGROUND:
Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) is a complex multifactorial disorder of unknown cause having multi-system manifestations. Although the aetiology of CFS/ME remains elusive, immunological dysfunction and more particularly reduced cytotoxic activity in natural killer (NK) cells is the most consistent laboratory finding. The Transient Receptor Potential (TRP) superfamily of cation channels play a pivotal role in the pathophysiology of immune diseases and are therefore potential therapeutic targets. We have previously identified single nucleotide polymorphisms in TRP genes in peripheral NK cells from CFS/ME patients. We have also described biochemical pathway changes and calcium signaling perturbations in NK cells from CFS/ME patients. Notably, we have previously reported a decrease of TRP cation channel subfamily melastatin member 3 (TRPM3) function in NK cells isolated from CFS/ME patients compared with healthy controls after modulation with pregnenolone sulfate and ononetin using a patch-clamp technique. In the present study, we aim to confirm the previous results describing an impaired TRPM3 activity in a new cohort of CFS/ME patients using a whole cell patch-clamp technique after modulation with reversible TRPM3 agonists, pregnenolone sulfate and nifedipine, and an effective TRPM3 antagonist, ononetin. Indeed, no formal research has commented on using pregnenolone sulfate or nifedipine to treat CFS/ME patients while there is evidence that clinicians prescribe calcium channel blockers to improve different symptoms.
METHODS:
Whole-cell patch-clamp technique was used to measure TRPM3 activity in isolated NK cells from twelve age- and sex-matched healthy controls and CFS/ME patients, after activation with pregnenolone sulfate and nifedipine and inhibition with ononetin.
RESULTS:
We confirmed a significant reduction in amplitude of TRPM3 currents after pregnenolone sulfate stimulation in isolated NK cells from another cohort of CFS/ME patients compared with healthy controls. The pregnenolone sulfate-evoked ionic currents through TRPM3 channels were again significantly modulated by ononetin in isolated NK cells from healthy controls compared with CFS/ME patients. In addition, we used nifedipine, another reversible TRPM3 agonist to support the previous findings and found similar results confirming a significant loss of the TRPM3 channel activity in CFS/ME patients.
CONCLUSIONS:
Impaired TRPM3 activity was validated in NK cells isolated from CFS/ME patients using different pharmacological tools and whole-cell patch-clamp technique as the gold standard for ion channel research. This investigation further helps to establish TRPM3 channels as a prognostic marker and/ or a potential therapeutic target for CFS/ME.
PMID:  31014226  DOI:  10.1186/s10020-019-0083-4

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Pain Res Treat 2019 Jan 16;2019:2623161. doi: 10.1155/2019/2623161. eCollection 2019.
Motor Cortex Function in Fibromyalgia: A Study by Functional Near-Infrared Spectroscopy.
Gentile E1, Ricci K1, Delussi M1, Brighina F2, de Tommaso M1.

Abstract
Previous studies indicated changes of motor cortex excitability in fibromyalgia (FM) patients and the positive results of transcranial stimulation techniques. The present study aimed to explore the metabolism of motor cortex in FM patients, in resting state and during slow and fast finger tapping, using functional Near-Infrared Spectroscopy (fNIRS), an optical method which detects in real time the metabolism changes in the cortical tissue. We studied 24 FM patients and 24 healthy subjects. We found a significant slowness of motor speed in FM patients compared to controls. During resting state and slow movement conditions, the metabolism of the motor areas was similar between groups. The oxyhemoglobin concentrations were significantly lower in patients than in control group during the fast movement task. This abnormality was independent from FM severity and duration. The activation of motor cortex areas is dysfunctional in FM patients, thus supporting the rationale for the therapeutic role of motor cortex modulation in this disabling disorder.
PMID:30792923 PMCID:PMC6354141   DOI:10.1155/2019/2623161
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Is insulin resistance the cause of fibromyalgia? A preliminary report
Miguel A. Pappolla , Laxmaiah Manchikanti,Clark R. Andersen,Nigel H. Greig,Fawad Ahmed,
Xiang Fang,Michael A. Seffinger,Andrea M. Trescot

• Published: May 6, 2019
• https://doi.org/10.1371/journal.pone.0216079

Abstract
Fibromyalgia (FM) is one of the most frequent generalized pain disorders with poorly understood neurobiological mechanisms. This condition accounts for an enormous proportion of healthcare costs. Despite extensive research, the etiology of FM is unknown and thus, there is no disease modifying therapy available for this condition. We show that most (if not all) patients with FM belong to a distinct population that can be segregated from a control group by their glycated hemoglobin A1c (HbA1c) levels, a surrogate marker of insulin resistance (IR). This was demonstrated by analyzing the data after introducing an age stratification correction into a linear regression model. This strategy showed highly significant differences between FM patients and control subjects (p < 0.0001 and p = 0.0002, for two separate control populations, respectively). A subgroup of patients meeting criteria for pre-diabetes or diabetes (patients with HbA1c values of 5.7% or greater) who had undergone treatment with metformin showed dramatic improvements of their widespread myofascial pain, as shown by their scores using a pre and post-treatment numerical pain rating scale (NPRS) for evaluation. Although preliminary, these findings suggest a pathogenetic relationship between FM and IR, which may lead to a radical paradigm shift in the management of this disorder.
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Brain Imaging and behaviour  2019  pp1-16
Resting-state functional connectivity, cognition, and fatigue in response to cognitive exertion: a novel study in adolescents with chronic fatigue syndrome

• Authors
• Elisha K. Josev,Charles B. Malpas,Marc L. Seal, Adam Scheinberg  Lionel Lubitz
• Kathy Rowe,Sarah J. Knight

First Online: 17 May 2019
Abstract
Emerging evidence suggests that central nervous system dysfunction may underlie the core symptoms of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) in adults, such as cognitive disturbance, fatigue and post-exertional malaise. Research into brain dysfunction in the pediatric CFS/ME context, however, is severely lacking. It is unclear whether the adolescent CFS/ME brain functions differently compared with healthy peers, particularly in situations where significant mental effort is required. This study used resting-state functional MRI in a novel repeated-measures design to evaluate intrinsic connectivity, cognitive function, and subjective fatigue, before and after a period of cognitive exertion in 48 adolescents (25 CFS/ME, 23 healthy controls). Results revealed little evidence for a differential effect of cognitive exertion in CFS/ME compared with controls. Both groups demonstrated a similar rate of reduced intrinsic functional connectivity within the default mode network (DMN), reduced sustained attentional performance, slower processing speed, and increased subjective fatigue as a result of cognitive exertion. However, CFS/ME adolescents consistently displayed higher subjective fatigue, and controls outperformed the CFS/ME group overall on cognitive measures of processing speed, sustained attention and new learning. No brain-behavior relationships were observed between DMN connectivity, cognitive function, and fatigue over time. These findings suggest that effortful cognitive tasks may elicit similar levels of energy expenditure across all individuals in the form of reduced brain functioning and associated fatigue. However, CFS/ME may confer a lower starting threshold from which to access energy reserves and cognitive resources when cognitive effort is required.
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Brain, Behavior, and Immunity
Available online 7 June 2019
Patients with Fibromyalgia and Chronic Fatigue Syndrome show increased hsCRP compared to healthy controls
NinaGrovenacEgil A.ForsbSolveig KlæboReitanac
https://doi.org/10.1016/j.bbi.2019.06.010Get rights and content
Abstract
Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are both chronic disorders that have a devastating effect on the lives of the affected patients and their families. Both conditions have overlapping clinical features that partly resemble those of inflammatory disorders. The etiology is still not understood, and it is suggested that the immune system might be a contributing factor. So far, the results are inconclusive. The purpose of this study was to compare the two conditions and investigate the level of the inflammatory marker high-sensitivity CRP (hsCRP) in CFS and FM patients compared to healthy controls.
Female participants aged 18–60 years were enrolled in this study. The group consisted of 49 CFS patients, 57 FM patients, and 54 healthy controls. hsCRP levels were significantly higher for both the CFS and the FM groups compared to healthy controls when adjusting for age, smoking, and BMI (p < .001). There was no difference between the two patient groups. The level of hsCRP was affected by BMI but not by age and smoking.
Patients with CFS and FM have higher concentrations of hsCRP compared to healthy controls. This remains significant even after adjusting for BMI. CFS and FM cannot be distinguished from each other on the basis of hsCRP in our study.
PAIN. JUN 2019
DOI: 10.1097/j.pain.0000000000001640
,  

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PMID: 31219947 Issn Print: 0304-3959 Publication Date: 2019/06/01
Altered microbiome composition in individuals with fibromyalgia
Amir Minerbi;Emmanuel Gonzalez;Nicholas Brereton;Abraham Anjarkouchian;Ken Dewar;Mary-Ann Fitzcharles;Stéphanie Chevalier;Yoram Shir;

• Abstract:

Fibromyalgia (FM) is a prevalent syndrome, characterised by chronic widespread pain, fatigue and impaired sleep, that is challenging to diagnose and difficult to treat. The microbiomes of 77 women with FM and that of 79 control participants were compared using 16S rRNA gene amplification and whole genome sequencing. When comparing FM patients to unrelated controls using differential abundance analysis, significant differences were revealed in several bacterial taxa. Variance in the composition of the microbiomes was explained by FM-related variables more than by any other innate or environmental variable and correlated with clinical indices of FM. In line with observed alteration in butyrate metabolising species, targeted serum metabolite analysis verified differences in the serum levels of butyrate and propionate in FM patients. Using machine learning algorithms, the microbiomecomposition alone allowed for the classification of patients and controls (ROC AUC 87.8%). To the best of our knowledge, this is the first demonstration of gut microbiome alteration in non-visceral pain. This observation paves the way for further studies, elucidating the pathophysiology of FM, developing diagnostic aids and possibly allowing for new treatment modalities to be explored.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
© 2019 International Association for the Study of Pain
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Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome. 
Physiological Reports, 2019 Jun; 7(11) http://bit.ly/2XQM6Ty 
Lien K1,2, Johansen B3, Veierød MB4, Haslestad AS1, Bøhn SK1, Melsom MN5, Kardel KR1, Iversen PO1,6.
Abstract
Post-exertional malaise and delayed recovery are hallmark symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies on repeated cardiopulmonary exercise testing (CPET) show that previous exercise negatively affects oxygen uptake (VO2 ) and power output (PO) in ME/CFS. Whether this affects arterial lactate concentrations ([Laa ]) is unknown. We studied 18 female patients (18-50 years) fulfilling the Canadian Consensus Criteria for ME/CFS and 15 healthy females (18-50 years) who underwent repeated CPETs 24 h apart (CPET1 and CPET2 ) with [Laa ] measured every 30th second. VO2 at peak exercise (VO2peak ) was lower in patients than in controls on CPET1 (P < 0.001) and decreased in patients on CPET2 (P < 0.001). However, the difference in VO2peak between CPETs did not differ significantly between groups. [Laa ] per PO was higher in patients during both CPETs (Pinteraction  < 0.001), but increased in patients and decreased in controls from CPET1 to CPET2 (Pinteraction  < 0.001). Patients had lower VO2 (P = 0.02) and PO (P = 0.002) at the gas exchange threshold (GET, the point where CO2 production increases relative to VO2 ), but relative intensity (%VO2peak ) and [Laa ] at GET did not differ significantly from controls on CPET1 . Patients had a reduction in VO2 (P = 0.02) and PO (P = 0.01) at GET on CPET2 , but no significant differences in %VO2peak and [Laa ] at GET between CPETs. Controls had no significant differences in VO2 , PO or %VO2peak at GET between CPETs, but [Laa ] at GET was reduced on CPET2 (P = 0.008). In conclusion, previous exercise deteriorates physical performance and increases [Laa ] during exercise in patients with ME/CFS while it lowers [Laa ] in healthy subjects.
© 2019 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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The ‘Cognitive Behavioural Model’ Of Chronic Fatigue Syndrome: Critique Of A Flawed Model 
Keith Geraghty, Leonard Jason, Madison Sunnquist, David Tuller, Charlotte Blease and Charles Adeniji (The following paragraphs are taken from the study – The Editors)
 Chronic fatigue syndrome/myalgic encephalomyelitis is a debilitating illness that greatly impacts the lives of sufferers. A cognitive behavioural model attempts to explain illness onset and continuance with a hypothesis that the illness is perpetuated by patients’ irrational beliefs and avoidance behaviours. This theory underpins the promotion of cognitive behavioural therapy, a treatment that aims to change beliefs and behaviours. This article reports on a detailed review of the cognitive behavioural model. Our review finds that the model lacks high-quality evidential support, conflicts with accounts given by most patients and fails to account for accumulating biological evidence of pathological and physiological abnormalities found in patients. There is little scientific credibility in the claim that psycho-behavioural therapies are a primary treatment for this illness. The CBM of ME/CFS CBT originated in the ground-breaking work of Beck in the 1960s and 1970s, as an experimental psychological treatment for depression (Beck, 1976). Since then, the application of CBT has widened to the treatment of anxiety, phobias, obsessive compulsive disorders and more recently, ME/CFS (Wessely et al., 1989). In the United Kingdom, in the late 1980s/early 1990s, psychiatrists proposed that Beck’s CBT could be used to treat ME/CFS. A model of CFS was proposed by psychiatry that dismissed Ramsay’s ME organic infectious disease in favour of a mostly psychogenic model of CFS. The ‘cognitive behavioural model’ of CFS is Beck’s CBT modified and applied to CFS. In this sense, the CBM of ME/CFS is distinct from Beck’s CBM for depression – and must be assessed on its own merits. Proponents of the CBM write, cognitive behavioural models propose that beliefs about the unacceptability of experiencing or expressing negative thoughts and emotions can play a central role in the development and maintenance of clinical problems and can be associated with a poorer prognosis or treatment outcome. (Rimes and Chalder, 2010) Sharpe (2007, citing Wessely et al., 1989) concedes that the theory behind the use of CBT in CFS is weak: ‘… treatment is plausible, but lacks a theoretical rationale. It is possible to construct a hypothetical model by assuming that the aforementioned factors interact in self-perpetuating vicious circles’. The notion of ‘a cycle’ is repeated throughout the CBM literature. 61 Back to Table Of Contents Problematic evidence from clinical trials and practice Proponents of the CBM consistently argue that the model is validated via the success of CBT and GET in randomised controlled trials and clinical practice. It would be impossible to critique all CBT trial evidence within the confines of this article, thus we point readers to reviews of the field (Rimbaut et al., 2016) and systematic reviews (Larun et al., 2016; Price et al., 2008) that appear to show, prima facie, that CBT and GET outperform other treatments for ME/ CFS (mostly usual care) with small-tomodest effect sizes. However, this evidence is increasingly contested by reanalysis of data from clinical trials (Geraghty et al., 2017; Wilshire et al., 2018) and meta-reviews (Vink and VinkNiese, 2018). Many patients seen in CFS treatment studies appear to be drawn from psychiatric centres with high rates of psychiatric morbidity. In the study of Wessely and Powell (1989), 22 (47%) patients met the criteria for major depressive disorder. The inclusion of patients with mental health complaints that might explain their presenting fatigue is a contamination issue that persists to this day in clinical trials of CBT treatment for ME/CFS (Taylor et al., 2003). In Wessely and Powell’s work, approximately half of patients with CFS were indistinguishable from the control patients with psychiatric disorders, except for illness attribution and CFS diagnosis. Conclusion In this article, we reviewed the CBM of ME/CFS. This model is often cited in the literature as a model to guide clinical practice and treatment of this illness. We find this model to be primarily an idealised narrative model. It exists as a dogmatic model favoured by model promoters. Our review exposes stark weaknesses, inconsistencies and contradictions, both in its theoretical underpinnings and the research said to prove model validity. Our findings suggest the CBM is not fit for purpose, as it poorly reflects the accounts given by patients and it ignores the wealth of evidence showing biological, immune and neurological dysfunction in ME/CFS. Given that the CBM is cited as the basis for CBT and GET interventions, there is an urgent need for clinicians, therapists and health providers to review this treatment paradigm. Our findings help explain why so many patients reject psychotherapy. An alternative model should be formulated to better explain the biological factors that predispose, precipitate and perpetuate the illness. An explanatory model needs to closely resemble illness pathogenesis and provide logic-driven linkages between factors, including patients’ symptoms and illness behaviours. Source: http://bit.ly/2FdIGTJ Submitted by Prof. Leonard Jason
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Molecular Switch For 'Exhaustion Mode' Of Immune Cells Discovered TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection 
Francesca Alfei, Kristiyan Kanev, Maike Hofmann, Ming Wu, Hazem E. Ghoneim, Patrick Roelli, Daniel T. Utzschneider, Madlaina von Hösslin, Jolie G. Cullen, Yiping Fan, Vasyl Eisenberg, Dirk Wohlleber, Katja Steiger, Doron Merkler, Mauro Delorenzi, Percy A. Knolle, Cyrille J. Cohen, Robert Thimme, Benjamin Youngblood & Dietmar Zehn 
Nature , 17 June 2019
 Abstract Cytotoxic T-cells are essential mediators of protective immunity to viral infection and malignant tumors and are a key target for immunotherapy approaches. However, prolonged exposure to cognate antigen often attenuates the effector capacity of T-cells and limits their therapeutic potential. This process, known as T-cell exhaustion or dysfunction, is manifest through epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and up-regulate the expression of inhibitory receptors such as Programmed Cell-Death 1 (PD-1). Thus far, the underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T-cells are vaguely understood9– 12. Here we report that the development and maintenance of exhausted T-cell populations requires the thymocyte selection-associated high mobility group-box protein (Tox). Tox is induced by high antigen T-cell receptor stimulation and correlates with the presence of an “exhausted” phenotype during chronic Lymphocytic choriomeningitis virus and human hepatitis C virus infection. Removal of its DNA-binding domain reduces PD-1 expression, augments cytokine production, and results in a more polyfunctional T-cell phenotype. Such mutated T-cells initially mediate increased effector function and cause more severe immunopathology but ultimately undergo a massive decline in their quantity, notably among the subset of Tcf1+ self-renewing T cells. Altogether, we establish Tox as a critical factor for the normal progression of T-cell dysfunction, for the maintenance of exhausted T-cells during chronic infection, and we document a link between CD8 T-cell intrinsic suppression of effector function and protection against immune-pathology. 
Source: https://go.nature.com/2WNJKDG.
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Current Research Provides Insight into the Biological Basis and Diagnostic Potential for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Eiren Sweetman 1,Alex Noble 1,Christina Edgar 1,Angus Mackay 1,Amber Helliwell 1,Rosamund Vallings 2,Margaret Ryan 3 andWarren Tate 1,*
Diagnostics 2019, 9(3), 73; https://doi.org/10.3390/diagnostics9030073
Received: 30 May 2019 / Revised: 22 June 2019 / Accepted: 3 July 2019 / Published: 10 July 2019
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe fatigue illness that occurs most commonly following a viral infection, but other physiological triggers are also implicated. It has a profound long-term impact on the life of the affected person. ME/CFS is diagnosed primarily by the exclusion of other fatigue illnesses, but the availability of multiple case definitions for ME/CFS has complicated diagnosis for clinicians. There has been ongoing controversy over the nature of ME/CFS, but a recent detailed report from the Institute of Medicine (Academy of Sciences, USA) concluded that ME/CFS is a medical, not psychiatric illness. Importantly, aspects of the biological basis of the ongoing disease have been revealed over the last 2–3 years that promise new leads towards an effective clinical diagnostic test that may have a general application. Our detailed molecular studies with a preclinical study of ME/CFS patients, along with the complementary research of others, have reported an elevation of inflammatory and immune processes, ongoing neuro-inflammation, and decreases in general metabolism and mitochondrial function for energy production in ME/CFS, which contribute to the ongoing remitting/relapsing etiology of the illness. These biological changes have generated potential molecular biomarkers for use in diagnostic ME/CFS testing.  

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Altered microbiome composition in individuals with fibromyalgia
Minerbi, Amir1; Gonzalez, Emmanuel2,3; Brereton, Nicholas J.B.4; Anjarkouchian, Abraham5; Dewar, Ken3,6; Fitzcharles, Mary-Ann1,7; Chevalier, Stéphanie5,8,9; Shir, Yoram1
PAIN: June 18, 2019 - Volume Articles in Press - Issue - p
doi: 10.1097/j.pain.0000000000001640

• Abstract

Fibromyalgia (FM) is a prevalent syndrome, characterised by chronic widespread pain, fatigue and impaired sleep, that is challenging to diagnose and difficult to treat. The microbiomes of 77 women with FM and that of 79 control participants were compared using 16S rRNA gene amplification and whole genome sequencing. When comparing FM patients to unrelated controls using differential abundance analysis, significant differences were revealed in several bacterial taxa. Variance in the composition of the microbiomes was explained by FM-related variables more than by any other innate or environmental variable and correlated with clinical indices of FM. In line with observed alteration in butyrate metabolising species, targeted serum metabolite analysis verified differences in the serum levels of butyrate and propionate in FM patients. Using machine learning algorithms, the microbiomecomposition alone allowed for the classification of patients and controls (ROC AUC 87.8%). To the best of our knowledge, this is the first demonstration of gut microbiome alteration in non-visceral pain. This observation paves the way for further studies, elucidating the pathophysiology of FM, developing diagnostic aids and possibly allowing for new treatment modalities to be explored.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
© 2019 International Association for the Study of Pain

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Monitoring treatment harm in myalgic encephalomyelitis/chronic fatigue syndrome: A freedom-of-information study of National Health Service specialist centres in England
Graham McPhee, Adrian Baldwin, Tom Kindlon, First Published June 24, 2019 Research 
https://doi.org/10.1177/1359105319854532

Abstract
The use of graded exercise therapy and cognitive behavioural therapy for myalgic encephalomyelitis/chronic fatigue syndrome has attracted considerable controversy. This controversy relates not only to the disputed evidence for treatment efficacy but also to widespread reports from patients that graded exercise therapy, in particular, has caused them harm. We surveyed the National Health Service–affiliated myalgic encephalomyelitis/chronic fatigue syndrome specialist clinics in England to assess how harms following treatment are detected and to examine how patients are warned about the potential for harms. We sent 57 clinics standardised information requests under the United Kingdom’s Freedom of Information Act. Data were received from 38 clinics. Clinics were highly inconsistent in their approaches to the issue of treatment-related harm. They placed little or no focus on the potential for treatment-related harm in their written information for patients and for staff. Furthermore, no clinic reported any cases of treatment-related harm, despite acknowledging that many patients dropped out of treatment. In light of these findings, we recommend that clinics develop standardised protocols for anticipating, recording, and remedying harms, and that these protocols allow for therapies to be discontinued immediately whenever harm is identified.
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Unemployment and work disability in individuals with chronic fatigue syndrome/myalgic encephalomyelitis: a community-based cross-sectional study from Spain

• Jesús Castro-Marrero†Email authorView ORCID ID profile,Mónica Faro†, María Cleofé Zaragozá,Luisa Aliste,Tomás Fernández de Sevilla and
• José Alegre

BMC Public Health201919:840
https://doi.org/10.1186/s12889-019-7225-z       Published: 28 June 2019
Abstract
Background
Few reports have examined the association between unemployment and work disability in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). This study explored the key determinants of work disability in a CFS/ME cohort.
Methods
A community-based prospective study included 1086 CFS/ME patients aged 18–65 years. Demographic and clinical characteristics and outcome measures were recorded. Multiple linear regression analysis was performed to identify key risk indicators of work disability.
Results
Four hundred and fifty patients with CFS/ME were employed (41.4%) and 636 were unemployed (58.6%). Older age at pain onset (OR: 1.44; 95% CI: 1. 12–1.84, autonomic dysfunction (OR: 2.21; 95% CI: 1.71–2.87), neurological symptom (OR: 1.66; 95% CI: 1. 30–2.13) and higher scores for fatigue (OR: 2.61; 95% CI: 2.01–3.39), pain (OR: 2.09; 95% CI: 1.47–2.97), depression (OR: 1.98; 95% CI: 1. 20–3.26), psychopathology (OR: 1.98; 95% CI: 1.51–2.61) and sleep dysfunction (OR: 1.47; 95% CI: 1. 14–1.90) were all associated with a higher risk of work disability due to illness.
Conclusions
Using an explanatory approach, our findings suggest that unemployment is consistently associated with an increased risk of work disability due to CFS/ME, although further more rigorous research is now needed to help in targeting interventions at the workplace.
_____________________________________________________________________________________

Front. Pediatr., 24 May 2019 | https://doi.org/10.3389/fped.2019.00206
Genetic Predisposition for Immune System, Hormone, and Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study
Melanie Perez1, Rajeev Jaundoo2,3, Kelly Hilton1, Ana Del Alamo1,3, Kristina Gemayel1, Nancy G. Klimas1,3,4, Travis J. A. Craddock1,2,3,5* and Lubov Nathanson1,3*
Introduction: Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a multifactorial illness of unknown etiology with considerable social and economic impact. To investigate a putative genetic predisposition to ME/CFS we conducted genome-wide single-nucleotide polymorphism (SNP) analysis to identify possible variants.
Methods: 383 ME/CFS participants underwent DNA testing using the commercial company 23andMe. The deidentified genetic data was then filtered to include only non-synonymous and nonsense SNPs from exons and microRNAs, and SNPs close to splice sites. The frequencies of each SNP were calculated within our cohort and compared to frequencies from the Kaviar reference database. Functional annotation of pathway sets containing SNP genes with high frequency in ME/CFS was performed using over-representation analysis via ConsensusPathDB. Furthermore, these SNPs were also scored using the Combined Annotation Dependent Depletion (CADD) algorithm to gauge their deleteriousness.
Results: 5693 SNPs were found to have at least 10% frequency in at least one cohort (ME/CFS or reference) and at least two-fold absolute difference for ME/CFS. Functional analysis identified the majority of SNPs as related to immune system, hormone, metabolic, and extracellular matrix organization. CADD scoring identified 517 SNPs in these pathways that are among the 10% most deleteriousness substitutions to the human genome.
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Epstein-Barr Virus dUTPase Induces Neuroinflammatory Mediators: Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Marshall V. Williams PhD      Brandon Cox     William P. Lafuse PhD      Maria Eugenia Ariza, PhD 
DOI: https://doi.org/10.1016/j.clinthera.2019.04.009     Clinical Therapeutics
Abstract
Neuroinflammation is a common feature in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), affecting 85%–90% of all patients, yet the underlying mechanism or mechanisms responsible for the initiation and/or promotion of this process is largely unknown. Multiple reports, however, have suggested a role for Epstein-Barr virus (EBV), in particular, in ME/CFS, but its potential role, if any, in the neuroinflammatory process has not been addressed. In support of this premise, studies by our group have found that the EBV protein deoxyuridine triphosphate nucleotidohydrolase (dUTPase) induces anxiety and sickness behaviors in female mice. We also found that a small subset of patients with ME/CFS exhibited prolonged and significantly elevated neutralizing antibodies against EBV dUTPase protein in serum, which inversely correlated with ME/CFS symptoms. A larger ME/CFS case–control cohort study further confirmed that a significant percentage of patients with ME/CFS (30.91%–52.7%) were simultaneously producing antibodies against multiple human herpesviruses-encoded dUTPases and/or human dUTPase. Altogether, these findings suggest that EBV dUTPase protein may be involved in the neuroinflammatory process observed in ME/CFS. Thus, the aim of the present study was to determine whether the EBV dUTPase protein could contribute to neuroinflammation by altering the expression of genes involved with maintaining blood–brain barrier (BBB) integrity and/or modulating synaptic plasticity.
Methods
With the use of human immortalized astrocytes, microglia, and cerebral microvascular endothelial cells, we conducted time-course (0–24 h) experiments with EBV dUTPase protein (10 μg/mL) to determine what effect(s) it may have on the expression of genes involved with BBB permeability, astrocytes and microglia cell function, tryptophan metabolism, and synaptic plasticity by quantitative reverse transcription polymerase chain reaction (qRT-PCR). In parallel, in vivo studies were conducted in female C57Bl/6 mice. Mice were injected by the intraperitoneal route with EBV dUTPase protein (10 μg) or vehicle daily for 5 days, and the brains were collected and processed for further qRT-PCR analysis of the in vivo effect of the dUTPase on the dopamine/serotonin and γ-aminobutyric acid/glutamate pathways, which are important for brain function, using RT2 Profiler PCR Arrays.
Findings
EBV dUTPase protein altered the expression in vitro (12 of 15 genes and 32 of 1000 proteins examined) and in vivo (34 of 84 genes examined) of targets with central roles in BBB integrity/function, fatigue, pain synapse structure, and function, as well as tryptophan, dopamine, and serotonin metabolism.
Implications
The data suggest that in a subset of patients with ME/CFS, the EBV dUTPase could initiate a neuroinflammatory reaction, which contributes to the fatigue, excessive pain, and cognitive impairments observed in these patients.
_____________________________________________________________________________________

Searching for Serum Antibodies to Neuronal Proteins in Patients With Myalgic Encephalopathy/Chronic Fatigue Syndrome
Maria PiaGiannoccaro1JudithCossins1KariSørland2ØysteinFluge2AngelaVincent1
https://doi.org/10.1016/j.clinthera.2019.04.001Get rights and content
Abstract
Purpose
A role for the immune system in causing myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is long suspected, but few studies have looked for specific autoantibodies that might contribute to the symptoms. Our aim was to look for evidence of antibodies to neuronal proteins in patients with ME/CFS.
Methods
Sera samples from 50 patients and 50 healthy individuals were sent coded to the Neuroimmunology Laboratory in Oxford. Screening for antibody binding to neuronal tissue was performed on brain tissue and neuronal cultures. Specific serum antibodies were assessed by antigen-specific cell-based assays and radioimmunoassays. After antibody testing, the associations between seropositive status and clinical data were investigated.
Findings
Overall, 8 patients and 11 participants were found to have some serum immunoreactivity toward neuronal or neuromuscular junction proteins, but only 1 patient and 2 participants had specific serum antibodies. Nevertheless, seropositive status in patients with ME was associated with shorter duration since onset and a more severe disease.
Implications
The results indicate no overall increased frequency of antibodies to neuronal proteins in ME/CSF and no evidence of a specific antibody that might be causative or contribute to clinical features in patients. However, the association of seropositive status with shorter duration of disease and more severe symptoms suggests a possible role of antibodies at onset in some patients and should be the focus of future studies.
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Diagnostics 2019, 9(3), 82; https://doi.org/10.3390/diagnostics9030082
Article
The IDO Metabolic Trap Hypothesis for the Etiology of ME/CFS
Alex A. Kashi 1,Ronald W. Davis 1,2 and Robert D. Phair 3,*
Stanford Genome Technology Center, Stanford University, Palo Alto, CA 94304, USA
Departments of Biochemistry and Genetics, Stanford University, Stanford, CA 94305, USA
Integrative Bioinformatics Inc., Mountain View, CA 94041, USA
Received: 24 May 2019 / Accepted: 24 July 2019 / Published: 26 July 2019
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating noncommunicable disease brandishing an enormous worldwide disease burden with some evidence of inherited genetic risk. Absence of measurable changes in patients’ standard blood work has necessitated ad hoc symptom-driven therapies and a dearth of mechanistic hypotheses regarding its etiology and possible cure. A new hypothesis, the indolamine-2,3-dioxygenase (IDO) metabolic trap, was developed and formulated as a mathematical model. The historical occurrence of ME/CFS outbreaks is a singular feature of the disease and implies that any predisposing genetic mutation must be common. A database search for common damaging mutations in human enzymes produces 208 hits, including IDO2 with four such mutations. Non-functional IDO2, combined with well-established substrate inhibition of IDO1 and kinetic asymmetry of the large neutral amino acid transporter, LAT1, yielded a mathematical model of tryptophan metabolism that displays both physiological and pathological steady-states. Escape from the pathological one requires an exogenous perturbation. This model also identifies a critical point in cytosolic tryptophan abundance beyond which descent into the pathological steady-state is inevitable. If, however, means can be discovered to return cytosolic tryptophan below the critical point, return to the normal physiological steady-state is assured. Testing this hypothesis for any cell type requires only labelled tryptophan, a means to measure cytosolic tryptophan and kynurenine, and the standard tools of tracer kinetics.

​Lyme disease: summary of NICE guidance
BMJ 2018; 361 doi: https://doi.org/10.1136/bmj.k1261 (Published 12 April 2018) Cite this as: BMJ 2018;361:k1261
 

1. Maria Cruickshank, senior research fellow1, Norma O’Flynn, chief operating officer1,
2. Saul N Faust, professor of paediatric immunology and infectious diseases, director of NIHR Clinical Research Facility2
3. on behalf of the Guideline Committee

 

• Lyme disease can occur anywhere in the UK
• Erythema migrans is diagnostic of Lyme disease. Use a combination of clinical presentation and laboratory testing to guide diagnosis and treatment in people without erythema migrans
• Serological testing is a two tier approach: a sensitive initial test is performed first (ELISA), followed by a more specific confirmatory test (immunoblot) in case of a positive or equivocal initial result
• Symptoms of Lyme disease may take months or years to resolve even after treatment for several reasons, including alternative diagnoses, reinfection, treatment failure, immune reaction, and organ damage caused by Lyme disease
• Consider a second course of antibiotics for people with ongoing symptoms as treatment may have failed

Lyme disease is caused by a specific group of Borrelia burgdorferi bacteria, which can be transmitted to humans through a bite from an infected tick. This can result in a number of clinical problems ranging from skin rash to serious involvement of organ systems, including arthritis, and neurological problems. People with skin and non-specific symptoms most commonly present to their general practitioner and are often treated in primary care, whereas people with symptoms affecting organ systems are commonly referred to specialists.
The guideline focuses on diagnosis and management of Lyme disease according to clinical presentation and symptoms rather than using the differing classifications of Lyme disease, which are poorly defined and contested. There is a lack of good quality evidence on the epidemiology, prevalence, diagnosis, and management of Lyme disease.
This article summarises the most recent recommendations from the National Institute for Health and Care Excellence (NICE).1

 
Emotional awareness and expression therapy, cognitive behavioral therapy, and education for fibromyalgia: a cluster-randomized controlled trial
Lumley, Mark A.a,*; Schubiner, Howardb; Lockhart, Nancy A.a; Kidwell, Kelley M.c; Harte, Steven E.d,e; Clauw, Daniel J.d,e,f; Williams, David A.d,e,f,g
PAIN: December 2017 - Volume 158 - Issue 12 - p 2354–2363
doi: 10.1097/j.pain.0000000000001036
Research Paper

• Abstract

Patients with fibromyalgia (FM) experience increased lifetime levels of psychosocial adversity, trauma, and emotional conflict. To address these risk factors, we developed emotion awareness and expression therapy (EAET) and tested its benefits against an active control condition, FM education, and the field's gold standard intervention for FM, cognitive behavioral therapy (CBT) for symptom management. Adults with FM (N = 230) formed 40 treatment groups, which were randomized to EAET, CBT, or education and given 8, 90-minute sessions. Patient-reported outcomes were assessed at baseline, posttreatment, and 6-month follow-up (primary end point). Retention of patients to follow-up was excellent (90.4%). Intent-to-treat analyses indicated that although EAET did not differ from FM education on pain severity (primary outcome), EAET had significantly better outcomes than FM education on overall symptoms, widespread pain, physical functioning, cognitive dysfunction, anxiety, depression, positive affect, and life satisfaction (between-condition d's ranging from 0.29-0.45 SD) and the percentage of patients reporting being “very much/much” improved (34.8% vs 15.4%). Emotional awareness and expression therapy did not differ from CBT on the primary or most secondary outcomes, but compared to CBT, EAET led to significantly lower FM symptoms (d = 0.35) and widespread pain (d = 0.37) and a higher percentage of patients achieving 50% pain reduction (22.5% vs 8.3%). In summary, an intervention targeting emotional awareness and expression related to psychosocial adversity and conflict was well received, more effective than a basic educational intervention, and had some advantages over CBT on pain. We conclude that EAET should be considered as an additional treatment option for FM.
© 2017 International Association for the Study of Pain

 
Chronic exposure to insufficient sleep alters processes of pain habituation and sensitizationSimpson, Norah, S.a; Scott-Sutherland, Jenniferb; Gautam, Shivac; Sethna, Navild; Haack, Monikab,*
PAIN: January 2018 - Volume 159 - Issue 1 - p 33–40
doi: 10.1097/j.pain.0000000000001053
Chronic pain conditions are highly comorbid with insufficient sleep. While the mechanistic relationships between the 2 are not understood, chronic insufficient sleep may be 1 pathway through which central pain-modulatory circuits deteriorate, thereby contributing to chronic pain vulnerability over time. To test this hypothesis, an in-laboratory model of 3 weeks of restricted sleep with limited recovery (5 nights of 4-hour sleep per night followed by 2 nights of 8-hour sleep per night) was compared with 3 weeks of 8-hour sleep per night (control protocol). Seventeen healthy adults participated, with 14 completing both 3-week protocols. Measures of spontaneous pain, heat-pain thresholds, cold-pain tolerance (measuring habituation to cold over several weeks), and temporal summation of pain (examining the slope of pain ratings during cold water immersion) were assessed at multiple points during each protocol. Compared with the control protocol, participants in the sleep-restriction protocol experienced mild increases in spontaneous pain (P < 0.05). Heat-pain thresholds decreased after the first week of sleep restriction (P < 0.05) but normalized with longer exposure to sleep restriction. By contrast, chronic exposure to restricted sleep was associated with decreased habituation to, and increased temporal summation in response to cold pain (both P < 0.05), although only in the past 2 weeks of the sleep-restriction protocol. These changes may reflect abnormalities in central pain-modulatory processes. Limited recovery sleep did not completely resolve these alterations in pain-modulatory processes, indicating that more extensive recovery sleep is required. Results suggest that exposure to chronic insufficient sleep may increase vulnerability to chronic pain by altering processes of pain habituation and sensitization.
Pain-modulatory processes deteriorate with more chronic forms of sleep insufficiency and a couple of nights with limited recovery sleep do not resolve alterations.
Corresponding author. Address: 330 Brookline Ave, Dana 779, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Tel.: 617-667-5234. E-mail address: mhaack@bidmc.harvard.edu
Received March 28, 2017  Received in revised form July 28, 2017  Accepted August 03, 2017
© 2018 International Association for the Study of Pain

 
Tai Chi Beats Aerobic Exercise for Fibromyalgia
Damian McNamara
March 22, 2018
 
Compared with aerobic exercise, the traditional martial art of tai chi is as good as, or better than, aerobic exercise, for improving the overall severity of fibromyalgia symptoms, new research shows.
Results of a 52-week single-blind trial showed that in addition to fibromyalgia symptom relief, tai chi was associated greater improvements in depression, anxiety, self-efficacy, and the mental component of the Short-Form Health Survey (SF-36) quality-of-life measure.
"Compared with aerobic exercise, the most commonly prescribed non-drug treatment, tai chi appears as effective as or better for managing fibromyalgia," the investigators, led by Chenchen Wang, MD, Tufts University School of Medicine in Boston, Massachusetts, write. "This mind-body approach may be considered a therapeutic option in the multidisciplinary management of fibromyalgia."
The study was published online March 21 in the BMJ.

 
Clin Exp Immunol.  2017 Feb; 187(2): 284–293.
Published online 2016 Nov 23. doi:  10.1111/cei.12882
Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels
T. Nguyen,  1 , 2 S. Johnston, 1 , 2 L. Clarke, 1 , 2 P. Smith, 1 D. Staines, 1 , 2 and S. Marshall‐Gradisnik 1 , 2
AbstractTransient receptor potential melastatin subfamily 3 (TRPM3) ion channels play a role in calcium (Ca2+ ) cell signalling. Reduced TRPM3 protein expression has been identified in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) patients. However, the significance of TRPM3 and association with intracellular Ca2+ mobilization has yet to be determined. Fifteen CFS/ME patients (mean age 48·82 ± 9·83 years) and 25 healthy controls (mean age 39·2 ± 12·12 years) were examined. Isolated natural killer (NK) cells were labelled with fluorescent antibodies to determine TRPM3, CD107a and CD69 receptors on CD56dim CD16+ NK cells and CD56bright CD16dim/- NK cells. Ca2+ flux and NK cytotoxicity activity was measured under various stimulants, including pregnenolone sulphate (PregS), thapsigargin (TG), 2-aminoethoxydiphenyl borate (2APB) and ionomycin. Unstimulated CD56bright CD16dim/- NK cells showed significantly reduced TRPM3 receptors in CFS/ME compared with healthy controls (HC). Ca2+ flux showed no significant difference between groups. Moreover, PregS-stimulated CD56bright CD16dim/- NK cells showed a significant increase in Ca2+ flux in CFS/ME patients compared with HC. By comparison, unstimulated CD56dim CD16+ NK cells showed no significant difference in both Ca2+ flux and TRPM3 expression. PregS-stimulated 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 CD56dim CD16+ NK cells increased K562 cell lysis prior to PregS stimulation in CFS/ME patients compared with HC. Differential expression of TRPM3 and Ca2+ flux between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in CFS/ME.
Transient receptor potential melastatin subfamily 3 (TRPM3) ion channels play a role in calcium (Ca2+) cell signalling. Reduced TRPM3 protein expression has been identified in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) patients. However, the significance of TRPM3 and association with intracellular Ca2+ mobilization has yet to be determined. Fifteen CFS/ME patients (mean age 48·82 ± 9·83 years) and 25 healthy controls (mean age 39·2 ± 12·12 years) were examined. Isolated natural killer (NK) cells were labelled with fluorescent antibodies to determine TRPM3, CD107a and CD69 receptors on 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.

 
J Pain 2018 Apr;19(4):410-417. doi: 10.1016/j.jpain.2017.11.013. Epub 2017 Dec 14.
Daily Fluctuations of Progesterone and Testosterone Are Associated With Fibromyalgia Pain Severity.
Schertzinger M1, Wesson-Sides K1, Parkitny L1, Younger J2.
 
Abstract
The purpose of this longitudinal blood sampling study was to examine relationships between sex hormones and fibromyalgia pain. Eight women meeting case definition criteria for fibromyalgia provided venous blood samples and reported their fibromyalgia pain severity over 25 consecutive days. All women exhibited normal menstrual cycles and were not taking oral contraceptives. Cortisol, and the sex hormones estradiol, progesterone, and testosterone, were assayed from serum. A linear mixed model was used to determine if fluctuations of sex hormones were associated with changes in pain severity. In the entire sample, day to day changes in progesterone (P = .002) as well as testosterone (P = .015) were significantly and inversely correlated with pain severity. There was no relationship between estradiol and pain (P = .551) or cortisol and pain (P = .633). These results suggest that progesterone and testosterone play a protective role in fibromyalgia pain severity. Sex and other hormones may serve to increase as well as decrease fibromyalgia pain severity.
PERSPECTIVE:
Sex hormones fluctuate normally in women with fibromyalgia, but may still contribute to pain severity.




 
Be Wary of Liver Injury From Herbals or Dietary SupplementsDavid A. Johnson, MD
May 07, 2018
 
Dietary supplements are regarded by the US Food and Drug Administration (FDA) as a food but not as a drug. The use of herbal and dietary supplements is common in the United States, with surveys suggesting that up to 50% of adults use them, and sales of these products (most typically vitamins and minerals) were estimated to be nearly $40 billion in 2014.[1] The allure of these agents is far-reaching and includes claims for bodybuilding, weight loss, reduction of stress/anxiety, and enhanced immunity or sexual performance.
Associated with their use, however, is an increasing awareness of resultant drug-induced liver injury (DILI).[1] Recent data suggest that herbal and dietary supplements account for approximately 20% of drug-induced hepatotoxicity in the United States.[1] In other countries, they may account for a high rate of DILI-notably ≥ 70% in Singapore and South Korea.[2]
Study Summary
The focus of this viewpoint is to highlight key messages from a 2-day research symposium, sponsored by the American Association for the Study of Liver Diseases and the National Institutes of Health, on the challenges associated with DILI, as presented in a recent article by Navarro and colleagues.[1] The Drug-Induced Liver Injury Network, a program funded by the National Institute of Diabetes and Digestive and Kidney Diseases, also provides insight into this problem.
Anabolic steroids are a major implicated agent in DILI. Many bodybuilding supplements include anabolic steroids, which can induce prolonged cholestatic but self-limited liver injury.[1] The bilirubin level may be in the range of 40-50 mg/dL, but chronic liver injury or death is unusual. For the most part, these agents involve synthetic derivatives of testosterone, added illicitly without a prescription.
Weight-loss agents have also been associated with DILI, but with more of a hepatocellular pattern of injury and most notably related to a specific product, OxyELITE Pro®. Aegeline, an alkaloid from the fruit of the bael tree that has been used for centuries as a digestive aid, was added to the product in March 2013.[1] This product was recalled from the market in November 2013, after an FDA warning in October 2013 that certain OxyElite Pro products and another supplement, Versa-1, were considered adulterated because they contained aegeline (a new dietary ingredient), for which evidence of safety was not provided.[3] This addition of aegeline was suspected to be a factor in cases of fatal liver failure and urgent liver transplantation.
Green tea extract, derived from the plant Camellia sinensis, is another notable supplement identified in DILI.[1] Its weight-reduction claims are attributed to purported enhancement of fat metabolism. This additive has been increasingly linked to acute hepatocellular injury, which is idiosyncratic, typically within 3 months of initiation of use. Approximately 10% of these cases have been fatal.[1]Some countries (eg, Spain, France) have removed weight-loss products containing green tea extract from the market; however, green tea extract remains available in the United States.
According to Navarro and colleagues, other herbal supplements that have been implicated in DILI include black cohosh, kratom, valerian, wormwood, cat's claw, artist's conk, fo-ti, and red yeast rice.[1
Viewpoint
There is increasing evidence of significant hepatotoxicity associated with the use of herbal and dietary supplements. Given that many, if not most, patients do not report the use of these agents when asked about medications, it is critical for healthcare providers to ask patients to disclose this use and also to accurately define their use. Having patients bring in the supplement package for review by their providers would be helpful, although it is often very difficult to determine the specific agents or amounts involved, because many are included in multi-ingredient nutritional supplements. Heightened suspicion should be the standard for any patient presenting with acute liver injury. DILI presents many challenges in diagnosis and management, but the first step is a heightened awareness of the harm associated with these purportedly "health-promoting" herbal and dietary supplements.
Suggested Reading
Navarro VJ, Barnhart H, Bonkovsky HL, et al. Liver injury from herbals and dietary supplements in the US Drug Induced Liver Injury Network. Hepatology. 2014;60:1399-1408. 

 
Task Related Cerebral Blood Flow Changes Of Patients With Chronic Fatigue Syndrome: An Arterial Spin Labeling Study.
Abstract:
PURPOSE: One hallmark of chronic fatigue syndrome (ME/CFS) is task related worsening of fatigue. Global brain hypoperfusion, abnormal regional activation, and altered functional connectivity of brain areas associated with cognition and memory have been reported but remain controversial.
METHODS: We enrolled 17 female participants fulfilling the CDC Criteria for ME/CFS and 16 matched healthy controls (HC). Using a 3T-Phillips Achieva MRI-scanner, pseudo-continuous arterial spin-labeling (pCASL), was used to study the dynamics of regional cerebral blood flow (rCBF) and their relationship to mental fatigue in ME/CFS patients and HC during a demanding cognitive task, i.e. modified Paced-Auditory-Serial-Addition-Testing (PASAT).
RESULTS: ME/CFS subjects reported more fatigue than HC at baseline (p < .01). Global brain perfusion of ME/CFS and HC subjects was similar at rest. The PASAT resulted in significantly increased fatigue in ME/CFS participants and HC. Although not different between groups, overall CBF significantly increased over the first 3 min of the PASAT and then decreased thereafter. Regional CBF (rCBF) changes were significantly different between groups during the post-task recovery period. Whereas improvement of fatigue of ME/CFS subjects was associated with decreased rCBF in both superior temporal gyri (STG), precuneus, and fusiform gyrus, it was associated with increased rCBF in the same areas in HC.
CONCLUSIONS: Our results suggest that ME/CFS is associated with normal global CBF at rest and during a strenuous task (PASAT); however rCBF of several brain regions associated with memory, goal-oriented attention, and visual function was differentially associated with recovery from fatigue in ME/CFS patients and HC.
Source: Staud R, Boissoneault J, Craggs JG, Lai S, Robinson ME. Task Related Cerebral Blood Flow Changes of Patients with Chronic Fatigue Syndrome: An Arterial Spin Labeling Study. Fatigue. 2018;6(2):63-79. doi: 10.1080/21641846.2018.1453919. Epub 2018 Mar 20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914525/  (Full study)
Posted in Neurology 2018, 

 
Weighting Of Orthostatic Intolerance Time Measurements With Standing Difficulty Score Stratifies ME/CFS Symptom Severity And Analyte Detection
Abstract:
BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is clinically defined and characterised by persistent disabling tiredness and exertional malaise, leading to functional impairment.
METHODS: This study introduces the weighted standing time (WST) as a proxy for ME/CFS severity, and investigates its behaviour in an Australian cohort. WST was calculated from standing time and subjective standing difficulty data, collected via orthostatic intolerance assessments. The distribution of WST for healthy controls and ME/CFS patients was correlated with the clinical criteria, as well as pathology and cytokine markers. Included in the WST cytokine analyses were activins A and B, cytokines causally linked to inflammation, and previously demonstrated to separate ME/CFS from healthy controls. Forty-five ME/CFS patients were recruited from the CFS Discovery Clinic (Victoria) between 2011 and 2013. Seventeen healthy controls were recruited concurrently and identically assessed.
RESULTS: WST distribution was significantly different between ME/CFS participants and controls, with six diagnostic criteria, five analytes and one cytokine also significantly different when comparing severity via WST. On direct comparison of ME/CFS to study controls, only serum activin B was significantly elevated, with no significant variation observed for a broad range of serum and urine markers, or other serum cytokines.
CONCLUSIONS: The enhanced understanding of standing test behaviour to reflect orthostatic intolerance as a ME/CFS symptom, and the subsequent calculation of WST, will encourage the greater implementation of this simple test as a measure of ME/CFS diagnosis, and symptom severity, to the benefit of improved diagnosis and guidance for potential treatments.
Source: Richardson AM, Lewis DP, Kita B, Ludlow H, Groome NP, Hedger MP, de Kretser DM, Lidbury BA. Weighting of orthostatic intolerance time measurements with standing difficulty score stratifies ME/CFS symptom severity and analyte detection. J Transl Med. 2018 Apr 12;16(1):97. doi: 10.1186/s12967-018-1473-z. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1473-z 

 
Integration Of DNA Methylation & Health Scores Identifies Subtypes In Myalgic Encephalomyelitis/Chronic Fatigue SyndromeAbstract:
AIM: To identify subtypes in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) based on DNA methylation profiles and health scores.
METHODS: DNA methylome profiles in immune cells were integrated with symptomatology from 70 women with ME/CFS using similarity network fusion to identify subtypes.
RESULTS: We discovered four ME/CFS subtypes associated with DNA methylation modifications in 1939 CpG sites, three RAND-36 categories and five DePaul Symptom Questionnaire measures. Methylation patterns of immune response genes and differences in physical functioning and postexertional malaise differentiated the subtypes.
CONCLUSION: ME/CFS subtypes are associated with specific DNA methylation differences and health symptomatology and provide additional evidence of the potential relevance of metabolic and immune differences in ME/CFS with respect to specific symptoms.
Source: de Vega WC, Erdman L, Vernon SD, Goldenberg A, McGowan PO. Integration of DNA methylation & health scores identifies subtypes in myalgic encephalomyelitis/chronic fatigue syndrome. Epigenomics. 2018 Apr 25. doi: 10.2217/epi-2017-0150. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29692205
Posted in Genetics
 

 
Good outlook for patients with confirmed Lyme neuroborreliosisBMJ 2018; 361 doi: https://doi.org/10.1136/bmj.k2284 (Published 30 May 2018) Cite this as: BMJ 2018;361:k2284

1. Saul N Faust, professor of paediatric immunology and infectious diseases and director1,
2. Stephen Barton, retired marketer and Lyme disease patient2,
3. Caroline Rayment, general practitioner3,
4. Norma O’Flynn, chief operating officer and general practitioner4

1. Correspondence to: S Faust s.faust@soton.ac.uk

New study should kick start a more rigorous approach to Lyme research
In the linked paper (doi:10.1136/bmj.k1998), Obel and colleagues report on one of the largest, and highest quality longitudinal follow-up studies to date of people with neurological forms of Lyme disease.1 The study included more than 2000 people with neuroborreliosis and 20 000 controls and the data are reassuring. If you are a patient with a confirmed microbiological diagnosis and neurological symptoms of Lyme disease, this will have no effect on your survival, wellbeing (health status), or social parameters (such as school results and marriage and divorce rates) 10 years after your diagnosis compared with a control population.
This means that you will be able to recover fully and lead a normal working life, although if you are an adult you may have marginally less income and activity in the labour market than you did before the infection (rather than in comparison with the control population). Development, health, and educational achievement were not different in children diagnosed as having neuroborreliosis compared with controls.

 
Neurosci. 2018 Apr 26;12:78. doi: 10.3389/fnbeh.2018.00078. eCollection 2018. 
The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Lacourt TE1, Vichaya EG1, Chiu GS1, Dantzer R1, Heijnen CJ1.
Inflammation, the brain and energy metabolism – it’s like the trifecta in chronic fatigue syndrome (ME/CFS) research. It seems like virtually everyone in the ME/CFS field believes that all three are involved but that belief only carries so much weight in a small field. What this field really needs is buy-in from outside researchers who can help move it forward.
That appears to have happened recently when a major research group lead by Robert Dantzer penned a review paper proposing that low-grade inflammation is causing energy production problems in chronic fatigue syndrome (ME/CFS) and probably many other diseases. The authors didn’t shy away from the chronic fatigue syndrome (ME/CFS) connection. In fact, they lead their review paper off with it, placing the fatigue in ME/CFS in the same context as the fatigue in cancer, MS, rheumatoid arthritis and others.
The study was published in the Frontiers in Neuroscience journal series which is touted as the 1st most cited series in the Neurosciences journal field.
The Dantzer group’s involvement in the intersection between inflammation and energy production is welcome but not entirely surprising; it’s a logical outcome of their past work. Dantzer spearheaded the now accepted idea that the immune system produces the symptoms of “sickness behavior” (fatigue, headache, muscle aches, sore throat, etc.) that occur during an infection which serve to reduce our energy usage and to keep us isolated from others (they posit to prevent pathogen spread).
What’s new is his group’s focus on the energy production process itself – a focus, interestingly, made possible largely by the work of ME/CFS researchers. The piece, with lead author Tamara LaCourt, shows how low-grade inflammation can cause the same energy problems we’re seeing in ME/CFS: a metabolic switch from energy-efficient, oxygen-based energy production process to a fast-acting, inefficient glycolysis-based approach.
Immune cells aren’t like other cells; jumping into action causes them to rev their motors up tremendously, placing enormous stress on their energy production systems. As they do this, they switch from a focus on aerobic energy metabolism to what the authors call “aerobic glycolysis” in order to churn out energy more quickly. That process results in less mitochondrial energy production and the increased production of toxic by-products like lactate.  Plus, over time this process results in reduced nutrient availability and less energy for the rest of the body.
 
Several studies from the Solve ME/CFS Initiative are examining whether the energy production of immune cells in ME/CFS is up to the task.
Prolonged inflammation also tends to result in two other energy production problems: increased insulin resistance and reduced glucose tolerance. Reduced glucose tolerance smacks glucose uptake by immune cells at the very time that they’re clamoring for it, causing the body to break down fats and proteins, thus removing resources it would ordinarily use elsewhere.  In yet another whack at the energy production, inflammation increases reactive oxygen species production which can hammer mitochondrial energy production.
The authors believe that neurons – which rely on glycolytic processes in astrocytes to get their energy – may be hit hardest by chronic inflammation.  This is because insulin resistance – a common outcome of chronic inflammation – destroys the glycolytic process in astrocytes, causing neurons to get their energy from fats – a slower and less efficient process.
Miller’s work on ME/CFS suggests that problems with the basal ganglia – the dopamine-producing center of the brain – may be causing problems with movement, reward and fatigue in ME/CFS. That’s a particularly interesting finding given that dopaminergic neurons in the brain are particularly vulnerable to inflammation. Shungu’s studies, which have consistently found high lactate and low gluthathione levels in the ventricles of ME/CFS patients brains, suggest that high levels of oxidative stress could be causing inflammation in the brain itself.
Plus, even low-level inflammation can disrupt a key element in ME/CFS and FM – sleep – which, in turn, increases fatigue. Simply altering one’s circadian rhythm (i.e. one’s sleep times) can have significant metabolic effects, leading to increased glucose levels and decreased insulin sensitivity.  The effects don’t end with sleep; sleep deprivation results in the need for increased energy expenditures the next day.
Then add in the extra ten percent in extra energy needs that chronic low-level inflammation imposes on the body – and the potential for a dramatic drop in energy production rises.   (We’ll find out more about total energy production in ME/CFS during the metabolic chamber tests in the NIH’s intramural study).
The authors believe that impaired energy production represents a “final common pathway” in persistent fatigue.

 
Frontiers in Immunology2018; 9: 1028.
Published online 2018 May 9. doi:  10.3389/fimmu.2018.01028
PMCID: PMC5954087
PMID: 29867995
Association of T and NK Cell Phenotype With the Diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Jose Luis Rivas,1,* Teresa Palencia,1 Guerau Fernández,2 and Milagros García1,3
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a pathological condition characterized by incapacitating fatigue and a combination of neurologic, immunologic, and endocrine symptoms. At present its diagnosis is based exclusively on clinical criteria. Several studies have described altered immunologic profiles; therefore, we proposed to further examine the more significant differences, particularly T and NK cell subpopulations that could be conditioned by viral infections, to discern their utility in improving the diagnosis and characterization of the patients. The study included 76 patients that fulfilled the revised Canadian Consensus Criteria (CCC 2010) for ME/CFS and 73 healthy controls, matched for age and gender. Immunophenotyping of different T cell and natural killer cell subpopulations in peripheral blood was determined by flow cytometry. ME/CFS patients showed significantly lower values of T regulatory cells (CD4+CD25++(high)FOXP3+) and higher NKT-like cells (CD3+CD16+/−CD56+) than the healthy individuals. Regarding NK phenotypes, NKG2C was significantly lower and NKCD69 and NKCD56 bright were significantly higher in the patients group. A classification model was generated using the more relevant cell phenotype differences (NKG2C and T regulatory cells) that was able to classify the individuals as ME/CFS patients or healthy in a 70% of cases. The observed differences in some of the subpopulations of T and NK cells between patients and healthy controls could define a distinct immunological profile that can help in the diagnostic process of ME/CFS patients, contribute to the recognition of the disease and to the search of more specific treatments. However, more studies are needed to corroborate these findings and to contribute to establish a consensus in diagnosis.
Keywords: chronic fatigue syndrome, natural killer cells, T regulatory cells, NKp46, NKG2C, diagnosis, biomarker
Go to:
 

 
Large NK Cell Study Points to Autoimmunity and Inflammation in Chronic Fatigue Syndrome (ME/CFS)June 14, 2018
Problems with natural killer (NK) cell functioning have been like an anchor in the storm for immunologists interested in chronic fatigue syndrome (ME/CFS). While other immune results like cytokines have flipped and flopped all over the place, the NK cytotoxic results have been solid. Almost every study has found that when given the chance to kill infected cells, the NK cells in ME/CFS patients poop out.  (The studies which have not found differences in NK cell functioning have tended not to use whole blood or used older samples – suggesting that something in the blood could be impairing NK cell functioning in ME/CFS.)
Dr. Daniel Peterson, Sierra Internal Medicine and Simmaron Scientific Advisor
The most extensive study – a year-long 2012 study involving Dr. Peterson and Griffith University in Australia – found reduced natural killer cell functioning at all time points. (Peterson has a long history of interest in natural killer cells; he was a co-author of the first study, over thirty years ago, to find deficient NK cell functioning in chronic fatigue syndrome (ME/CFS).)
NK cells are important because they maintain the lines of our initial immune defense, holding the fort, so to speak, until the big guns – the T and B cells- wipe out the infection. – They also regulate the immune response.
Normally our cells signal that they are infected by displaying peptide fragments from the pathogen (using MHC Class 1 molecules) on their surface. NK cells then hunt out and destroy these infected cells. However, some pathogens have learned how to prevent the cells they’ve infected from displaying these peptide fragments.
If NK cells and other parts of the innate immune response can’t hold back the invaders, the pathogens may invade more deeply into the body, potentially causing more problems before the adaptive immune response (T and B-cells) can kick in.
A deficient early response to pathogens would then very likely translate into more symptoms. We don’t know when the problems with NK cell killing got started in ME/CFS, but if they were in place prior to the illness or occurred early in the illness they could have played a role in the inception of ME/CFS as people who have more trouble fighting off a pathogen; i.e. people with more severe symptoms, are more likely to come down with ME/CFS.
Once ME/CFS has begun, the inhibited NIK killing response could mean more trouble removing tumor and infected cells – particularly herpes virus infected cells- as people deficient in NK cells  have trouble fighting off herpes viruses.
NK cells, then, are vitally important, but attempts to identify issues other than cytotoxic killing abilities have been less successful. NK cells come in different types (cytotoxic and regulatory) and the balance of these subpopulations is important. Some studies have found differences in these subpopulations in ME/CFS and some have not.
Many of those studies, however, have been small and used less than stringent criteria for defining ME/CFS. A Spanish group decided to rectify those problems with a more definitive study which examined NK cell populations in a larger study (n=149) with patients who met the Canadian Consensus Criteria for ME/CFS. In order to ensure they captured all factors in the blood that might be whacking NK cells, they used whole blood and analyzed it within 6 hours of collection.
Then they tried to reverse engineer their results to see if a diagnostic test could be developed which simply charted which kinds of NK cells a person had. That was pretty good, but then they went further and asked if people who were worse off had different subpopulations of NK cells or more evidence of herpes virus reactivations (EBV, HMCV).

 
Fever of Unknown Origin in an Adult? Consider Periodic Fever SyndromesPaul G. Auwaerter, MD - Medscape - Jul 02, 2018.
Johns Hopkins University School of Medicine.
 
Fevers of unknown origin (FUO) are a not infrequent cause for ID consultation. Fellows, residents, or students often go straight to the usual definition of FUO, but I ask them to pause and consider whether the patient truly fits the FUO pattern that has been used since the early 1960s: unexplained fever lasting 3 or more weeks versus a longer-term pattern, such as episodic FUO which often have a benign diagnosis. Some fevers occur periodically and are not limited to a day or two. People might have fevers lasting 5-7 days at a time, and when you closely question them, it seems that they have fevers once or twice a month, or every 4-8 weeks. These fevers seem to have a periodicity.
We don't typically encounter periodic FUO in adult infectious diseases, but they can certainly occur and are worth considering, especially in the outpatient clinic. We've seen a number of these patients over the years and it's always gratifying if you can get to a diagnosis.
A recent patient—a 23-year-old, accompanied by his mother—had a history of problems as a youth with recurrent and severe sore throats that didn't seem to be due to Group A streptococcal infections. He had a tonsillectomy which seemed to solve this problem through his elementary and high school years; however, in college, he started to have very frequent sore throats. These were not Group A strep-related, and he had swollen glands and rather high fevers (up to 102-103˚ F), chills, sores in his mouth, and occasionally other complaints of feeling run down. This might last 5-7 days and then abate.
This patient was referred to us as having a FUO, but upon interviewing him, we learned that these fevers were occurring about once every 2 months, and then becoming even more frequent, occurring every 2-4 weeks. He has taken copious quantities of antibiotics which seemed to yield some benefit, but it was unclear whether this was just a time issue. When lab tests were done during these flare-ups, there were marked elevations in C-reactive protein levels and erythrocyte sedimentation rate.
Unlike children (for whom we have a long list of possible genetic bases for periodic fever), adults have their own menu of periodic fevers to consider. These include familial Mediterranean fever, the TNF receptor–associated periodic syndrome (known as TRAPS), or cryopyrin-associated periodic syndromes.[1] Many of these patients have other signs and symptoms, such as rash or abdominal complaints, and a positive family history with fairly high frequency. These fevers can be diagnosed using genetic means; however, there is one entity that deserves consideration for which this patient fit fairly well—periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome).
PFAPA was first described in children, but in 2008 it was described for the first time in adults.[2] We've diagnosed several of these patients and have referred some to the National Institutes of Health for further study. Of interest, these patients often have a history of frequent sore throats as a child, with improvement after tonsillectomy. As adults, they present once again with similar symptoms. They generally lack belly symptoms and often have an exclusive response to prednisone in the course of a few hours. The basis for this condition is not well understood. These patients may have disorders of innate immunity or IL-1-like responses.[3] The genetic basis isn't fully known, although it's generally helpful to exclude other genetic explanations. A number of companies are providing increasingly lower-cost genetic panels to assess for some of the other genetic syndromes. You can find out more about the availability of these genetic tests here, although insurers might not pay for them, even though the costs are dropping. A number of my patients have been willing to pursue this route.
The PFAPA syndrome is a diagnosis of exclusion if it fits. Some patients will not have all of the components, although our 23-year-old patient did. Patients are often gratified just to have the syndromic name, and some are willing to soldier on through, perhaps using nonsteroidal drugs. Sometimes, when they are feeling especially ill, a brief course of prednisone seems helpful. Others have suggested that cimetidine is helpful, although I haven't tried that.
In conclusion, there is certainly a rationale for taking some time to decide what kind of fever you might be evaluating, particularly in the outpatient setting. If there is a concern for periodic fever, take a step back and think about some of the periodic fever syndromes that might occur in adults. You might have to pursue genetic testing. If you can get a diagnosis, it's often gratifying to the patients, who are highly frustrated and might have been diagnosed with other conditions, such as fibromyalgia, chronic fatigue syndrome, or other somatic disorders. So, it is worth considering.
Thanks very much for listening.
 References
Medscape Infectious Diseases © 2018  WebMD, LLC 

 
Reduced Selective Learning in Patients With Fibromyalgia vs Healthy Controls
Ann Meulders; Yannick Boddez; Fernando Blanco; Maaike Van Den Houte; Johan W.S. Vlaeyen
 
Abstract
 
Impaired selective fear learning has been advanced as a core mechanism involved in excessive spreading of protective responses such as pain-related fear and avoidance leading to disability in chronic pain conditions. Using the litmus test for selective learning effects, the blocking procedure, we tested the hypothesis that patients with fibromyalgia (FM) show less selective threat learning than healthy controls (HCs). We introduce a novel selective learning task based around a clinical diary scenario. On a trial-by-trial basis, participants rated whether they expected certain situations (A, B, Z, and X) in the diary of a fictive FM patient would trigger pain in that patient. The procedure did not involve any experimental pain induction because the verbal outcomes "pain" or "no pain" were used. During the elemental acquisition phase, one situation was followed by "pain" (A+, eg, "Kim slept badly, and reports pain"), whereas another situation was followed by "no pain" (Z-, eg, "Kim was stressed, and reports no pain"). During the compound acquisition phase, another situation (X), referred to as the blocked stimulus, was presented in compound with a previously pain-eliciting situation and also paired with "pain" (AX+, eg, Kim slept badly" and "Kim has vacuumed," and reports pain). Simultaneously, a novel situation was introduced and also followed by "pain" (B+). Within-group comparisons showed blocking (ie, significant difference between B and X) in the HCs, but not in the patients with FM. This study is the first in directly assessing differences in selective learning between patients with FM and HCs using a blocking procedure.

 
Distribution of mast cell subtypes in interstitial cystitis: implications for novel diagnostic and therapeutic strategies?

• Shabana T Malik1, Brian R Birch2, David Voegeli1, Vipul Foria3, Alan J Cooper4, Andrew F Walls2, Bashir A Lwaleed1

Journal of Clinical pathology Vol 71, issue 9
AbstractAims To identify the presence and geographical distribution of mast cell (MC) subtypes: MCT (tryptase positive–chymase negative) and MCTC (tryptase positive–chymase positive) in bladder tissue.
Methods Bladder tissue was obtained from patients with painful bladder syndrome/interstitial cystitis (n=14) and normal histology from University Hospital Southampton tissue bank. Sequential tissue slices were immunohistochemically stained for MC subtypes using anti-MC tryptase (for MCT and MCTC) and anti-MC chymase (for MCTC). Stained sections were photographed, and positively stained MCs were quantified using ImageJ. Data were analysed using descriptive statistics and individual paired t-tests.
Results There was a significant difference in the density of MCs between each layer of the disease bladder, with the greatest accumulation within the detrusor (p<0.001). There was a significant increase in MCTC subtype in the lamina (p=0.009) in painful bladder syndrome/interstitial cystitis.
Conclusions Our results suggest that mastocytosis is present within all layers of disease bladder, especially the muscle layer. The varying increase in MC subtypes in the lamina and mucosa may explain the variability in painful bladder syndrome/interstitial cystitis symptoms. A high influx of MCTC in the mucosa of individuals who also had ulceration noted within their diagnostic notes may be of the Hunner’s ulcer subclassification. These findings suggest a relationship between the pathogenesis of MC subtypes and the clinical presentation of painful bladder syndrome/interstitial cystitis. A cohort study would further elucidate the diagnostic and/or therapeutic potential of MCs in patients with painful bladder syndrome/interstitial cystitis.
http://dx.doi.org/10.1136/jclinpath-2017-204881

 
Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndromeAuthor links open overlay panelLeighton R.BarndenaZack Y.ShanaDonald R.StainesaSonyaMarshall-GradisnikaKevinFineganbTimothyIrelandbSandeepBhutab
NeuroImage: ClinicalVolume 20, 2018, Pages 102-109
AbstractWe recruited 43 Chronic Fatigue Syndrome (CFS) subjects who met Fukuda criteria and 27 healthy controls and performed 3T MRI T1 and T2 weighted spin-echo (T1wSE and T2wSE) scans. T1wSE signal follows T1 relaxation rate (1/T1 relaxation time) and responds to myelin and iron (ferritin) concentrations. We performed MRIsignal level group comparisons with SPM12. Spatial normalization after segmentation was performed using T2wSE scans and applied to the coregistered T1wSE scans. After global signal-level normalization of individual scans, the T1wSE group comparison detected decreased signal-levels in CFS in a brainstem region (cluster-based inference controlled for family wise error rate, PFWE= 0.002), and increasedsignal-levels in large bilateral clusters in sensorimotor cortex white matter (cluster PFWE < 0.0001). Moreover, the brainstem T1wSE values were negatively correlated with the sensorimotor values for both CFS (R2 = 0.31, P = 0.00007) and healthy controls (R2 = 0.34, P = 0.0009), and the regressions were co-linear. This relationship, previously unreported in either healthy controls or CFS, in view of known thalamic projection-fibre plasticity, suggests brainstem conduction deficits in CFS may stimulate the upregulation of myelin in the sensorimotor cortex to maintain brainstem – sensorimotor connectivity. VBM did not find group differences in regional grey matteror white matter volumes. We argued that increased T1wSE observed in sensorimotor WM in CFS indicates increased myelination which is a regulatory response to deficits in the brainstem although the causality cannot be tested in this study. Altered brainstem myelin may have broad consequences for cerebral function and should be a focus of future research.

 
Visual Aspects of Reading Performance in Myalgic Encephalomyelitis (ME)Rachel L. Wilson, Kevin B. Paterson, Victoria McGowan and Claire V. Hutchinson*

• Department of Neuroscience, Psychology and Behaviour, College of Life Sciences, University of Leicester, Leicester, United Kingdom

People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) report vision-related reading difficulty, although this has not been demonstrated objectively. Accordingly, we assessed reading speed and acuity, including crowded acuity and acuity for isolated words using standardized tests of reading and vision, in 27 ME/CFS patients and matched controls. We found that the ME/CFS group exhibited slower maximum reading speed, and had poorer crowded acuity than controls. Moreover, crowded acuity was significantly associated with maximum reading speed, indicating that patients who were more susceptible to visual crowding read more slowly. These findings suggest vision-related reading difficulty belongs to a class of measureable symptoms for ME/CFS patients.

Infection Elicited Autoimmunity and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model

Jonas Blomberg 1, Carl-Gerhard Gottfries 2, Amal Elfaitouri 3, Muhammad Rizwan 1 and Anders Rosén 4
Department of Medical Sciences, Uppsala University, Clinical Microbiology, Academic Hospital, Uppsala, Sweden
Front. Immunol., 15 February 2018 | https://doi.org/10.3389/fimmu.2018.00229

Abstract
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.

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00229/full

 
Medical Cannabis for the Treatment of FibromyalgiaGeorge Habib, MD, MPH; Suheil Artul, MD
J Clin Rheumatol. 2018;24(5):255-258. 
Abstract
Background: Fibromyalgia is a chronic pain syndrome, characterized by chronic musculoskeletal pain, fatigue, and mood disturbances. There are nearly no data on the effect of medical cannabis (MC) treatment on patients with fibromyalgia.
Methods: Data were obtained from the registries of 2 hospitals in Israel (Laniado Hospital and Nazareth Hospital) on patients with a diagnosis of fibromyalgia who were treated with MC. After obtaining patient consent, demographic, clinical, and laboratory parameters were documented. All the patients also completed the Revised Fibromyalgia Impact Questionnaire regarding the period before and after MC treatment.
Results: Thirty patients were identified, and 26 patients were included in the study. There were 19 female patients (73%), and the mean age of the study group was 37.8 ± 7.6 years. The mean dosage of MC was 26 ± 8.3 g per month, and the mean duration of MC use was 10.4 ± 11.3 months. After commencing MC treatment, all the patients reported a significant improvement in every parameter on the questionnaire, and 13 patients (50%) stopped taking any other medications for fibromyalgia. Eight patients (30%) experienced very mild adverse effects.
 
Conclusions: Medical cannabis treatment had a significant favorable effect on patients with fibromyalgia, with few adverse effects.

 
Brain, Behavior, and Immunity     Available online 14 September 2018
Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation
DanielAlbrechta1AntonForsbergb1AngelicaSandströmcdCourtneyBerganaDianaKadetoffcdeEkaterinaProtsenkoaJonLampafYvonneC.LeeghCarolineOlgartHöglundiCiprianCatanaaSimonCervenkabOluwaseunAkejujMatsLekandercdkGeorgeCohenlChristerHalldinbNormanTaylorjMinhaeKimlJacob M.Hookerl…Marco L.Loggiaa2
https://doi.org/10.1016/j.bbi.2018.09.018
Fibromyalgia patients exhibit elevated cortical levels of [11C]PBR28 signal.
[11C]PBR28 signal was correlated with subjective fatigue in patients.
Results from [11C]PBR28 SUVR and VT analyses show strong regional overlap.
No differences in [11C]-L-deprenyl-D2 signal implicate microglia, not astrocytes.
Our data support glial modulation as a potential therapeutic strategy for FM.
Abstract
Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [11C]-L-deprenyl-D2 PET, thought to primarily reflect astrocytic (but not microglial) signal.
Thirty-one FM patients and 27 healthy controls (HC) were examined using [11C]PBR28 PET. 11 FM patients and 11 HC were scanned using [11C]-L-deprenyl-D2 PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (VT) were computed from the [11C]PBR28 data. [11C]-L-deprenyl-D2 was quantified using λ k3. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables.
Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [11C]PBR28 VT and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [11C]-L-deprenyl-D2 signal, including those demonstrating elevated [11C]PBR28 signal in patients (p’s ≥ 0.53, uncorrected). The elevations in [11C]PBR28 VT and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [11C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p’s < 0.03). SUVR was not significantly associated with any other clinical variable.
Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [11C]PBR28 signal were not also accompanied by increased [11C]-L-deprenyl-D2 signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [11C]-L-deprenyl-D2 signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.

 
Chinese Medical journal META ANALYSIS

Year : 2018  |  Volume : 131  |  Issue : 7  |  Page : 829-838

Mindfulness Meditation for Primary Headache Pain: A Meta-Analysis

Qiang Gu1, Jin-Chao Hou2, Xiang-Ming Fang1
1 School of Medicine, Zhejiang University, Hangzhou, Zhejiang 210029, China
2 Department of Anesthesiology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 210029, China
Date of Submission
05-Dec-2017
Date of Web Publication
22-Mar-2018

 
 

 

Abstract

Background: Several studies have reported that mindfulness meditation has a potential effect in controlling headaches, such as migraine and tension-type headache; however, its role remains controversial. This review assessed the evidence regarding the effects of mindfulness meditation for primary headache pain.
Methods: Only English databases (PubMed, Cochrane Central Register of Controlled Trials [the Cochrane Library], PsycINFO, Psychology and behavioral science collection, PsyArticles, Web of Science, and Scopus) were searched from their inception to November 2016 with the keywords (“meditation” or “mindfulness” or “vipassana” or “dzogchen” or “zen” or “integrative body-mind training” or “IBMT” or “mindfulness-based stress reduction” or “MBSR” or “mindfulness-based cognitive therapy” or “MBCT” and “Headache” or “Head pain” or “Cephalodynia” or “Cephalalgia” or “Hemicrania” or “Migraine”). Titles, abstracts, and full-text articles were screened against study inclusion criteria: controlled trials of structured meditation programs for adult patients with primary headache pain. The quality of studies included in the meta-analysis was assessed with the Yates Quality Rating Scale. The meta-analysis was conducted with Revman 5.3.
Results: Ten randomized controlled trials and one controlled clinical trial with a combined study population of 315 patients were included in the study. When compared to control group data, mindfulness meditation induced significant improvement in pain intensity (standardized mean difference, −0.89; 95% confidence interval, −1.63 to −0.15; P = 0.02) and headache frequency (−0.67; −1.24 to −0.10; P = 0.02). In a subgroup analysis of different meditation forms, mindfulness-based stress reduction displayed a significant positive influence on pain intensity (P < 0.000). Moreover, 8-week intervention had a significant positive effect (P < 0.000).
Conclusions: Mindfulness meditation may reduce pain intensity and is a promising treatment option for patients. Clinicians may consider mindfulness meditation as a viable complementary and alternative medical option for primary headache.

 
Association of Coffee Drinking With Mortality by Genetic Variation in Caffeine MetabolismFindings From the UK Biobank
Erikka Loftfield, PhD1; Marilyn C. Cornelis, PhD2; Neil Caporaso, MD3; et al Kai Yu, PhD4; Rashmi Sinha, PhD1; Neal Freedman, PhD1
JAMA Intern Med. 2018;178(8):1086-1097. doi:10.1001/jamainternmed.2018.2425
Key Points
Question  Moderate coffee consumption has been inversely associated with mortality; however, does heavy intake, particularly among those with common genetic polymorphisms that impair caffeine metabolism, increase risk of mortality?
Findings  This large prospective cohort study of a half million people found inverse associations for coffee drinking with mortality, including among participants drinking 1 up to 8 or more cups per day. No differences were observed in analyses that were stratified by genetic polymorphisms affecting caffeine metabolism.
Meaning  This study provides further evidence that coffee drinking can be part of a healthy diet and offers reassurance to coffee drinkers.
Abstract
Importance  Prospective cohorts in North America, Europe, and Asia show consistent inverse associations between coffee drinking and mortality, including deaths from cardiovascular disease and some cancers. However, concerns about coffee, particularly among people with common genetic polymorphisms affecting caffeine metabolism and among those drinking more than 5 cups per day, remain.
Objective  To evaluate associations of coffee drinking with mortality by genetic caffeine metabolism score.
Design, Setting, and Participants  The UK Biobank is a population-based study that invited approximately 9.2 million individuals from across the United Kingdom to participate. We used baseline demographic, lifestyle, and genetic data form the UK Biobank cohort, with follow-up beginning in 2006 and ending in 2016, to estimate hazard ratios (HRs) for coffee intake and mortality, using multivariable-adjusted Cox proportional hazards models. We investigated potential effect modification by caffeine metabolism, defined by a genetic score of previously identified polymorphisms in AHR, CYP1A2, CYP2A6, and POR that have an effect on caffeine metabolism. Of the 502 641 participants who consented with baseline data, we included those who were not pregnant and had complete data on coffee intake and smoking status (n = 498 134).
Exposures  Total, ground, instant, and decaffeinated coffee intake.
Main Outcomes and Measures  All-cause and cause-specific mortality.
Results  The mean age of the participants was 57 years (range, 38-73 years); 271 019 (54%) were female, and 387 494 (78%) were coffee drinkers. Over 10 years of follow-up, 14 225 deaths occurred. Coffee drinking was inversely associated with all-cause mortality. Using non–coffee drinkers as the reference group, HRs for drinking less than 1, 1, 2 to 3, 4 to 5, 6 to 7, and 8 or more cups per day were 0.94 (95% CI, 0.88-1.01), 0.92 (95% CI, 0.87-0.97), 0.88 (95% CI, 0.84-0.93), 0.88 (95% CI, 0.83-0.93), 0.84 (95% CI, 0.77-0.92), and 0.86 (95% CI, 0.77-0.95), respectively. Similar associations were observed for instant, ground, and decaffeinated coffee, across common causes of death, and regardless of genetic caffeine metabolism score. For example, the HRs for 6 or more cups per day ranged from 0.70 (95% CI, 0.53-0.94) to 0.92 (95% CI, 0.78-1.10), with no evidence of effect modification across strata of caffeine metabolism score (P = .17 for heterogeneity).
Conclusions and Relevance  Coffee drinking was inversely associated with mortality, including among those drinking 8 or more cups per day and those with genetic polymorphisms indicating slower or faster caffeine metabolism. These findings suggest the importance of noncaffeine constituents in the coffee-mortality association and provide further reassurance that coffee drinking can be a part of a healthy diet.
 

 
Impact of Empathy in the Patient-Doctor Relationship on Chronic Pain Relief and Quality of Life: A Prospective Study in Spanish Pain Clinics
Luz Cánovas, PhD
Pain Clinic, Complejo Hospitalario Universitario de Ourense (CHUO), Ourense, Spain
Correspondence to: Luz Cánovas, PhD, Pain Clinic, Complejo Hospitalario Universitario de Ourense (CHUO), Ramon Puga Noguerol 54, 32005 Ourense, Spain. Tel: +34-98-838-5500; Fax: 98-838-5551; E-mail: maria.de.la.luz.canovas.martinez@sergas.es.
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Luz Cánovas, PhD Antonio-José Carrascosa, PhD, Modesto García, PhD, Mariano Fernández, PhD, , Almudena Calvo, PhD, Vicente Monsalve, PhD, José-Francisco Soriano, PhD
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Department of Anesthesiology, Hospital Civil (Complejo Hosp. Regional Carlos Haya), Málaga, Spain
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Medical Department, Mundipharma, S.L., Madrid, Spain
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Pain Clinic, Consorci Hospital General Universitari de València, Valencia, Spain
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Department of Psychology, University of Valencia, Valencia, Spain
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Pain Medicine, Volume 19, Issue 7, 1 July 2018, Pages 1304–1314, https://doi.org/10.1093/pm/pnx160
Published:13 July 2017
Abstract
Objective
To assess the impact of the empathy of physicians, perceived by patients with chronic pain, regarding pain relief and health-related quality of life (HR-QoL).
Methods
A prospective non-interventional study was conducted in 2,898 patients with moderate to severe chronic pain who were referred to pain clinics. The same physician visited each patient at baseline and after one and three months. Study questionnaires included the Jefferson Scale of Patient Perceptions of Physician Empathy (JSPPPE), the Life Orientation Test–Revised (LOT-R), the Pain Coping Questionnaire (CAD-R), the Brief Pain Inventory Short Form (BPI-SF), and the EuroQol-5D (EQ-5D). Regression analyses were used to evaluate the independent contribution of the changes in perceived empathy over pain intensity and improvement of HR-QoL.
Results
BPI-SF scores for pain intensity, rated as worst, least, average, and current pain, decreased significantly (P < 0.001) from baseline to month 3, with reductions of 33.7%, 42.5%, 40.0%, and 46.9%, respectively. Pain intensity decreased from 6.3 ± 1.5 at baseline to 4.7 ± 1.8 at one month and 3.8 ± 1.9 at three months (P < 0.050). Significant (P < 0.001) improvements in the EQ-5D tariff (+37.1%) and EQ-5D VAS (+26.7%) were also recorded. In the linear regression analysis, JSPPPE and LOT-R, but not CAD-R, were significantly associated with pain relief and HR-QoL.
Conclusions
Physicians’ empathy and patients’ dispositional optimism have a role in determining positive outcomes in patients with chronic pain. Physicians’ empathy may therefore be a suitable, yet relatively unexplored, target for intervention.

 
A new hypothesis for the pathophysiology of complex regional pain syndromeMarcRussoaPeterGeorgiusbDanielle MSantarellia
https://doi.org/10.1016/j.mehy.2018.07.026Get rights and content
Medical Hypotheses  Volume 119, October 2018, Pages 41-53 
Abstract
Complex Regional Pain Syndrome (CRPS) has defied a clear unified pathological explanation to date. Not surprisingly, treatments for the condition are limited in number, efficacy and their ability to enact a cure. Whilst many observations have been made of physiological abnormalities, how these explain the condition and who does and doesn’t develop CRPS remains unclear. We propose a new overarching hypothesis to explain the condition that invokes four dynamically changing and interacting components of tissue trauma, pathological pain processing, autonomic dysfunction (both peripheral and central) and immune dysfunction, primarily involving excessive and pathological activation of dendritic cells following trauma or atrophy. We outline pathophysiological changes that may initiate a cascade of events involving dendritic cells and the cholinergic anti-inflammatory pathway resulting in the condition, and the changes that maintain the condition into its chronic phase. This hypothesis should provide fertile ground for further investigations and development of new treatments that holistically address the nature of the disorder along its developmental continuum.
 

 
Graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome is not effective and unsafe. Re-analysis of a Cochrane review
Mark Vink, Alexandra Vink-Niese,First Published October 8, 2018 Review Article                         
https://doi.org/10.1177/2055102918805187
Abstract
The analysis of the 2017 Cochrane review reveals flaws, which means that contrary to its findings, there is no evidence that graded exercise therapy is effective. Because of the failure to report harms adequately in the trials covered by the review, it cannot be said that graded exercise therapy is safe. The analysis of the objective outcomes in the trials provides sufficient evidence to conclude that graded exercise therapy is an ineffective treatment for myalgic encephalomyelitis/chronic fatigue syndrome.
Keywords chronic fatigue syndrome, Cochrane review, graded exercise therapy, myalgic encephalomyelitis
 

 
CD24 Expression and B Cell Maturation Shows a Novel Link With Energy Metabolism: Potential Implications for Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Fane F. K. Mensah1, Christopher W. Armstrong2, Venkat Reddy1, Amolak S. Bansal3, Saul Berkovitz4, Maria J. Leandro1 and Geraldine Cambridge1*

• 1Division of Medicine, Centre of Rheumatology Research, University College London, London, United Kingdom
• 2Bio 21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, Australia
• 3Department of Immunology, Epsom and St. Helier University Hospitals NHS Trust, Carshalton, United Kingdom
• 4Chronic Fatigue Service, Royal London Hospital of Integrated Medicine, University College Hospitals NHS Trust, London, United Kingdom

 
CD24 expression on pro-B cells plays a role in B cell selection and development in the bone marrow. We previously detected higher CD24 expression and frequency within IgD+ naïve and memory B cells in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) compared with age-matched healthy controls (HC). Here, we investigated the relationship between CD24 expression and B cell maturation. In vitro stimulation of isolated B cells in response to conventional agonists were used to follow the dynamics of CD24 positivity during proliferation and differentiation (or maturation). The relationship between CD24 expression to cycles of proliferation and metabolism in purified B cells from HC was also investigated using phospho-flow (phosphorylation of AMPK-pAMPK), 1proton nuclear magnetic resonance and Mitotracker Far-red (Mitochondrial mass-MM). In vitro, in the absence of stimulation, there was an increased percentage of CD24+ viable B cells in ME/CFS patients compared to HC (p < 0.05) following 5 days culture. Following stimulation with B cell agonists, percentage of CD24+B cells in both naïve and memory B cell populations decreased. P < 0.01). There was a negative relationship between percentage of CD24+B cells with MM (R2 = 0.76; p < 0.01), which was subsequently lost over sequential cycles of proliferation. There was a significant correlation between CD24 expression on B cells and the usage of glucose and secretion of lactate in vitro. Short term ligation of the B cell receptor with anti-IgM antibody significantly reduced the viability of CD24+ memory B cells compared to those cross-linked by anti-IgD or anti-IgG antibody. A clear difference was found between naïve and memory B cells with respect to CD24 expression and pAMPK, most notably a strong positive association in IgD+IgM+ memory B cells. In vitro findings confirmed dysregulation of CD24-expressing B cells from ME/CFS patients previously suggested by immunophenotype studies of B cells from peripheral blood. CD24-negative B cells underwent productive proliferation whereas CD24+ B cells were either unresponsive or susceptible to cell death upon BCR-engagement alone. We suggest that CD24 expression may reflect variations in energy metabolism on different B cell subsets.

 
The Probiotics Trend: Should We Be All In or Call Time Out? - Medscape - Nov 09, 2018. David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School,Norfolk, Virginia.
 
The ingestion of dietary live bacteria supplementation, or probiotics, has become widespread in recent years. In the United States, it is estimated that approximately 4 million adults consume probiotics on a daily basis.[1]Furthermore, nearly 60% of care providers recommend probiotic supplements on a routine basis.[2]
This trend warrants further scrutiny, and three recently published studies give us more information about whether we should be all in on probiotics or call time out on their increasing use.
 
Is Their Effect Consistent and Durable?
The first study,[3] which comes to us from the Weizmann Institute in Rehovot, Israel, looked at the durability of the effect of these probiotics.
Researchers began by giving probiotics to germ-free mice, in which they were actually able to induce the desired microbial changes. When they gave the probiotics to mice that were already colonized with their own innate bacteria, however, there were evident resistance patterns. They were not able to induce the colonization that they thought they would when they gave the probiotic. The same effect was evident when they tested it in humans. There seems to be certain bacterial resistant patterns in hosts that either facilitate or block the colonization intended by this probiotic effect.
Probiotics are recommended for a variety of clinical reasons, including fortifying the immune system, protecting against cardiovascular or metabolic diseases, enhancing post-infectious health, and improving bowel function. But this study indicates that probiotics may not actually have these intended effects.
This raises a couple of concerns. First, when probiotics are given, it may not stick. Second, and quite interestingly, when it does stick, the effect might be quite variable in the colon. This was shown when researchers found that stool and biopsy microbiome analyses were not equivalent. In other words, there were variations across the microbiome and geographic variance within the colon where the biome would resist or enhance the colonization based on that probiotic effect.
 
Do They Help Post-antibiotic Recovery?
 
The second study,[4] which also comes from the brilliant researchers at the Weizmann Institute, looked at post-antibiotic microbiome changes in mice and humans who were given either multistrain probiotics or autologous fecal microbiome transplantation (ie, transferring the pre-antibiotic microbiome back to subjects via their earlier stool).
Researchers found that there was a rapid reconstitution of the normal biome when they gave the patients their pre-antibiotic stool back. Comparatively, the use of probiotics was associated with a marked delay in patients being able to return to what their normal microbiome was before antibiotics.
 
This study shows that we may want to reconsider the use of probiotics in the post-antibiotic setting, as they may actually delay the return to the normal biome. Instead, there may be existing or as-yet-undeveloped strategies that allow for reconstitution of the microbiome by targeting the individual host microbiome.
 
Have They Been Proven Safe?
The third study[5] deals with the safety of various strategies for modifying the microbiota. This comprehensive meta-analysis, published in the Annals of Internal Medicine, looked at approximately 340 studies, of which 245 specifically evaluated probiotics.It was remarkable how few of these studies actually reported adverse events of harm. Nearly a third or more of all trials included reported no adverse event monitoring or harm, whereas 98% provided no adequate documentation, validation, or standardization in reporting adverse events or serious adverse events. Given the high variability in the quality of existing data, the authors concluded that it may be too premature to make any broad conclusions about the safety of these interventions.
Certainly, just like any other medication, potential harm needs to be assessed in probiotics. This is especially true given that probiotics contain a variety of additives. For example, a couple of years ago, a group of researchers from Columbia University in New York City found that of the 22 market-leading probiotics they studied, 12 contained gluten.[6] Of these 12 products, eight claimed to be "gluten free" on their labeling.
The over-the-counter industry is fairly loosely regulated, particularly as it applies to probiotics. Their additives may cause symptoms in and of themselves, and we have to remember our first rule in medicine is to do no harm. Probiotics may have some benefit in select patients, but in others there may be some harm. Particular caution should be exercised for immunosuppressed and immunocompromised patients, as well as those in the hospital with indwelling lines, in whom there have been reports of mortality and disseminated fungemias.[7,8]
When it comes to a verdict, I'd lean more toward "time out" than going "all in." Probiotics have a lot to potentially offer, but we may be better off delivering and tailoring to the individual host rather than adopting a one-size-fits-all approach.

 
Front. Pediatr., 15 November 2018 | https://doi.org/10.3389/fped.2018.00352
Blood Volume Status in ME/CFS Correlates With the Presence or Absence of Orthostatic Symptoms: Preliminary Results
C. (Linda) M. C. van Campen1*, Peter C. Rowe2 and Frans C. Visser1

• 1Stichting Cardiozorg, Hoofddorp, Netherlands
• 2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Introduction: Conflicting data have been published on the reduction of circulating blood volume in adults with Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The aim of the present study was to compare blood volumes based on the presence or absence of orthostatic symptoms.
 
Methods and results: Twenty consecutive adults with ME/CFS participated in the study. All underwent dual isotope blood volume measurement and were evaluated for a clinical suspicion of orthostatic intolerance (OI). The mean age was 34 (10) years, and median duration of disease was 7.5 (6–10) years. The mean (SD) absolute blood volume was 59 (8) ml/kg, a value −11 (7) ml/kg below the reference blood volume. Of the 12 patients, 4 had no OI and 8 had a clinical suspicion of OI. In 8 patients with OI, absolute blood volumes were significantly lower than for the 4 without OI (56 [2] vs. 66 [5]; p < 0.05) as were the differences between the measured and the reference blood volume (−14 [2]; vs. −4 [3]; p < 0.02).
 
Conclusions: Adults with ME/CFS had a significantly lower blood volume if they had a clinical suspicion of OI compared to those without a clinical suspicion of OI, as well as a significantly lower blood volume compared to the expected value. The data suggest that accounting for symptoms of OI could enhance the detection of the subset with reduced blood volume.

 
Front. Pediatr., 16 November 2018 | https://doi.org/10.3389/fped.2018.00349
Low Sensitivity of Abbreviated Tilt Table Testing for Diagnosing Postural Tachycardia Syndrome in Adults With ME/CFS
C. (Linda) M. C. van Campen1, Peter C. Rowe2* and Frans C. Visser1

• 1Stichting CardioZorg, Hoofddorp, Netherlands
• 2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

 
Introduction: Orthostatic intolerance is common among individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In some ME/CFS case definitions, orthostatic intolerance is considered a core feature of the disorder. Some studies have employed tilt table tests lasting 2–5 min to diagnose one common form of orthostatic intolerance, postural tachycardia syndrome (POTS). We examined the diagnostic yield of abbreviated durations of tilt testing in adults meeting criteria for
ME/CFS, and identified the proportion with POTS misdiagnosed using testing of <10 min.
 
Methods: Eligible participants were consecutive individuals satisfying study criteria for ME/CFS and POTS evaluated at the Stichting CardioZorg (SCZ, Hoofddorp, NL) between November 2012 and August 2018. Individuals being treated with medications commonly used to manage orthostatic intolerance were excluded. Head-up tilt table testing involved 15 min of supine posture then 20 min at 70 degrees upright. Only the data from the first 10-min upright were used. POTS was defined as an increase in HR during a maximum of 10 min of upright tilt of at least 30 beats per minute (bpm), in the absence of either classical or delayed orthostatic hypotension. We measured the time until HR criteria for POTS were reached using survival curves, and compared survival curves between subgroups divided by age, sex, disease duration, and degree of hypocapnia during the test.
 
Results: Of 627 individuals with ME/CFS evaluated during the study period, 155 met criteria for POTS. The median time to reaching HR criteria for POTS was 3 min. A two-minute tilt table test would miss 55% (95% CI, 48–63%) of those meeting POTS criteria over the course of 10 min upright. The median time to reaching HR criteria for POTS did not differ by sex, age, duration of ME/CFS, or hypocapnia during tilt.
 
Conclusions: Abbreviated tilt table testing misses a substantial proportion of those ultimately diagnosed with POTS during a 10-min tilt table test, and should be abandoned for the clinical diagnosis and in epidemiologic studies designed to estimate the prevalence of POTS among those with ME/CFS.
 

​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