European Journal of applied physiology
October 2019, Volume 119, Issue 10, pp 2375–2389| Cite as
Unexplained exertional intolerance associated with impaired systemic oxygen extraction

• Authors
• Kathryn H. MelamedMário Santos Rudolf K. F. Oliveira  Mariana Faria Urbina Donna Felsenstein Alexander R. Opotowsky Aaron B. Waxman David M. Systrom

Abstract
Purpose
The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).
Methods
We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].
Results
Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).
Conclusions
We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.
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European Journal of applied physiology
October 2019, Volume 119, Issue 10, pp 2375–2389| Cite as
Unexplained exertional intolerance associated with impaired systemic oxygen extraction

• Authors
• Kathryn H. MelamedMário Santos Rudolf K. F. Oliveira  Mariana Faria Urbina Donna Felsenstein Alexander R. Opotowsky Aaron B. Waxman David M. Systrom

Abstract
Purpose
The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).
Methods
We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].
Results
Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2 nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).
Conclusions
We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.
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Journal of Clinical Investigation
Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations
Alexandra H. Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L. Peterson, Marco Maynard, C. Gunnar Gottschalk, and Maureen R. Hanson 
First published December 12, 2019 
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines. We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.

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Epidemiology and Community Health: Research report
Influence of sleep problems and co-occurring musculoskeletal pain on long-term prognosis of chronic low back pain: the HUNT Study
Eivind Schjelderup Skarpsno, Paul Jarle Mork, Tom Ivar Lund Nilsen, 
Anne Lovise Nordstoga
Abstract
Background We investigated the influence of sleeplessness and number of insomnia symptoms on the probability of recovery from chronic low back pain (LBP), and the possible interplay between sleeplessness and co-occurring musculoskeletal pain on this association.
Methods The study comprised data on 3712 women and 2488 men in the Norwegian HUNT study who reported chronic LBP at baseline in 1995–1997. A modified Poisson regression model was used to calculate adjusted risk ratios (RRs) for the probability of recovery from chronic LBP at follow-up in 2006–2008, associated with sleep problems and co-occurring musculoskeletal pain at baseline.
Results Compared with persons without sleeplessness, persons who often/always experienced sleeplessness had a lower probability of recovery from chronic LBP (RR 0.65, 95% CI 0.57 to 0.74 in women and RR 0.81, 95% CI 0.69 to 0.95 in men). Although there was no clear evidence of statistical interaction between sleeplessness and co-occurring musculoskeletal pain, women and men who often/always experienced sleeplessness and had ≥5 additional chronic pain sites had RRs of recovery of 0.40 (95% CI 0.33 to 0.48) and 0.59 (95% CI 0.45 to 0.78), respectively, compared with persons without sleeplessness and 1–2 chronic pain sites.
Conclusion These findings suggest that preventing or reducing sleep problems among people with chronic LBP may have the potential of improving the long-term prognosis of this condition, also among those with several additional pain sites.
View Full Text
http://dx.doi.org/10.1136/jech-2019-212734
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Journal: Fatigue: Biomedicine, Health & Behavior 
Low-dose naltrexone in the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Olli Polo,Pia Pesonen &Essi Tuominen
Received 13 Sep 2019, Accepted 11 Nov 2019, Published online: 19 Nov 2019

• https://doi.org/10.1080/21641846.2019.1692770

ABSTRACT
Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a common medical condition that limits physical and cognitive functions, with no known effective medical treatment.
Methods: We report on the safety and effectiveness data accumulated in clinical practice when treating ME/CFS with low-dose naltrexone (LDN, 3.0 – 4.5 mg/day). The medical records from 218 patients who received ar diagnosis of ME/CFS and LDN treatment during 2010–2014 were retrospectively analyzed.
Results: Outcome data were available in 92.2% of patients with an average follow-up time of 1.7 years. A positive treatment response to LDN was reported by 73.9% of the patients. Most patients experienced improved vigilance/alertness and improved physical and cognitive performance. Some patients reported less pain and fever, while 18.3% of patients did not report any treatment response to LDN. Mild adverse effects (insomnia, nausea) were common at the beginning of the treatment. Neither severe adverse effects nor long-term adverse symptoms were reported.
Conclusions: The high frequency of treatment response and good safety profile observed in this retrospective open label study could prompt prospective controlled studies to confirm the feasibility of LDN in alleviating ME/CFS symptoms.

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Brain Behav Immun. 2019 Nov 20. pii: S0889-1591(19)30762-7. doi: 10.1016/j.bbi.2019.11.015. 
Identification of actin network proteins, talin-1 and filamin-A, in circulating extracellular vesicles as blood biomarkers for human myalgic encephalomyelitis/chronic fatigue syndrome.
Eguchi A1, Fukuda S2, Kuratsune H2, Nojima J3, Nakatomi Y4, Watanabe Y5, Feldstein AE
1 Department of Gastroenterology and Hepatology, School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; JST, PRETO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan; Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA 92093, USA. Electronic address: akieguchi@clin.medic.mie-u.ac.jp.
2 Department of Health Welfare Sciences, Kansai University of Welfare Sciences, Kashiwara 582-0026, Japan; Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8586, Japan; RIKEN, Center for Biosystems Dynamics Research, Kobe 650-0047, Japan.
3 Department of Laboratory Science, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan.
4 Nakatomi Fatigue Care Clinic, Osaka 541-0043, Japan.
5 Department of Endocrinology, Metabolism and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8586, Japan; RIKEN, Center for Biosystems Dynamics Research, Kobe 650-0047, Japan; RIKEN Compass to Healthy Life Research Complex Program, Kobe 650-0047, Japan.
6 Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA 92093, USA.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including pain, depression, and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30-50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here we show that actin network proteins in circulating extracellular vesicles (EVs) offer specific non-invasive biomarkers for ME/CFS. We found that circulating EVs were significantly increased in ME/CFS patients correlating to C-reactive protein, as well as biological antioxidant potential. Area under the receiver operating characteristic curve for circulating EVs was 0.80, allowing correct diagnosis in 90-94% of ME/CFS cases. From two independent proteomic analyses using circulating EVs from ME/CFS, healthy controls, idiopathic chronic fatigue, and depression, proteins identified from ME/CFS patients are involved in focal adhesion, actin skeletal regulation, PI3K-Akt signaling pathway, and Epstein-Barr virus infection. In particular, talin-1, filamin-A, and 14-3-3 family proteins were the most abundant proteins, representing highly specific ME/CFS biomarkers. Our results identified circulating EV number and EV-specific proteins as novel biomarkers for diagnosing ME/CFS, providing important information on the pathogenic mechanisms of ME/CFS.
Copyright © 2019 Elsevier Inc. All rights reserved.PMID:31759091 DOI:10.1016/j.bbi.2019.11.015
Research:   REVIEW

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Understanding neuromuscular disorders in chronic fatigue syndrome
Yves Jammes, Frédérique Retornaz2
Abstract
Muscle failure has been demonstrated in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Neurophysiological tools demonstrate the existence of both central and peripheral fatigue in these patients. Central fatigue is deduced from the reduced amplitude of myopotentials evoked by transcranial magnetic stimulation of the motor cortex as well as by the muscle response to interpolated twitches during sustained fatiguing efforts. An impaired muscle membrane conduction velocity assessed by the reduced amplitude and lengthened duration of myopotentials evoked by direct muscle stimulation is the defining feature of peripheral fatigue. Some patients with ME/CFS show an increased oxidative stress response to exercise. The formation of lipid hydroperoxides in the sarcolemma, which alters ionic fluxes, could explain the reduction of muscle membrane excitability and potassium outflow often measured in these patients. In patients with ME/CFS, the formation of heat shock proteins (HSPs) is also reduced. Because HSPs protect muscle cells against the deleterious effects of reactive oxygen species, the lack of their production could explain the augmented oxidative stress and the consecutive alterations of myopotentials which could open a way for future treatment of ME/CFS.
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Brief Cognitive Behavioral Therapy For Chronic Pain
Results From a Clinical Demonstration Project in Primary Care Behavioral Health
Beehler, Gregory P. MA, PhD*,†; Murphy, Jennifer L. PhD‡,§; King, Paul R. PhD*,∥; Dollar, Katherine M. PhD¶; Kearney, Lisa K. PhD, ABPP¶,#; Haslam, Aaron PhD**; Wade, Michael MS¶; Goldstein, Wade R. MA*
The Clinical Journal of Pain: October 2019 - Volume 35 - Issue 10 - p 809–817
doi: 10.1097/AJP.0000000000000747
 
Abstract
Objectives: 
Although cognitive behavioral therapy is an effective intervention for chronic pain, it is a lengthy treatment typically applied only in specialty care settings. The aim of this project was to collect preliminary effectiveness data for Brief Cognitive Behavioral Therapy for Chronic Pain (Brief CBT-CP), an abbreviated, modular form of treatment designed for use in primary care. 
Methods: 
A clinical demonstration project was conducted in which Brief CBT-CP was delivered to primary care patients by 22 integrated care providers practicing in the Primary Care Behavioral Health model of Veterans Health Administration primary care clinics. Brief measures were used at each appointment to collect patient-reported clinical outcomes. 
Results: 
One hundred eighteen patients provided sufficient data for analysis (male, 75%; mean age, 51.4 y). Multilevel modeling suggested that a composite measure of pain intensity and functional limitations showed statistically significant improvements by the third appointment (Cohen’s d=0.65). Pain-related self-efficacy outcomes showed a similar pattern of results but of smaller effect size (Cohen’s d=0.22). The exploratory analysis identified that Brief CBT-CP modules addressing psychoeducation and goal setting, pacing, and relaxation training were associated with the most significant gains in treatment outcomes. 
Discussion: 
These findings provide early support for the effectiveness of Brief CBT-CP when delivered by providers in every day Primary Care Behavioral Health settings. Results are discussed in relation to the need for additional research regarding the potential value of employing safe, population-based, nonpharmacological approaches to pain management in primary care. 
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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Bragee Clinics report
Signs of Intracranial Hypertension, Hypermobility and 
Craniocervical Obstructions in patients with 
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Björn Bragée , Anastasios Michos, Brandon Drum, Mikael Fahlgren, Robert 
Szulkin, Bo C Bertilson


Division of Family Medicine and Primary Care, 
Department of Neurobiology, Care Sciences 
and Society, Karolinska Institutet, Stockholm, Sweden
Division of Family Medicine and Primary Care,Stockholm Health Care Services, Region 
Stockholm, Huddinge, Sweden
ME center, Bragée Clinics, Stockholm, Sweden


Objective: To test the hypothesis that hypermobility and craniocervical obstructions is overrepresented in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and that a large portion of these patients may have a degree of intracranial hypertension explaining many of the symptoms of the ME/CFS syndrome. 
Methods: This is a retrospective cross-sectional study, performed at a specialist clinic for referred patients with severe ME/CFS fulfilling the Canada Consensus Criteria. The first 272 consecutive patients with ME/CFS were invited, and 229 of these whom had signed the informed consent within six weeks were included. Hypermobility was assessed using the Beighton score. The position of cerebellar tonsils, the optic nerve sheath diameter and eyeball transverse diameter were measured in magnetic resonance imaging scans of the brain as measures correlated to intracranial hypertension. Findings of obstructions in the craniocervical junction and the cervical spine were assessed through MRI scans of the cervical spine. Radiological assessments were made by an experienced radiologist. 
Results: 190 women with a mean age of 45 years and 39 males with a mean age of 44 years were included. Hypermobility was found in 111 (49%) of the patients. Of the 205 patients with brain MRI scanning, increased diameter of the optic nerve sheath was found in 112 patients (55%), signs of possible intracranial hypertension expressed as the quote of the diameter of optic nerve/eyeball transverse diameter in left or right side were present in 171 patients (83%), and values seen with more severe states of intracranial hypertension were found in 65 of the patients (32%). Obstruction in the foramen magnum by cerebellar tonsils under the McRae line was found in 115 patients (56%). Findings of obstruction of the cervical spinal canal were found in 100 of the 125 patients (80%) with cervical scans. There was a significant overrepresentation of signs of hypermobility, intracranial hypertension and obstructions in the cranio-cervical region compared with general population. 
Conclusion: These findings, which confirms our hypothesis, may explain the widespread symptoms these patients express. If confirmed in further studies, new diagnostic and therapeutic approaches to this widespread neurological syndrome should be considered.
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From Cold Spring Harbor Laboratory
Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Ece Karhan, Courtney Gunter, Vida Ravanmehr, Meghan Horne, Lina Kozhaya, Stephanie Renzullo, Lindsey Placek, Joshy George,  View ORCID ProfilePeter N. Robinson, Suzannne D Vernon, Lucinda Bateman, Derya Unutmaz
doi: https://doi.org/10.1101/2019.12.23.887505
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions. We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNgamma;, GranzymeA and IL-17 upon activation. Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity). In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.
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Scientific Reports  MC6906377   2019; 9: 18817.
Published online 2019 Dec 11. doi: 10.1038/s41598-019-55473-4 PMCID: PMC6906377
PMID: 31827223
Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome
Alaa Ghali,1 Carole Lacout,1 Maria Ghali,2 Aline Gury,1 Anne-Berengere Beucher,1 Pierre Lozac’h,1 Christian Lavigne,1 and Geoffrey Urbanski  (France)
Abstract
Elevated blood lactate after moderate exercise was reported in some of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We hypothesised that blood lactate could be also elevated in resting conditions. We aimed investigating the frequency of elevated lactate at rest in ME/CFS patients, and comparing characteristics of ME/CFS patients with and without elevated lactate. Patients fulfilling international consensus criteria for ME/CFS who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2017 were included retrospectively. All patients were systematically hospitalised for an aetiological workup and overall assessment. We reviewed their medical records for data related to the assessment: clinical characteristics, comorbidities, fatigue features, post-exertional malaise (PEM) severity, and results of 8 lactate measurements at rest. Patients having ≥1 lactate measurement ≥2 mmol/L defined elevated lactate group. The study included 123 patients. Elevated (n = 55; 44.7%) and normal (n = 68; 55.3%) lactate groups were comparable except for PEM, which was more severe in the elevated lactate group after adjusting for age at disease onset, sex, and comorbidities (OR 2.47, 95% CI: 1.10–5.55). ME/CFS patients with elevated blood lactate at rest may be at higher risk for more severe PEM. This finding may be of interest in ME/CFS management.
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December 27, 2019
Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia DisorderA Phase 3 Randomized Clinical Trial
Russell Rosenberg, PhD1; Patricia Murphy, PhD2,3; Gary Zammit, PhD4; et alDavid Mayleben, PhD5; Dinesh Kumar, PhD3; Shobha Dhadda, PhD3; Gleb Filippov, MD, PhD3; Antonia LoPresti, MD3; Margaret Moline, PhD3
JAMA Netw Open. 2019;2(12):e1918254. doi:10.1001/jamanetworkopen.2019.18254
Key Points
Question  Does lemborexant therapy effectively treat insomnia disorder in patients 55 years and older compared with placebo and zolpidem tartrate extended release therapy?
Findings  In this randomized double-blind clinical trial of 1006 participants 55 years and older with insomnia disorder, lemborexant therapy significantly improved both latency to persistent sleep and sleep maintenance (wake-after-sleep onset and sleep efficiency) compared objectively via polysomnography with both placebo and zolpidem tartrate extended release therapy. Efficacy was also demonstrated on patient-reported end points of sleep onset, sleep efficiency, and wake-after-sleep onset for both doses of lemborexant compared with placebo.
Meaning  Lemborexant therapy may provide an additional option for sleep onset and sleep maintenance difficulties in older patients with insomnia disorder.
Abstract
Importance  Insomnia disorder is prevalent and associated with health risks in older adults; however, efficacy and safety issues with existing treatments create significant unmet needs in this patient population.
Objective  To compare treatment with the orexin receptor antagonist lemborexant with placebo and zolpidem tartrate extended release in participants with insomnia disorder.
Design, Setting, and Participants  The Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1) clinical trial was a global randomized double-blind parallel-group placebo-controlled active-comparator phase 3 study conducted at 67 sites in North America and Europe from May 31, 2016, to January 30, 2018. Data analyses were conducted from January 31, 2018, to September 10, 2018. Participants were 55 years and older with insomnia disorder characterized by reported sleep maintenance difficulties and confirmed by sleep history, sleep diary, and polysomnography. Participants could have also had sleep onset difficulties.
Interventions  Participants received placebo, zolpidem tartrate extended release (6.25 mg), or lemborexant (5 mg or 10 mg) for 1 month at bedtime.
Main Outcomes and Measures  Paired polysomnograms were collected at baseline, the first 2 nights, and the last 2 nights of treatment. The primary end point was the change from baseline in latency to persistent sleep for lemborexant therapy vs placebo. Key secondary end points were changes from baseline in sleep efficiency and wake-after-sleep onset compared with placebo, and wake-after-sleep onset in the second half of the night compared with zolpidem therapy.
Results  Among 1006 participants randomized (placebo, n = 208; zolpidem, n = 263; lemborexant 5 mg, n = 266; and lemborexant 10 mg, n = 269), 869 (86.4%) were women and the median age was 63 years (range, 55-88 years). Both doses of lemborexant therapy demonstrated statistically significant greater changes from baseline on objective sleep onset as assessed by latency to persistent sleep (log transformed) that was measured using polysomnography at the end of 1 month of treatment (nights 29 and 30) compared with placebo (primary end point for least squares geometric means treatment ratio vs placebo: for lemborexant 5 mg, 0.77; 95% CI, 0.67-0.89; P < .001; for lemborexant 10 mg, 0.72; 95% CI, 0.63-0.83; P < .001). For nights 29 and 30, as measured using polysomnography, the mean change from baseline in sleep efficiency (LSM treatment difference vs placebo for lemborexant 5 mg, 7.1%; 95% CI, 5.6%-8.5%; P < .001 and for lemborexant 10 mg, 8.0%; 95% CI, 6.6%-9.5%; P < .001) and wake-after-sleep onset (least squares mean treatment ratio vs placebo for lemborexant 5 mg, −24.0 min; 95% CI, −30.0 to −18.0 min; P < .001 and for lemborexant 10 mg, −25.4 min; 95% CI, −31.4 to −19.3 min; P < .001) were significantly greater for both doses of lemborexant therapy compared with placebo. Also, for nights 29 and 30, wake-after-sleep onset in the second half of the night (least squares mean treatment difference vs zolpidem for lemborexant 5 mg, −6.7 min; 95% CI, −11.2 to −2.2 min; P = .004 and for lemborexant 10 mg, −8.0 min; 95% CI, −12.5 to −3.5 min; P < .001) was significantly greater for both doses of lemborexant therapy compared with zolpidem therapy measured using polysomnography. Six participants (4 in the zolpidem group and 2 in the lemborexant 5 mg group) reported serious adverse events; none were treatment-related. Other adverse events were mostly mild or moderate in severity.
Conclusions and Relevance  In this randomized clinical trial, lemborexant therapy significantly improved both sleep onset and sleep maintenance, including in the second half of the night, compared with both placebo and zolpidem measured objectively using polysomnography. Lemborexant therapy was well tolerated.
Trial Registrations  ClinicalTrials.gov identifier: NCT02783729; EudraCT identifier: 2015-001463-39
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Transient receptor potential melastatin 2 channels are overexpressed in myalgic encephalomyelitis/chronic fatigue syndrome patients
Cassandra Balinas, Helene Cabanas, Donald Staines Sonya Marshall-Gradisnik 
Journal of Translational Medicine volume 17, Article number: 401 (2019)  
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is hallmarked by a significant reduction in natural killer (NK) cell cytotoxicity, a mechanism tightly regulated by calcium (Ca2+). Interestingly, interleukin-2 (IL-2) increases NK cell cytotoxicity. Transient receptor potential melastatin 2 (TRPM2) ion channels are fundamental for Ca2+ signalling in NK cells. This pilot investigation aimed to characterise TRPM2 and CD38 surface expression in vitro on NK cells in ME/CFS patients. This investigation furthermore examined the pharmaceutical effect of 8-bromoadenosine phosphoribose (8-Br-ADPR) and N6-Benzoyladenosine-3′,5′-cyclic monophosphate (N6-Bnz-cAMP) on TRPM2 and CD38 surface expression and NK cell cytotoxicity between ME/CFS and healthy control (HC) participants.
Methods
Ten ME/CFS patients (43.45 ± 12.36) and 10 HCs (43 ± 12.27) were age and sex-matched. Isolated NK cells were labelled with fluorescent antibodies to determine baseline and drug-treated TRPM2 and CD38 surface expression on NK cell subsets. Following IL-2 stimulation, NK cell cytotoxicity was measured following 8-Br-ADPR and N6-Bnz-cAMP drug treatments by flow cytometry.
Results
Baseline TRPM2 and CD38 surface expression was significantly higher on NK cell subsets in ME/CFS patients compared with HCs. Post IL-2 stimulation, TRPM2 and CD38 surface expression solely decreased on the CD56DimCD16+ subset. 8-Br-ADPR treatment significantly reduced TRPM2 surface expression on the CD56BrightCD16Dim/− subset within the ME/CFS group. Baseline cell cytotoxicity was significantly reduced in ME/CFS patients, however no changes were observed post drug treatment in either group.


Conclusion
Overexpression of TRPM2 on NK cells may function as a compensatory mechanism to alert a dysregulation in Ca2+ homeostasis to enhance NK cell function in ME/CFS, such as NK cell cytotoxicity. As no improvement in NK cell cytotoxicity was observed within the ME/CFS group, an impairment in the TRPM2 ion channel may be present in ME/CFS patients, resulting in alterations in [Ca2+]i mobilisation and influx, which is fundamental in driving NK cell cytotoxicity. Differential expression of TRPM2 between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in ME/CFS.
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Original Paper   Published: 23 January 2020
The Prevalence of Pediatric Myalgic Encephalomyelitis/Chronic Fatigue Syndrome in a Community-Based Sample

• Leonard A. Jason, Ben Z. Katz, Madison Sunnquist, Chelsea Torres, Joseph Cotler & Shaun Bhatia 

Child & Youth Care Forum (2020)Cite this article
Abstract
Background
Most pediatric prevalence studies of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have been based upon data from tertiary care centers, a process known for systematic biases such as excluding youth of lower socioeconomic status and those less likely to have access to health care. In addition, most pediatric ME/CFS epidemiologic studies have not included a thorough medical and psychiatric examination. The purpose of this study was to determine the prevalence of pediatric ME/CFS from an ethnically and sociodemographically diverse community-based random sample.
Method
A sample of 10,119 youth aged 5–17 from 5622 households in the Chicagoland area were screened. Following evaluations, a team of physicians made final diagnoses. Youth were given a diagnosis of ME/CFS if they met criteria for three selected case definitions. A probabilistic, multi-stage formula was used for final prevalence calculations.
Results
The prevalence of pediatric ME/CFS was 0.75%, with a higher percentage being African American and Latinx than Caucasian. Of the youth diagnosed with ME/CFS, less than 5% had been previously diagnosed with the illness.
Conclusions
Many youth with the illness have not been previously diagnosed with ME/CFS. These findings point to the need for better ways to identify and diagnose youth with this illness.
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Comprehensive Circulatory Metabolomics in ME/CFS Reveals Disrupted Metabolism of Acyl Lipids and Steroids
by Arnaud Germain 1,Dinesh K. Barupal 2,Susan M. Levine 1 andMaureen R. Hanson 1,*
1
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
2
UC Davis Genome Center—Metabolomics, University of California, Davis, CA 95616, USA
*
Author to whom correspondence should be addressed.
Metabolites 2020, 10(1), 34; https://doi.org/10.3390/metabo10010034 (registering DOI)
Received: 20 December 2019 / Revised: 9 January 2020 / Accepted: 12 January 2020 / Published: 14 January 2020
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Abstract
The latest worldwide prevalence rate projects that over 65 million patients suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an illness with known effects on the functioning of the immune and nervous systems. We performed an extensive metabolomics analysis on the plasma of 52 female subjects, equally sampled between controls and ME/CFS patients, which delivered data for about 1750 blood compounds spanning 20 super-pathways, subdivided into 113 sub-pathways. Statistical analysis combined with pathway enrichment analysis points to a few disrupted metabolic pathways containing many unexplored compounds. The most intriguing finding concerns acyl cholines, belonging to the fatty acid metabolism sub-pathway of lipids, for which all compounds are consistently reduced in two distinct ME/CFS patient cohorts. We compiled the extremely limited knowledge about these compounds and regard them as promising in the quest to explain many of the ME/CFS symptoms. Another class of lipids with far-reaching activity on virtually all organ systems are steroids; androgenic, progestin, and corticosteroids are broadly reduced in our patient cohort. We also report on lower dipeptides and elevated sphingolipids abundance in patients compared to controls. Disturbances in the metabolism of many of these molecules can be linked to the profound organ system symptoms endured by ME/CFS patients. View Full-Text
Keywords: ME/CFS; metabolomics; acyl cholines; steroids; dipeptides; lipids
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“Altered T cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)”
Principal Investigators: Liisa Selin (PhD), Anna Gil (PhD)
University of Massachusetts Medical School
Our understanding of the immunological defects present in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is severely lacking compared to other disorders, leading to a major barrier to research, diagnosis, and treatment. ME/CFS is a complex disorder affecting numerous organ systems and biological processes with studies focusing on changes in cytokines, metabolism, and identifying a potential causative infectious agent. In this pilot study, we propose to examine the role of a novel subset of immune cells, CD4+CD8+ T cells in the pathology of ME/CFS.
We recently discovered not only an increased frequency of this otherwise rare T cell in a group of ME/CFS patients we were studying, but also that they were highly activated producing unusual cytokines. We observed a difference in the activation profile of these cells in mild and severe cases of ME/CFS. In my long career of studying human T cell responses during viral infections I have never previously observed an increase in this cell type. We will examine the role they may play in the highly dysregulated immune response of ME/CFS patients. Much of the published data seems to suggest that ME/CFS may be preceded by infection, and the chronic manifestation of illness may represent an altered host response to infection, or an inability to resolve inflammation.
Based on our preliminary data, we will examine in a larger cohort, whether this unique subset of CD4+CD8+ T cells is increased in all ME/CFS donors, or does it only occur in a subgroup. We will also assess its role in mediating the disease by examining its frequency and alterations in its function in ME/CFS patients, manifesting either a mild or severe form of the disease as compared to healthy donors. Also, T cells have unique receptors (TCR) that they use to recognize foreign pathogens and eliminate them. Sometimes these TCR also inadvertently recognize self-proteins and lead to autoimmune diseases.
In our preliminary studies examining the TCR repertoire of the CD4+CD8+ population there was strong evidence they were expanded by recognizing an antigen. At this time, we do not know if this is a self or a pathogen antigen. We will therefore explore the TCR repertoire of this unique population of CD4+CD8+ T cells in order to find characteristics that will help us identify the potential antigen that is driving their expansion and activation. This would be a major step in the field potentially leading to the identification a specific infectious or autoimmune response that could be the main driver of the immunological basis of ME/CFS. Studying these unique cells (CD4+CD8+ T cells) in a larger population of ME/CFS patients has the potential to give us a biomarker (much needed for this disease) while giving us clues to the mechanisms driving the pathology of ME/CFS and thus therapy.
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Tick-Borne Encephalitis Virus, United Kingdom
Maya Holding; Stuart D. Dowall; Jolyon M. Medlock; Daniel P. Carter; Steven T. Pullan; James Lewis; Richard Vipond; Mara S. Rocchi; Matthew Baylis; Roger Hewson
Emerging Infectious Diseases. 2020;26(1):90-96. 
Abstract
During February 2018–January 2019, we conducted large-scale surveillance for the presence and prevalence of tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) in sentinel animals and ticks in the United Kingdom. Serum was collected from 1,309 deer culled across England and Scotland. Overall, 4% of samples were ELISA-positive for the TBEV serocomplex. A focus in the Thetford Forest area had the highest proportion (47.7%) of seropositive samples. Ticks collected from culled deer within seropositive regions were tested for viral RNA; 5 of 2,041 ticks tested positive by LIV/TBEV real-time reverse transcription PCR, all from within the Thetford Forest area. From 1 tick, we identified a full-length genomic sequence of TBEV. Thus, using deer as sentinels revealed a potential TBEV focus in the United Kingdom. This detection of TBEV genomic sequence in UK ticks has important public health implications, especially for undiagnosed encephalitis.
Introduction
The only tickborne flavivirus in the United Kingdom documented to cause disease in vertebrates is louping ill virus (LIV), a vivirus transmitted by the deer/sheep tick, Ixodes ricinus.[1] This tick species is the most abundant and widely distributed tick species in the United Kingdom and a known vector of Lyme borreliosis. LIV is most commonly detected in sheep, cattle, and red grouse and has been reported in Scotland, Wales, and England (primarily Cumbria, Devon, and North Yorkshire).[1] Humans are incidental hosts for LIV, and infection has been reported infrequently; ≈45 clinical cases have been linked to encephalitis during the past 85 years.[1,2] However, the short window of acute infection leads to uncertainty about whether suspected cases resulted from LIV infection or some other cause, although serologic analysis to analyze recent exposure through induction of IgM-specific responses, in combination with clinical symptoms, could inform a presumptive diagnosis. Human cases are mostly linked to occupational exposure, particularly in abattoir or farm workers and occasionally in laboratory staff.[2] Although the UK Animal and Plant Health Agency holds a database of confirmed diagnoses of LIV in livestock,[3,4] the distribution and regional prevalence of LIV has not been fully defined. Records of distribution and regional prevalence are based on voluntary submissions by farmers and veterinarians from symptomatic livestock,[1] from which private submissions are not integrated. Serologic analysis has been complicated; some animals received vaccination before its withdrawal.
Tick-borne encephalitis virus (TBEV) is a closely related flavivirus that, although known to be less virulent than LIV for sheep,[5] causes a neurologic disease (tick-borne encephalitis [TBE]) after transmission to humans by infected ticks, producing clinical disease in an estimated one third of TBEV infections.[6] TBE typically has a biphasic course starting with a prodromal phase with influenza-like symptoms, followed by a symptom-free interval before neurologic disease occurs; neurologic disease ranges from mild meningitis to severe encephalitis with or without myelitis and spinal paralysis.[7] Three classic subtypes of TBEV are recognized: European (TBEV-Eu), Siberian, and Far Eastern. Two additional TBEV subtypes have recently been proposed: Baikalian subtype and the Himalayan subtype.[8] TBEV-Eu is the prevailing subtype in Western Europe where it is primarily transmitted by I. ricinus ticks and is maintained within forest and meadow biotypes in endemic foci. In the United Kingdom, TBE is considered an imported disease; opportunities for the virus to become established principally are limited because the UK climate was not thought to support the specific conditions required for enzoonotic cycles to be established for TBEV to become endemic.[9] However, changes in climate have affected the emergence, distribution, and abundance of I. ricinus in the United Kingdom;[10] thus, the risk for tickborne disease has increased.[11] A recent study provided evidence that co-infestation of tick larvae and nymphs occurs in small mammals in UK woodland.[12] The increasing range of TBEV in Western Europe was underscored recently when the Netherlands reported its first human case in 2016.[13] Moreover, retrospective serologic screening of deer serum samples and molecular analysis of questing ticks found evidence of TBEV circulation in the Netherlands as far back as 2010 and 2015.[13,14] Given the increasing possibility that TBEV could be circulating in the United Kingdom, Public Health England developed a surveillance program focusing on wild animals and ticks.
In TBEV-endemic areas in continental Europe, the prevalence of TBEV in questing ticks is low, rarely exceeding 1% even in regions where the incidence of human infections is high.[15] Therefore, instead of screening ticks directly, we used sentinel animals first to identify serologic evidence of TBEV to highlight sites for focused tick testing by specific TBEV detection using real-time reverse transcription PCR (rRT-PCR). Deer are proven as reliable sentinels for identifying areas where TBEV is present[13,15] because they have a limited home range, are available in large numbers, and are broadly dispersed within the surveillance areas. They also show long-lasting antibody responses after natural exposure to flaviviruses.[15,16]
For our study, collectors retrieved blood samples from deer culled in England and Scotland during February 2018–January 2019; when available, they also collected tick samples. We tested the blood samples for TBEV or LIV antibodies and the ticks for the presence of viral RNA by rRT-PCR.
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Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations
Alexandra H. Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L. Peterson, Marco Maynard, C. Gunnar Gottschalk, and Maureen R. Hanson
First published December 12, 2019 – Journal of clinical investigation 
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients. To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines. We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.
Graphical Abstract
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Medicine. 98(43):e17600, OCTOBER 2019
DOI: 10.1097/MD.0000000000017600
,  
PMID: 31651868
Issn Print: 0025-7974
Publication Date: October 2019
Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and meta-analysis
Maximillian Nelson;Jasvir Bahl;Jonathan Buckley;Rebecca Thomson;Kade Davison;


Abstract Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition with no reliable diagnostic biomarkers. Studies have shown evidence of autonomic dysfunction in patients with ME/CFS, but results have been equivocal. Heart rate (HR) parameters can reflect changes in autonomic function in healthy individuals; however, this has not been thoroughly evaluated in ME/CFS. 
Methods: A systematic database search for case-control literature was performed. Meta-analysis was performed to determine differences in HR parameters between ME/CFS patients and controls. 
Results: Sixty-four articles were included in the systematic review. HR parameters assessed in ME/CFS patients and controls were grouped into ten categories: resting HR (RHR), maximal HR (HRmax), HR during submaximal exercise, HR response to head-up tilt testing (HRtilt), resting HR variability (HRVrest), HR variability during head-up tilt testing (HRVtilt), orthostatic HR response (HROR), HR during mental task(s) (HRmentaltask), daily average HR (HRdailyaverage), and HR recovery (HRR) Meta-analysis revealed RHR (MD±95% CI=4.14±1.38, P
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Journal of Epidemiological Research:International Peer-Reviewed and Open Access Journal for the epidemiological specialists
Home > Vol 5, No 1 (2019) > Lin
Incidence rates of brain cancer following an outbreak of Chronic Fatigue Syndrome
Cheng-Te Major Lin, Naji Younes, Paul H. Levine
Abstract
Previous studies utilizing data from the Nevada Cancer Registry suggested a transient increase in non-Hodgkin’s lymphoma (NHL) and brain cancer in northern Nevada following an outbreak of Chronic Fatigue Syndrome (CFS) in that area which was not seen in southern Nevada which had no reported CFS outbreaks.  A subsequent study from the National Cancer Institute (NCI) using data from the NCI’s Surveillance, Epidemiology and End Results (SEER) Program and Medicare documented the association between CFS and NHL on a national basis but no other cancer association was seen.  Since brain cancer has a younger age distribution than NHL, we returned to the Nevada Cancer Registry and used ten more years of data and additional analyses to determine if there was an association between CFS and brain cancer by age.  This study confirmed the increased incidence of brain cancer following the outbreak in northern Nevada but not southern Nevada with the increase limited to the under 65 age group, thus explaining why the SEER-Medicare analysis only analyzing data in the 65 and above age group did not detect this association.
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The physiological timeline of post exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
L Hodges T Nielsen D Cochrane D Baken
First published: 08 January 2020 – Translational Sports Medicine.
 https://doi.org/10.1002/tsm2.133
Abstract
With fatigue being such a dominant feature, it is important to define the timeline and its impact following exertion in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This study aimed to investigate the physiological effects of repeated graded maximal exercise testing at 48 and 72 hours, along with analysing the reported time to recover from repeated graded exercise tests (PEM). ME/CFS (n = 16), age and gender matched controls (n=16) were randomly assigned to either a 48‐hour or 72‐hour protocol. Each participant completed a maximal incremental cycle exercise test on day one and again at either 48‐hours (48‐h) or 72‐hours (72‐h) later. Physiological responses were analysed at peak work rate (PWR). There were significant differences in both peak VO2 and workload (p<0.05) in the 48‐h ME/CFS group compared to the 48‐h controls in both test 1 and test 2. Significant differences in peak VO2 and workload were only demonstrated in test 2 in participants in the ME/CFS 72‐h group. There was a small but insignificant decrease in both peak VO2 and workload in the ME/CFS group at 48‐h. Interestingly those in the 72‐h ME/CFS protocol demonstrated an increase in workload (10 Watts), despite no change in VO2peak. Subjective data demonstrated the 48‐hour ME/CFS group reported significantly longer time to recover.
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RESEARCH ARTICLE (Open Access)
 Contents Vol 11(4)
A neuro-inflammatory model can explain the onset, symptoms and flare-ups of myalgic encephalomyelitis/chronic fatigue syndrome
Angus Mackay 1
Journal of Primary Health Care 11(4) 300-307 https://doi.org/10.1071/HC19041
Published: 29 November 2019
Journal Compilation © Royal New Zealand College of General Practitioners 2019 This is an open access article licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License
Abstract
A neuro-inflammatory model is proposed to explain the onset, symptoms and perpetuation of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) via characteristic flare-ups (relapses). In this article, I explore the proposition that a range of triggers (intense physiological stressors such as severe viral infections, chemical toxin exposure or emotional trauma) in ME/CFS-predisposed people causes disruption in the neural circuitry of the hypothalamus (paraventricular nucleus), which induces a neuro-inflammatory reaction in the brain and central nervous system of ME/CFS patients, via over-active innate immune (glial) cells. Resulting dysfunction of the limbic system, the hypothalamus and consequently of the autonomic nervous system can then account for the diverse range of ME/CFS symptoms. Ongoing stressors feed into a compromised (inflamed) hypothalamus and if a certain (but variable) threshold is exceeded, a flare-up will ensue, inducing further ongoing neuro-inflammation in the central nervous system, thus perpetuating the disease indefinitely.


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    •    Published: 06 January 2020
Systematic review of randomized controlled trials for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

• Do-Young Kim, Jin-Seok Lee, Samuel-Young Park, Soo-Jin Kim & 
• Chang-Gue Son 

Journal of Translational Medicine volume 18, Article number: 7 (2020) Cite this article
Abstract
Background
Although medical requirements are urgent, no effective intervention has been proven for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). To facilitate the development of new therapeutics, we systematically reviewed the randomized controlled trials (RCTs) for CFS/ME to date.
Methods
RCTs targeting CFS/ME were surveyed using two electronic databases, PubMed and the Cochrane library, through April 2019. We included only RCTs that targeted fatigue-related symptoms, and we analyzed the data in terms of the characteristics of the participants, case definitions, primary measurements, and interventions with overall outcomes.
Results
Among 513 potentially relevant articles, 55 RCTs met our inclusion criteria; these included 25 RCTs of 22 different pharmacological interventions, 28 RCTs of 18 non-pharmacological interventions and 2 RCTs of combined interventions. These studies accounted for a total of 6316 participants (1568 males and 4748 females, 5859 adults and 457 adolescents). CDC 1994 (Fukuda) criteria were mostly used for case definitions (42 RCTs, 76.4%), and the primary measurement tools included the Checklist Individual Strength (CIS, 36.4%) and the 36-item Short Form health survey (SF-36, 30.9%). Eight interventions showed statistical significance: 3 pharmacological (Staphypan Berna, Poly(I):poly(C12U) and CoQ10 + NADH) and 5 non-pharmacological therapies (cognitive-behavior-therapy-related treatments, graded-exercise-related therapies, rehabilitation, acupuncture and abdominal tuina). However, there was no definitely effective intervention with coherence and reproducibility.
Conclusions
This systematic review integrates the comprehensive features of previous RCTs for CFS/ME and reflects on their limitations and perspectives in the process of developing new interventions.
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J of Translational medicine 2020 Jan 6;18(1):4. doi: 10.1186/s12967-019-02184-z.
Reduced heart rate variability predicts fatigue severity in individuals with chronic fatigue syndrome/myalgic encephalomyelitis.
Escorihuela RM1, Capdevila L2, Castro JR3, Zaragozà MC4, Maurel S5, Alegre J6, Castro-Marrero J7.
Abstract
BACKGROUND:
Heart rate variability (HRV) is an objective, non-invasive tool to assessing autonomic dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). People with CFS/ME tend to have lower HRV; however, in the literature there are only a few previous studies (most of them inconclusive) on their association with illness-related complaints. To address this issue, we assessed the value of different diurnal HRV parameters as potential biomarker in CFS/ME and also investigated the relationship between these HRV indices and self-reported symptoms in individuals with CFS/ME.
METHODS:
In this case-control study, 45 female patients who met the 1994 CDC/Fukuda definition for CFS/ME and 25 age- and gender-matched healthy controls underwent HRV recording-resting state tests. The intervals between consecutive heartbeats (RR) were continuously recorded over three 5-min periods. Time- and frequency-domain analyses were applied to estimate HRV variables. Demographic and clinical features, and self-reported symptom measures were also recorded.
RESULTS:
CFS/ME patients showed significantly higher scores in all symptom questionnaires (p < 0.001), decreased RR intervals (p < 0.01), and decreased HRV time- and frequency-domain parameters (p < 0.005), except for the LF/HF ratio than in the healthy controls. Overall, the correlation analysis reached significant associations between the questionnaires scores and HRV time- and frequency-domain measurements (p < 0.05). Furthermore, separate linear regression analyses showed significant relationships between self-reported fatigue symptoms and mean RR (p = 0.005), RMSSD (p = 0.0268) and HFnu indices (p = 0.0067) in CFS/ME patients, but not in healthy controls.
CONCLUSIONS:
Our findings suggest that ANS dysfunction presenting as increased sympathetic hyperactivity may contribute to fatigue severity in individuals with ME/CFS. Further studies comparing short- and long-term HRV recording and self-reported outcome measures with previous studies in larger CFS/ME cohorts are urgently warranted.
PMID: 31906988
 
PMCID:PMC6943898
 
DOI:10.1186/s12967-019-02184-z
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Psychoneuroendocrinology – vol 113.  March 2020, 104578
The role of low-grade inflammation in ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) - associations with symptoms
Martin AJonsjöabfGunnar LOlssonabRikard WicksellcKjellAlvingdLindaHolmströmaeAnnaAndreassonfg
https://doi.org/10.1016/j.psyneuen.2019.104578Get rights and content
Highlights
Associations between inflammatory markers and common symptoms in ME/CFS.
Higher levels of markers were significantly associated with higher levels of symptoms.
Biological sex moderated several associations.
Abstract
Background
Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) often present with a range of flu-like symptoms resembling sickness behavior as well as widespread pain and concentration deficits. The aim of this study was to explore the association between inflammatory markers previously shown to be related to fatigue severity in ME/CFS and common ME/CFS symptoms post-exertional fatigue, impaired cognitive processing, musculoskeletal pain and recurrent flu-like symptoms, and the moderating effect of sex on these associations.
Methods
53 adult patients diagnosed with ME/CFS at a specialist clinic were included in the study. Fasting blood plasma was analyzed using the Olink Proseek Multiplex Inflammation panel (β-NGF, CCL11, CXCL1, CXCL10, IL-6, IL-7, IL-8, IL-10, IL-18, TGF-α, TGF-β-1 and SCF) and BioRad Human Cytokine Type 1 assay (TNF-α). Participants rated the average severity of symptoms (0–10) based on the 2011 International Consensus Criteria of ME/CFS during a structured clinical interview. Associations between inflammatory markers and symptom severity were analyzed using bivariate correlations and moderated regression analyses bootstrapped with 5000 repetitions.
Results and conclusions
Only β-NGF was associated with the fatigue severity measure. However, higher levels of CCL11, CXCL10, IL-7, TNF-α and TGF-β-1 were significantly associated with higher levels of impaired cognitive processing and musculoskeletal pain, and sex was a significant moderator for CXCL10, IL-7 and TGF-β-1. Future studies should investigate the relationship between inflammatory markers and key symptoms in ME/CFS in a longitudinal design in order to explore if and for whom low-grade inflammation may contribute to illness development.
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• Open Access  Published: 22 January 2020

Health-related quality of life in patients with myalgic encephalomyelitis/chronic fatigue syndrome: an Australian cross-sectional study
N. Eaton-Fitch, S. C. Johnston, P. Zalewski, D. Staines & S. Marshall-Gradisnik 
Quality of Life Research (2020) 
Abstract
Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and debilitating disorder associated with significant disruptions in daily life including. This study aimed to examine the impact of sociodemographic and patient symptom characteristics on health-related quality of life (HRQoL) of Australians with ME/CFS.
Methods
Self-reported data collected from 480 individuals diagnosed with ME/CFS were obtained between August 2014 and August 2018. This cross-sectional survey analysed sociodemographic, symptom characteristics and HRQoL according to the 36-Item Health Survey (SF-36). Multivariate linear regression models were used to determine ME/CFS symptoms associated with eight domains of HRQoL.
Results
Reported HRQoL was significantly impaired in ME/CFS patients across all domains compared with the general population. Scores were the lowest for physical role (4.11 ± 15.07) and energy/fatigue (13.54 ± 13.94). Associations with females, higher body mass index (BMI), employment status, cognitive difficulties, sensory disturbances and cardiovascular symptoms were observed in the physical functioning domain. Impaired pain domain scores were associated with high BMI, annual visits to their general practitioner, flu-like symptoms and fluctuations in body temperature. Reduced well-being scores were associated with smoking status, psychiatric comorbidity, cognitive difficulties, sleep disturbances and gastrointestinal difficulties.
Conclusion
This study provides evidence that ME/CFS has a profound and negative impact on HRQoL in an Australian cohort.​

Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome
A systematic review and meta-analysis
Nelson, Maximillian J. PhDa,∗; Bahl, Jasvir S. BAppScia; Buckley, Jonathan D. PhDa; Thomson, Rebecca L. PhDa,b; Davison, Kade PhDa
Section Editor(s): NA.,
Medicine: October 2019 - Volume 98 - Issue 43 - p e17600
doi: 10.1097/MD.0000000000017600
Research Article: Systematic Review and Meta-Analysis
Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition with no reliable diagnostic biomarkers. Studies have shown evidence of autonomic dysfunction in patients with ME/CFS, but results have been equivocal. Heart rate (HR) parameters can reflect changes in autonomic function in healthy individuals; however, this has not been thoroughly evaluated in ME/CFS.
Methods: A systematic database search for case-control literature was performed. Meta-analysis was performed to determine differences in HR parameters between ME/CFS patients and controls.
Results: Sixty-four articles were included in the systematic review. HR parameters assessed in ME/CFS patients and controls were grouped into ten categories: resting HR (RHR), maximal HR (HRmax), HR during submaximal exercise, HR response to head-up tilt testing (HRtilt), resting HR variability (HRVrest), HR variability during head-up tilt testing (HRVtilt), orthostatic HR response (HROR), HR during mental task(s) (HRmentaltask), daily average HR (HRdailyaverage), and HR recovery (HRR) Meta-analysis revealed RHR (MD ± 95% CI = 4.14 ± 1.38, P < .001), HRtilt (SMD ± 95% CI = 0.92 ± 0.24, P < .001), HROR (0.50 ± 0.27, P < .001), and the ratio of low frequency power to high frequency power of HRVrest (0.39 ± 0.22, P < .001) were higher in ME/CFS patients compared to controls, while HRmax (MD ± 95% CI = –13.81 ± 4.15, P < .001), HR at anaerobic threshold (SMD ± 95% CI = –0.44 ± 0.30, P = 0.005) and the high frequency portion of HRVrest (–0.34 ± 0.22, P = .002) were lower in ME/CFS patients.
Conclusions: The differences in HR parameters identified by the meta-analysis indicate that ME/CFS patients have altered autonomic cardiac regulation when compared to healthy controls. These alterations in HR parameters may be symptomatic of the condition.
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Reduced diversity and altered composition of the gut microbiome in individuals with myalgic encephalomyelitis/chronic fatigue syndrome
Authors: Ludovic Giloteaux, L., Goodrich, J.K., Walters, W.A., Levine, S.M., Ley, R.E., & Hanson, M.R.
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918027/

Gastrointestinal disturbance is a common symptom of ME/CFS. This study examined the gut microbiota of ME/CFS patients and healthy controls.

These researchers found that ME/CFS patients have less biodiversity of gut microbiota compared with healthy controls. In addition, ME/CFS patients were more likely to have higher gut bacteria species which are reported as pro-inflammatory and less of those that are anti-inflammatory. There were also elevated levels of blood markers for microbial translocation (meaning that gut bacteria are found outside the gut) for ME/CFS patients than for healthy controls.

In summary, the results indicate imbalance or maladaptation of the gut microbiota in ME/CFS patients and an increased incidence of microbial translocation which may play a role in inflammatory symptoms of the illness.
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A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID)
Authors: Corbitt, M., Eaton-Fitch, N., Staines, D., Cabanas, H., & Marshall-Gradisnik, S.
Link: https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-019-1433-0

This literature review looked at whether there was a significant difference in cytokine levels between ME/CFS patients and healthy controls. The review examined 15 studies which met the criteria for further analysis.

Across the 15 studies, 64 cytokines were analysed. Despite moderate quality studies, results were inconclusive as to whether cytokines play a definitive role in ME/CFS other than “evidence of a concurrent inflammatory process.” 

The review also identified several limitations in these studies, including that most of the studies analyses used the Fukuda criteria, which is very broad, and means that characteristics of the patient samples are likely to differ between studies. 

The authors concluded that cytokines are unlikely to be useful as biomarkers for ME/CFS, and that more research is needed towards a diagnostic test and treatment for ME/CFS.


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Epstein-Barr virus (EBV) reactivation and therapeutic inhibitors
Jonathan R Kerr


Journal of Clinical pathology – Vol 72, Issue 10
Abstract
Epstein-Barr virus (EBV) is a ubiquitous human virus which infects almost all humans during their lifetime and following the acute phase, persists for the remainder of the life of the individual. EBV infects B lymphocytes leading to their immortalisation, with persistence of the EBV genome as an episome. In the latent phase, EBV is prevented from reactivating through efficient cytotoxic cellular immunity. EBV reactivates (lytic phase) under conditions of psychological stress with consequent weakening of cellular immunity, and EBV reactivation has been shown to occur in a subset of individuals with each of a variety of cancers, autoimmune diseases, the autoimmune-like disease, chronic fatigue syndrome/myalgic encephalitis and under other circumstances such as being an inpatient in an intensive care unit. Chronic EBV reactivation is an important mechanism in the pathogenesis of many such diseases, yet is rarely tested for in immunocompetent individuals. This review summarises the pathogenesis of EBV infection, EBV reactivation and its role in disease, and methods which may be used to detect it. Known inhibitors of EBV reactivation and replication are discussed, including drugs licensed for treatment of other herpesviruses, licensed or experimental drugs for various other indications, compounds at an early stage of drug development and nutritional constituents such as vitamins and dietary supplements.
http://dx.doi.org/10.1136/jclinpath-2019-205822

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Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients
Authors:    Jonas Blomberg, Muhammad Rizwan, Agnes Böhlin-Wiener, Amal Elfaitouri, Per Julin, Olof Zachrisson, Anders Rosén and Carl-Gerhard Gottfries
Institution: Section of Clinical Microbiology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Abstract
Myalgic encephalomyelitis, also referred to as chronic fatigue syndrome (ME/CFS) is a debilitating disease characterized by myalgia and a sometimes severe limitation of physical activity and cognition. It is exacerbated by physical and mental activity. Its cause is unknown, but frequently starts with an infection. The eliciting infection (commonly infectious mononucleosis or an upper respiratory infection) can be more or less well diagnosed. Among the human herpesviruses (HHV-1-8), HHV-4 (Epstein-Barr virus; EBV), HHV-6 (including HHV-6A and HHV-6B), and HHV-7, have been implicated in the pathogenesis of ME/CFS. It was therefore logical to search for serological evidence of past herpesvirus infection/reactivation in several cohorts of ME/CFS patients (all diagnosed using the Canada criteria). Control samples were from Swedish blood donors. We used whole purified virus, recombinant proteins, and synthetic peptides as antigens in a suspension multiplex immunoassay (SMIA) for immunoglobulin G (IgG). The study on herpesviral peptides based on antigenicity with human sera yielded novel epitope information. Overall, IgG anti-herpes-viral reactivities of ME/CFS patients and controls did not show significant differences. However, the high precision and internally controlled format allowed us to observe minor relative differences between antibody reactivities of some herpesviral antigens in ME/CFS versus controls. ME/CFS samples reacted somewhat differently from controls with whole virus HHV-1 antigens and recombinant EBV EBNA6 and EA antigens. We conclude that ME/CFS samples had similar levels of IgG reactivity as blood donor samples with HHV-1-7 antigens. The subtle serological differences should not be over-interpreted, but they may indicate that the immune system of some ME/CFS patients interact with the ubiquitous herpesviruses in a way different from that of healthy controls.
Publication:   Blomberg et al., Frontiers in Immunology, 2019 August 14; 10:1946
Comment by ME Research UK:  Published recently in Frontiers in Immunology is a new study – funded partly by ME Research UK – from the late Prof. Jonas Blomberg in Sweden. The researchers looked for evidence of past infection with, or reactivation of, the human herpesviruses HHV-4 (also known as Epstein–Barr virus), HHV-6 and HHV-7, which have been implicated in the pathogenesis of ME/CFS. Immunoglobulin G reactivity levels to these viruses were similar in serum samples from patients and control subjects, indicating that none of these herpesviruses are more common or intense in ME/CFS patients than in the rest of the population. However, the researchers did find subtle differences in antibody reactivities to whole virus HHV-1 antigens and some recombinant HHV-4 antigens in ME/CFS samples, suggesting that the immune system of patients may interact
Physiol.Rep    2019 Jun; 7(11): e14138.Published online 2019 Jun 3. doi: 10.14814/phy2.14138
PMCID: PMC6546966    PMID: 31161646
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Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome
Katarina Lien, 1 , 2 Bjørn Johansen, 3 Marit B. Veierød, 4 Annicke S. Haslestad, 1 Siv K. Bøhn, 1 Morten N. Melsom, 5 Kristin R. Kardel, 1 and Per O. Iversen 1 , 6
Author information Article notes Copyright and License information Disclaimer
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 (VO 2) 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 (CPET 1 and CPET 2) with [Laa] measured every 30th second. VO 2 at peak exercise (VO 2peak) was lower in patients than in controls on CPET 1 (P < 0.001) and decreased in patients on CPET 2 (P < 0.001). However, the difference in VO 2peak between CPETs did not differ significantly between groups. [Laa] per PO was higher in patients during both CPETs (P interaction < 0.001), but increased in patients and decreased in controls from CPET 1 to CPET 2 (P interaction < 0.001). Patients had lower VO 2 (P = 0.02) and PO (P = 0.002) at the gas exchange threshold (GET, the point where CO 2 production increases relative to VO 2), but relative intensity (%VO 2peak) and [Laa] at GET did not differ significantly from controls on CPET 1. Patients had a reduction in VO 2 (P = 0.02) and PO (P = 0.01) at GET on CPET 2, but no significant differences in %VO 2peak and [Laa] at GET between CPETs. Controls had no significant differences in VO 2, PO or %VO 2peak at GET between CPETs, but [Laa] at GET was reduced on CPET 2 (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.
Keywords: Elevated lactate, exercise intolerance, metabolism, oxygen uptake, post‐exertional malaise

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Lyme disease: chronic illness is rare, say experts
BMJ 2019; 367 doi: https://doi.org/10.1136/bmj.l5975 (Published 10 October 2019)Cite this as: BMJ 2019;367:l5975

•   Anna Harvey

People who have had Lyme disease rarely develop chronic problems, experts have said, warning that those who seek treatment abroad believing their symptoms are a result of the infection may be putting themselves at risk.
There are around 1000 laboratory confirmed cases of Lyme disease in England and Wales annually, with an estimated 2000 more cases successfully treated in primary care without positive blood tests, said experts at a briefing on the disease at the Science Media Centre on 9 October.
Of these patients, fewer than one in 20 experience residual symptoms.

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Effects of Smoking on Patients With Chronic Pain
A Propensity-weighted Analysis on the Collaborative Health Outcomes Information Registry
James S. Khan; Jennifer M. Hah; Sean C. Mackey
Pain. 2019;160(10):2374-2379. 
Abstract and Introduction
Abstract
Tobacco smoking is associated with adverse health effects, and its relationship to pain is complex. The longitudinal effect of smoking on patients attending a tertiary pain management center is not well established. Using the Collaborative Health Outcomes Information Registry of patients attending the Stanford Pain Management Center from 2013 to 2017, we conducted a propensity-weighted analysis to determine independent effects of smoking on patients with chronic pain. We adjusted for covariates including age, sex, body mass index, depression and anxiety history, ethnicity, alcohol use, marital status, disability, and education. We compared smokers and nonsmokers on pain intensity, physical function, sleep, and psychological and mood variables using self-reported NIH PROMIS outcomes. We also conducted a linear mixed-model analysis to determine effect of smoking over time. A total of 12,368 patients completed the CHOIR questionnaire of which 8584 patients had complete data for propensity analysis. Smokers at time of pain consultation reported significantly worse pain intensities, pain interference, pain behaviors, physical functioning, fatigue, sleep-related impairment, sleep disturbance, anger, emotional support, depression, and anxiety symptoms than nonsmokers (all P < 0.001). In mixed-model analysis, smokers tended to have worse pain interference, fatigue, sleep-related impairment, anger, emotional support, and depression over time compared with nonsmokers. Patients with chronic pain who smoke have worse pain, functional, sleep, and psychological and mood outcomes compared with nonsmokers. Smoking also has prognostic importance for poor recovery and improvement over time. Further research is needed on tailored therapies to assist people with chronic pain who smoke and to determine an optimal strategy to facilitate smoking cessation.


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Front. Immunol. | doi: 10.3389/fimmu.2019.02545
Naltrexone restores impaired transient receptor potential melastatin 3 ion channel function in natural killer cells from myalgic encephalomyelitis/chronic fatigue syndrome patients
Helene Cabanas1, 2, 3, 4*, Katsuhiko Muraki4, 5, Donald Staines1, 2, 3, 4 and Sonya Marshall-Gradisnik1, 2, 3, 4

• 1School of Medical Sciences, Griffith Health, Griffith University, Australia
• 2National Centre for Neuroimmunology and Emerging Diseases, Menzies Health Institute, Griffith University, Australia
• 3Menzies Health Institute, Griffith University, Australia
• 4National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Independent researcher, Australia
• 5School of Pharmacy, Aichi Gakuin University, Japan

Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a seriously long-term and debilitating illness of unknown cause hallmarked by chronic pain and fatigue, memory and concentration impairment, and inflammation. ME/CFS hypothesis involves ion channel disorders and more specifically impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signalling and Natural killer (NK) cell functions. Currently, substances called opioids, agonists of mu (µ)-opioid receptors (µOR), are the strongest painkillers clinically available for people suffering from strong or long-lasting pain characteristic of CFS/ME. µOR have been reported to specifically inhibit TRPM3 and to be expressed in immune cells where they play an immunomodulatory and immunosuppressive role. Naltrexone hydrochloride (NTX) acts as an antagonist to the μOR thus negating the inhibitory function of this opioid receptor on TRPM3. Therefore, understanding the mechanism of action for NTX in regulating and modulating TRPM3 channel function in NK cells will provide important information for the development of effective therapeutic interventions for ME/CFS.
Whole-cell patch-clamp technique was used to measure TRPM3 activity in Interleukin-2 (IL-2) stimulated and NTX-treated NK cells for 24 hours on sixteen age- and sex-matched healthy controls and CFS/ME patients, after modulation with pregnenolone sulfate (PregS), NTX and ononetin.
We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in Interleukin-2 (IL-2) stimulated NK cells after modulation with pregnenolone sulfate and ononetin. Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 hours with NTX. Moreover, we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating.
The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from CFS/ME patients, resulting in calcium signals remodelling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for CFS/ME. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.
Keywords: Transient Receptor Potential Melastatin 3 (TRPM3), Naltrexone, Calcium, Opioid Receptor, Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, Natural killer cells (NK cells), Whole-cell patch clamp electrophysiology
Received: 07 Aug 2019; Accepted: 14 Oct 2019.
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Exercise therapy for chronic fatigue syndrome – Cochrane amended review of the effectiveness of graded exercise therapy
Author: Larun, L., Brurberg, K.G., Odgaard‐Jensen, J., & Price, J.R.
Link: https://www.cochrane.org/news/publication-cochrane-review-exercise-therapy-chronic-fatigue-syndrome
Cochrane is an independent, international network of researchers, clinicians, patients, carers and others interested in health, which publishes systematic reviews of research into health interventions. Cochrane is very well-respected, and its reviews are highly influential. 

The Cochrane review of exercise therapy for ME/CFS (Larun et al, 2017) has been the subject of a formal complaint about its science and methodology. This complaint led to an update of the review, which Cochrane has now published. 

The updated review concludes that there is low-moderate certainty about the evidence that exercise therapy may alleviate some symptoms of ME/CFS, and recommends further research. The review acknowledges:

• The therapy’s long term effectiveness is uncertain due to a lack of follow-up in many studies.
• The risk of serious side effects and the effects of exercise therapy on pain, quality of life, and depression is uncertain, due either to lack of evidence or low quality evidence.
• Most studies are based on broader diagnostic criteria than are currently recommended for use and that “people diagnosed using other criteria may experience different effects.”

Overall, the review concludes that there is limited evidence that exercise therapy may provide short term benefit to some patients based on older, and broader diagnostic criteria for ME/CFS. In addition, Cochrane is uncertain, or very uncertain, about the long term benefits of exercise therapy and its associated risks. 

Importantly, Cochrane has committed to publish a full update of this review which will include the establishment of an independent advisory group which “will involve partners from patient-advocacy groups from different parts of the world”. Work will commence in 2020 and Emerge Australia has requested that they should be a part of this work. 
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Patients with Fibromyalgia and Chronic Fatigue Syndrome show increased hsCRP compared to healthy controls
Authors: Groven, N., Egil A.Fors, N.E, Reitanac, S.K,
Link: https://www.sciencedirect.com/science/article/pii/S0889159119302089
ME/CFS and Fibromyalgia (FM) both have clinical aspects which resemble inflammatory disorders and, in both conditions, it is thought that the immune system may play a role. C-reactive protein (CRP) is a blood marker which measures inflammation. This study used a high-sensitivity CRP (hsCRP) test, which is more sensitive than standard CRP tests, to examine CRP levels in both conditions as compared to healthy controls.

Results showed hsCRP levels were significantly higher for both the ME/CFS and FM groups compared to healthy controls and there were no differences between the two patient groups.

Overall, the higher hsCRP levels suggest inflammation is present in ME/CFS and FM patients, which may contribute to symptoms as inflammation is a well-known cause for fatigue and pain. The researchers note that inflammation could be both a target for treatment, as well as a marker to monitor the effectiveness of treatment.
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Editorial: Advances in ME/CFS Research and Clinical Care
Authors: Friedman, K.J.,   Bateman, K.,  Bested, A., & Nahle, Z.
Link: https://www.frontiersin.org/articles/10.3389/fped.2019.00370/full
This editorial provides an overview of a collection of 24 articles on ME/CFS published in the journals Frontiers in Neurology and Frontiers in Pediatrics. The collection, published between September 2018 and July 2019, sought to explore new and rejuvenated areas of ME/CFS research, as well as whether there have been improvements in clinical care. 

The editorial summarises the advances in ME/CFS research and clinical care over the last few decades, outlining the current lack of diagnostic methods and effective treatment for the illness and highlights the historical misunderstandings which patients have had to endure.

However, despite setbacks, advances are being made through the determination and compassion of those working in the field.  The collection includes: 
 

• Three papers which evaluated potential clinical biomarkers such as hand grip strength, 2-day, cardiopulmonary exercise, and tilt table testing for diagnosing postural orthostatic tachycardia syndrome (POTS).
• Current research into ME/CFS patient pathology including microbiome, neuroinflammation and cytokines, cardiovascular symptoms, and the establishment of biobanks to identify additional tissue abnormalities.
• Research into how ME/CFS affects adolescents and what treatment and support benefitted them the most.

The authors note the lack of articles in the collection which focus on those who are severely unwell, despite making up 25% of the ME/CFS patient population. However, as a result of the interest in the papers in this collection, the editors have been invited to create another collection, called "ME/CFS—The Severely Affected”, which will focus exclusively on severe patients.
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NeuroImage: Clinical Volume 24, 2019, 102045


Intra brainstem connectivity is impaired in chronic fatigue syndrome
Author links open overlay panelLeighton RBarndenaZack YShanabDonald RStainesaSonyaMarshall-GradisnikaKevinFinegancTimothyIrelandcSandeepBhutac
https://doi.org/10.1016/j.nicl.2019.102045Get rights and content
Highlights
RAS connectivity was detected in HC and CFS groups both during rest and tasks
Strong connections were active for CFS from hippocampus to midbrain and medulla.
RAS connectivity was diminished in CFS in the brainstem and to the hippocampus.
RAS nuclei generate oscillatory signals which facilitate thalamocortical signal coherence.
Impaired RAS affects cortical coherence necessary for attention, memory and problem solving.
Abstract
In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem. Here we analyse fMRI correlations to directly test connectivity within and from the brainstem. Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC). We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections. When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. In ME/CFS, connections were absent between medulla and midbrain nuclei, although hippocampal connections with these nuclei were enhanced. When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task. In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations. Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS.

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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) Cite this as: BMJ 2018;360:k851 
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.
Trial registration ClinicalTrials.gov NCT01420640.

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Clin Ther  2019 May;41(5):815-835.e6. doi: 10.1016/j.clinthera.2019.01.011. Epub 2019 Mar 6.
Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules.
Jeffrey MG1, Nathanson L2, Aenlle K3, Barnes ZM4, Baig M5, Broderick G6, Klimas NG7, Fletcher MA3, Craddock TJA8.
Author information
1
Institute for Neuro-Immune Medicine, Nova Southeastern University, Ft. Lauderdale, FL, USA; College of Psychology, Nova Southeastern University, Ft. Lauderdale, FL, USA.
Abstract
PURPOSE:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisymptom illness impacting up to 1 million people in the United States. As the pathogenesis and etiology of this complex condition are unclear, prospective treatments are limited. Identifying US Food and Drug Administration-approved drugs that may be repositioned as treatments for ME/CFS may offer a rapid and cost-effective solution.
METHODS:
Here we used gene-expression data from 33 patients with Fukuda-defined ME/CFS (23 females, 10 males) and 21 healthy demographically comparable controls (15 females, 6 males) to identify differential expression of predefined gene-module sets based on nonparametric statistics. Differentially expressed gene modules were then annotated via over-representation analysis using the Consensus Pathway database. Differentially expressed modules were then regressed onto measures of fatigue and cross-referenced with drug atlas and pharmacogenomics databases to identify putative treatment agents.
FINDINGS:
The top 1% of modules identified in males indicated small effect sizes in modules associated with immune regulation and mitochondrial dysfunction. In females, modules identified included those related to immune factors and cardiac/blood factors, returning effect sizes ranging from very small to intermediate (0.147 < Cohen δ < 0.532). Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor α, transforming growth factor β, and metabolic and cardiac modules were strongly correlated with multiple composite measures of fatigue. Cross-referencing identified genes with pharmacogenomics data indicated immunosuppressants as potential treatments of ME/CFS symptoms.
IMPLICATIONS:
The findings from our analysis suggest that ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation-based treatment strategies.
Copyright © 2019. Published by Elsevier Inc.
PMID:30851951 DOI:10.1016/j.clinthera.2019.01.011

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Neurosci Biobehav Rev. 2019 Dec;107:69-83. doi: 10.1016/j.neubiorev.2019.08.011. Epub 2019 Aug 26.
Inflammatory proteins are altered in chronic fatigue syndrome-A systematic review and meta-analysis.
Strawbridge R1, Sartor ML2, Scott F2, Cleare AJ2.
Author information
1
Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. Electronic address: Becci.strawbridge@kcl.ac.uk.
2
Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Abstract
Immune dysfunction has been posited as a key element in the aetiology of chronic fatigue syndrome (CFS) since the illness was first conceived. However, systematic reviews have yet to quantitatively synthesise inflammatory biomarkers across the literature. We undertook a systematic review and meta-analysis to quantify available data on circulating inflammatory proteins, examining studies recruiting patients with a CFS diagnosis and a non-affected control group. Results were meta-analysed from 42 studies. Patients with CFS had significantly elevated tumour necrosis factor (ES = 0.274, p < 0.001), interleukin-2 (ES = 0.203, p = 0.006), interleukin-4 (ES = 0.373, p = 0.004), transforming growth factor-β (ES = 0.967, p < 0.001) and c-reactive protein (ES = 0.622, p = 0.019). 12 proteins did not differ between groups. These data provide some support for an inflammatory component in CFS, although inconsistency of results indicates that inflammation is unlikely to be a primary feature in all those suffering from this disorder. It is hoped that further work will elucidate whether there are subgroups of patients with clinically-relevant inflammatory dysfunction, and whether inflammatory cytokines may provide a prognostic biomarker or moderate treatment effects.
Copyright © 2019 Elsevier Ltd. All rights reserved.
KEYWORDS:
CFS; Chronic fatigue syndrome; Inflammation; ME/CFS; Meta-Analysis; Systematic review
PMID:31465778
 
DOI:10.1016/j.neubiorev.2019.08.011

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BMC Neurology     December 2019, 19:275 
A logistic regression analysis of risk factors in ME/CFS pathogenesis

• Eliana M. LacerdaKeith Geraghty Caroline C. Kingdon Luigi Palla Luis Nacul

Abstract
Background
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease, whose exact cause remains unclear. A wide range of risk factors has been proposed that helps understanding potential disease pathogenesis. However, there is little consistency for many risk factor associations, thus we undertook an exploratory study of risk factors using data from the UK ME/CFS Biobank participants. We report on risk factor associations in ME/CFS compared with multiple sclerosis participants and healthy controls.
Methods
This was a cross-sectional study of 269 people with ME/CFS, including 214 with mild/moderate and 55 with severe symptoms, 74 people with multiple sclerosis (MS), and 134 healthy controls, who were recruited from primary and secondary health services. Data were collected from participants using a standardised written questionnaire. Data analyses consisted of univariate and multivariable regression analysis (by levels of proximity to disease onset).
Results
A history of frequent colds (OR = 8.26, P <= 0.001) and infections (OR = 25.5, P = 0.015) before onset were the strongest factors associated with a higher risk of ME/CFS compared to healthy controls. Being single (OR = 4.41, P <= 0.001), having lower income (OR = 3.71, P <= 0.001), and a family history of anxiety is associated with a higher risk of ME/CFS compared to healthy controls only (OR = 3.77, P < 0.001). History of frequent colds (OR = 6.31, P < 0.001) and infections before disease onset (OR = 5.12, P = 0.005), being single (OR = 3.66, P = 0.003) and having lower income (OR = 3.48, P = 0.001), are associated with a higher risk of ME/CFS than MS. Severe ME/CFS cases were associated with lower age of ME/CFS onset (OR = 0.63, P = 0.022) and a family history of neurological illness (OR = 6.1, P = 0.001).
Conclusions
Notable differences in risk profiles were found between ME/CFS and healthy controls, ME/CFS and MS, and mild-moderate and severe ME/CFS. However, we found some commensurate overlap in risk associations between all cohorts. The most notable difference between ME/CFS and MS in our study is a history of recent infection prior to disease onset. Even recognising that our results are limited by the choice of factors we selected to investigate, our findings are consistent with the increasing body of evidence that has been published about the potential role of infections in the pathogenesis of ME/CFS, including common colds/flu.

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.
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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.
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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.