Nicola M. Parry, DVM
July 31, 2017
Patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) have different circulating levels of two cytokines when compared with healthy individuals, a study has found. In addition, the circulating levels of 17 cytokines correlate with disease severity.
"Although only two cytokines were found to be different ([transforming growth factor-β (TGF-β)] higher and resistin lower) in ME/CFS patients compared with controls, 17 cytokines correlated with ME/CFS severity," the authors write. "Thirteen of these cytokines are proinflammatory and may contribute to many of the symptoms these patients experience for several years."
Jose G. Montoya, MD, from Stanford University School of Medicine in California, and colleagues published the results of their cross-sectional study online July 31 in the Proceedings of the National Academy of Sciences.
"There's been a great deal of controversy and confusion surrounding ME/CFS, even whether it is an actual disease," senior author Mark Davis, PhD, professor of immunology and microbiology and director of Stanford's Institute for Immunity, Transplantation and Infection, said in a news release. "Our findings show clearly that it's an inflammatory disease and provide a solid basis for a diagnostic blood test."
ME/CFS affects more than 1 million Americans and is characterized by unexplained chronic fatigue, as well as other symptoms including exertion intolerance, headaches, myalgias, and sleep and cognitive abnormalities. Although the pathogenesis of this disabling disorder remains incompletely understood, inflammation has long been considered to play a central role.
Surprisingly, however, traditional markers of inflammation that have been used in clinical practice, such as erythrocyte sedimentation rate and C-reactive protein, are rarely elevated in patients with ME/CFS. Nevertheless, studies have demonstrated changes in other inflammatory markers in this patient population.
For example, several studies have found increased numbers of circulating cytotoxic CD8+ cells expressing activation antigens in these patients; one study also described daily fluctuations of the pro-inflammatory adipokine leptin, and another study linked a distinct cytokine inflammatory profile with early disease.
The researchers therefore aimed to investigate whether patients with ME/CFS have an abnormal profile of circulating cytokines, and whether this profile correlates with disease severity and duration.
They analyzed blood samples from 192 ME/CFS patients and from 392 healthy individuals and performed immunological analyses of the samples, measuring the concentrations of 51 cytokines in each participant's blood.
When comparing patients with ME/CFS with healthy individuals, the investigators found differences in the circulating levels of only two of the 51 cytokines: TGF-β was increased (P = .0052) in patients with ME/CFS, and resistin was decreased (P = .0052). In addition, levels of resistin were significantly lower in patients with mild (P = .0370) and severe (P = .0208) ME/CFS.
Pro-inflammatory Cytokines Elevated
Concentrations of 17 cytokines correlated with disease severity, showing a statistically significant upward linear trend across the sequence of mild, moderate, and severe manifestations of ME/CFS: CCL11 (P = .0069), CXCL1 (P = .0266), CXCL10 (P = .0100), G-CSF (P = .0110), GM-CSF (P = .0063), interferon γ (P = .0101), interleukin 4 (IL-4; P = .0103), IL-5 (P = .0073), IL-7 (P = .0063), IL-12p70 (P = .0069), IL-13 (P = .0069), IL-17F (P = .0103), leptin (P = .0100), leukemia inhibitory factor (P = .0100), nerve growth factor (P = .0069), stem cell factor (P = .0145), and TGF-α (P = .0367).
Thirteen of these were pro-inflammatory. Elevations in these pro-inflammatory cytokines not only highlight the strong immune component of the disease but also likely contribute to many of the symptoms experienced by patients with ME/CFS, the authors write.
Although the researchers also examined the relationship between cytokine concentration and fatigue duration, they found that only the level of CXCL9 (monokine induced by interferon γ) inversely correlated with fatigue duration (P= .0123).
As TGF-β is predominantly considered to be an anti-inflammatory cytokine, the researchers explain that the elevated levels of TGF-β elevation in patients with ME/CFS may reflect down-regulatory activity by these patients' immune systems against continued inflammation. However, if this were true, TGF-β levels would be expected to correlate with ME/CFS severity, which was not the case in this study.
Thus, TGF-β may not always function to counteract inflammation. Instead, "its net effect may depend on the local immunological milieu at target tissues and the overall levels of TGF-β," they say.
Resistin has significant pro-inflammatory activity and is reportedly a marker of inflammation in patients with systemic lupus erythematosus and Crohn's disease. However, the authors are unclear why resistin levels showed an unusual trend, increasing in patients with mild to moderate ME/CFS, but decreasing in those with moderate to severe disease.
Acknowledging the cross-sectional design as one limitation of their study, the authors emphasize longitudinal studies are needed to determine whether patients with ME/CFS remain within their cytokine signature and disease severity category over time, or fluctuate among them.
"Future cytokine research in the peripheral blood of ME/CFS patients should embrace longitudinal designs and seek correlations with neuroradiology, neuroinflammation, and [cerebrospinal fluid]studies," the authors add.
Proc Natl Acad Sci U S A. Published online July 31, 2017.
Update and new insights in encephalitis
- Corresponding author. A. Mailles, Santé publique France, 12 rue du Val d'Osne, 94415 Saint-Maurice cedex, France.
Published online: May 10, 2017Accepted: May 1, 2017
; Received in revised form: April 30, 2017; Received: February 2, 2017;
Infectious encephalitis is a rare but severe medical condition resulting from direct invasion of the brain by viruses, bacteria, fungi or parasites, or indirect post-infectious immune or inflammatory disorders when the infectious agent does not cross the blood–brain barrier. Infectious encephalitis cases represent an interesting and accurate sentinel to follow up on trends in infectious diseases or to detect emerging infections. Using Pubmed and Embase, we searched the most relevant publications over the last years. We present here an update on the important findings and new data recently published about infectious encephalitis.
Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case–control study
- Tara Gomes, David N. Juurlink, Tony Antoniou, Muhammad M. Mamdani, J. Michael Paterson,
- Wim van den Brink
Published: October 3, 2017 - https://doi.org/10.1371/journal.pmed.1002396
Prescription opioid use is highly associated with risk of opioid-related death, with 1 of every 550 chronic opioid users dying within approximately 2.5 years of their first opioid prescription. Although gabapentin is widely perceived as safe, drug-induced respiratory depression has been described when gabapentin is used alone or in combination with other medications. Because gabapentin and opioids are both commonly prescribed for pain, the likelihood of co-prescription is high. However, no published studies have examined whether concomitant gabapentin therapy is associated with an increased risk of accidental opioid-related death in patients receiving opioids. The objective of this study was to investigate whether co-prescription of opioids and gabapentin is associated with an increased risk of accidental opioid-related mortality.
Methods and findings
We conducted a population-based nested case–control study among opioid users who were residents of Ontario, Canada, between August 1, 1997, and December 31, 2013, using administrative databases. Cases, defined as opioid users who died of an opioid-related cause, were matched with up to 4 controls who also used opioids on age, sex, year of index date, history of chronic kidney disease, and a disease risk index. After matching, we included 1,256 cases and 4,619 controls. The primary exposure was concomitant gabapentin use in the 120 days preceding the index date. A secondary analysis characterized gabapentin dose as low (<900 mg daily), moderate (900 to 1,799 mg daily), or high (≥1,800 mg daily). A sensitivity analysis examined the effect of concomitant nonsteroidal anti-inflammatory drug (NSAID) use in the preceding 120 days. Overall, 12.3% of cases (155 of 1,256) and 6.8% of controls (313 of 4,619) were prescribed gabapentin in the prior 120 days. After multivariable adjustment, co-prescription of opioids and gabapentin was associated with a significantly increased odds of opioid-related death (odds ratio [OR] 1.99, 95% CI 1.61 to 2.47, p < 0.001; adjusted OR [aOR] 1.49, 95% CI 1.18 to 1.88, p < 0.001) compared to opioid prescription alone. In the dose–response analysis, moderate-dose (OR 2.05, 95% CI 1.46 to 2.87, p < 0.001; aOR 1.56, 95% CI 1.06 to 2.28, p = 0.024) and high-dose (OR 2.20, 95% CI 1.58 to 3.08, p < 0.001; aOR 1.58, 95% CI 1.09 to 2.27, p = 0.015) gabapentin use was associated with a nearly 60% increase in the odds of opioid-related death relative to no concomitant gabapentin use. As expected, we found no significant association between co-prescription of opioids and NSAIDs and opioid-related death (OR 1.11, 95% CI 0.98 to 1.27, p = 0.113; aOR 1.14, 95% CI 0.98 to 1.32, p =0.083). In an exploratory analysis of patients at risk of combined opioid and gabapentin use, we found that 46.0% (45,173 of 98,288) of gabapentin users in calendar year 2013 received at least 1 concomitant prescription for an opioid. This study was limited to individuals eligible for public drug coverage in Ontario, we were only able to identify prescriptions reimbursed by the government and dispensed from retail pharmacies, and information on indication for gabapentin use was not available. Furthermore, as with all observational studies, confounding due to unmeasured variables is a potential source of bias.
Conclusions In this study we found that among patients receiving prescription opioids, concomitant treatment with gabapentin was associated with a substantial increase in the risk of opioid-related death. Clinicians should consider carefully whether to continue prescribing this combination of products and, when the combination is deemed necessary, should closely monitor their patients and adjust opioid dose accordingly. Future research should investigate whether a similar interaction exists between pregabalin and opioids.
Journal of Affective Disorders
Volume 225, Pages 13–17
Vegetarian diets and depressive symptoms among men
Joseph R. HibbelnKate Northstone, Jonathan Evans, Jean Golding
Little is known about mental health benefits or risks of vegetarian diets.
Vegetarian men had higher depression scores after adjustment for potential confounding factors.
Nutritional deficiencies may account for these findings, but reverse causation and residual confounding cannot be ruled out.
Vegetarian diets are associated with cardiovascular and other health benefits, but little is known about mental health benefits or risks.
To determine whether self-identification of vegetarian dietary habits is associated with significant depressive symptoms in men.
Self-report data from 9668 adult male partners of pregnant women in the Avon Longitudinal Study of Parents and Children (ALSPAC) included identification as vegetarian or vegan, dietary frequency data and the Edinburgh Post Natal Depression Scale (EPDS). Continuous and binary outcomes were assessed using multiple linear and logistic regression taking account of potential confounding variables including: age, marital status, employment status, housing tenure, number of children in the household, religion, family history of depression previous childhood psychiatric contact, cigarette and alcohol consumption.
Vegetarians [n = 350 (3.6% of sample)], had higher depression scores on average than non-vegetarians (mean difference 0.96 points [95%CI + 0.53, + 1.40]) and a greater risk for EPDS scores above 10 (adjusted OR = 1.67 [95% CI: 1.14,2.44]) than non-vegetarians after adjustment for potential confounding factors.
Vegetarian men have more depressive symptoms after adjustment for socio-demographic factors. Nutritional deficiencies (e.g. in cobalamin or iron) are a possible explanation for these findings, however reverse causation cannot be ruled out.
Original Investigation September 2017
Association of History of Dizziness and Long-term Adverse Outcomes With Early vs Later Orthostatic Hypotension Assessment Times in Middle-aged Adults
Stephen P. Juraschek, MD, PhD1,2,3,4; Natalie Daya, MHS1,2,3,4; Andreea M. Rawlings, PhD, MS1,2,3,4; et al Lawrence J. Appel, MD, MPH1,2,3,4; Edgar R. Miller III, MD, PhD1,2,3,4; B. Gwen Windham, MD, MHS5; Michael E. Griswold, PhD5,6; Gerardo Heiss, MD, MSc, PhD7; Elizabeth Selvin, PhD, MPH1,2,3,4
Author Affiliations Article Information
- 1Department of Medicine, The Johns Hopkins School of Medicine, Baltimore, Maryland
- 2Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- 3The Welch Center for Prevention, Epidemiology, and Clinical Research, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- 4Johns Hopkins Medical Institutions, Baltimore, Maryland
- 5Department of Medicine, University of Mississippi Medical Center, Jackson
- 6Center of Biostatistics, University of Mississippi Medical Center, Jackson
- 7Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill
Question Are orthostatic hypotension assessments performed within 1 minute of standing as informative for dizziness and long-term outcomes as assessments performed after 1 minute?
Findings In this cohort study of 11 429 adults with 4 orthostatic hypotension assessments performed 1 to 2 minutes after standing, orthostatic hypotension assessed within 1 minute of standing was associated with higher odds of dizziness and greater risk of falls, fracture, syncope, motor vehicle crash, and mortality than orthostatic hypotension assessed after 1 minute.
Meaning Contrary to prevailing recommendations to delay orthostatic hypotension assessments by 3 minutes, these findings suggest that orthostatic hypotension should be assessed within 1 minute of standing.
Importance Guidelines recommend assessing orthostatic hypotension (OH) 3 minutes after rising from supine to standing positions. It is not known whether measurements performed immediately after standing predict adverse events as strongly as measurements performed closer to 3 minutes.
Objective To compare early vs later OH measurements and their association with history of dizziness and longitudinal adverse outcomes.
Design, Setting, and Participants This was a prospective cohort study of middle-aged (range, 44-66 years) participants in the Atherosclerosis Risk in Communities Study (1987-1989).
Exposures Orthostatic hypotension, defined as a drop in blood pressure (BP) (systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg) from the supine to standing position, was measured up to 5 times at 25-second intervals.
Main Outcomes and Measures We determined the association of each of the 5 OH measurements with history of dizziness on standing (logistic regression) and risk of fall, fracture, syncope, motor vehicle crashes, and all-cause mortality (Cox regression) over a median of 23 years of follow-up (through December 31, 2013).
Results In 11 429 participants (mean age, 54 years; 6220 [54%] were women; 2934 [26%] were black) with at least 4 OH measurements after standing, after adjustment OH assessed at measurement 1 (mean [SD], 28 [5.4] seconds; range, 21-62 seconds) was the only measurement associated with higher odds of dizziness (odds ratio [OR], 1.49; 95% CI, 1.18-1.89). Measurement 1 was associated with the highest rates of fracture, syncope, and death at 18.9, 17.0, and 31.4 per 1000 person-years. Measurement 2 was associated with the highest rate of falls and motor vehicle crashes at 13.2 and 2.5 per 1000 person-years. Furthermore, after adjustment measurement 1 was significantly associated with risk of fall (hazard ratio [HR], 1.22; 95% CI, 1.03-1.44), fracture (HR, 1.16; 95% CI, 1.01-1.34), syncope (HR, 1.40; 95% CI, 1.20-1.63), and mortality (HR, 1.36; 95% CI, 1.23-1.51). Measurement 2 (mean [SD], 53 [7.5] seconds; range, 43-83 seconds) was associated with all long-term outcomes, including motor vehicle crashes (HR, 1.43; 95% CI, 1.04-1.96). Measurements obtained after 1 minute were not associated with dizziness and were inconsistently associated with individual long-term outcomes.
Conclusions and Relevance In contrast with prevailing recommendations, OH measurements performed within 1 minute of standing were the most strongly related to dizziness and individual adverse outcomes, suggesting that OH be assessed within 1 minute of standing.
Journal of General Internal MedicineISSN: 0884-8734 (Print) 1525-1497 (Online)
Tricyclic and Tetracyclic Antidepressants for the Prevention of Frequent Episodic or Chronic Tension-Type Headache in Adults: A Systematic Review and Meta-Analysis
- Jeffrey L. JacksonEmail author,Josephine M. Mancuso,Sarah Nickoloff’,Rebecca Bernstein
- Cynthia Kay
BackgroundTension-type headaches are a common source of pain and suffering. Our purpose was to assess the efficacy of tricyclic (TCA) and tetracyclic antidepressants in the prophylactic treatment of tension-type headache.
MethodsWe searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the ISI Web of Science, and clinical trial registries through 11 March 2017 for randomized controlled studies of TCA or tetracyclic antidepressants in the prevention of tension-type headache in adults. Data were pooled using a random effects approach.
Key ResultsAmong 22 randomized controlled trials, eight included a placebo comparison and 19 compared at least two active treatments. Eight studies compared TCAs to placebo, four compared TCAs to selective serotonin reuptake inhibitors (SSRIs), and two trials compared TCAs to behavioral therapies. Two trials compared tetracyclics to placebo. Single trials compared TCAs to tetracyclics, buspirone, spinal manipulation, transcutaneous electrical stimulation, massage, and intra-oral orthotics. High-quality evidence suggests that TCAs were superior to placebo in reducing headache frequency (weighted mean differences (WMD): −4.8 headaches/month, 95% CI: −6.63 to −2.95) and number of analgesic medications consumed (WMD: −21.0 doses/month, 95% CI: −38.2 to −3.8). TCAs were more effective than SSRIs. Low-quality studies suggest that TCAs are superior to buspirone, but equivalent to behavioral therapy, spinal manipulation, intra-oral orthotics, and massage. Tetracyclics were no better than placebo for chronic tension-type headache.
ConclusionsTricyclic antidepressants are modestly effective in reducing chronic tension-type headache and are superior to buspirone. In limited studies, tetracyclics appear to be ineffective in the prophylactic treatment of chronic tension-type headache.
The views reflected in this manuscript are those of the authors and should not be construed, in any way, to represent the views of the Department of Veterans Affairs.
To Serve Or Not To Serve: Ethical And Policy Implications Highlights
Some panels and commissions can have important public policy implications for our discipline. Ethical issues can arise about whether or not to serve on influential panels. Some policy commissions pursue missions that inadvertently instigate divisive friction.
A case study is presented regarding a decision not to serve on a controversial panel. Ethical challenges are explored regarding searching for alternative avenues for influencing policy.
Abstract The Institute of Medicine (IOM) is one of the nation’s more influential health related non-profit organizations. It plays a large role in shaping health policy by commissioning panels to develop “white papers” describing research and recommendations on a variety of health topics. These white paper publications are often used to help make policy decisions at the legislative and executive levels.
Such a prominent institution might seem like a natural ally for policy-related collaborative efforts. As community psychologists, we strongly endorse efforts to positively influence public policy at the national level. However, while serving on influential panels and commissions like the IOM might seem to be very much part of the ethos of our discipline, there are occasions when such institutions are pursuing a mission that inadvertently has the potential to instigate divisive friction among community activists and organizations.
A case study is presented whereby I describe my decision not to accept an invitation to serve on a controversial IOM panel. I explore the ethical challenges regarding maintaining my independence from this institution and its attempt to redefine chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME), as well as the process of searching for alternative avenues for collaborating with community activists to influence policy related to these debilitating illnesses.
Leonard A. Jason
Source: American Journal of Community Psychology. Published online: Sept. 18, 2017. doi:10.1002/ajcp.12181
Review Article: The Human Intestinal Virome In Health And Disease
S.R. Carding, N. Davis, L. Hoyles –
First published: 4 September 2017
Summary - Background The human virome consists of animal-cell viruses causing transient infections, bacteriophage (phage) predators of bacteria and archaea, endogenous retroviruses and viruses causing persistent and latent infections. High-throughput, inexpensive, sensitive sequencing methods and metagenomics now make it possible to study the contribution dsDNA, ssDNA and RNA virus-like particles make to the human virome, and in particular the intestinal virome.
To review and evaluate the pioneering studies that have attempted to characterise the human virome and generated an increased interest in understanding how the intestinal virome might contribute to maintaining health, and the pathogenesis of chronic diseases.
Relevant virome-related articles were selected for review following extensive language- and date-unrestricted, electronic searches of the literature.
The human intestinal virome is personalised and stable, and dominated by phages. It develops soon after birth in parallel with prokaryotic communities of the microbiota, becoming established during the first few years of life. By infecting specific populations of bacteria, phages can alter microbiota structure by killing host cells or altering their phenotype, enabling phages to contribute to maintaining intestinal homeostasis or microbial imbalance (dysbiosis), and the development of chronic infectious and autoimmune diseases including HIV infection and Crohn's disease, respectively.
Our understanding of the intestinal virome is fragmented and requires standardised methods for virus isolation and sequencing to provide a more complete picture of the virome, which is key to explaining the basis of viromedisease associations, and how enteric viruses can contribute to disease aetiologies and be rationalised as targets for interventions.
Source: http://bit.ly/2yAgxVh(also full text)
Reproducibility Of Peak Oxygen Consumption And The Impact Of Test Variability On Classification Of Individual Training Responses In Young Recreationally Active Adults
A Canadian study on exercise test from the School of Kinesiology and Health Studies, Queen's University, Kingston, ON, Canada
Brittany A. Edgett, Jacob T. Bonafiglia, James P. Raleigh, Mario P. Rotundo, Matthew D. Giles, Jonathan P. Whittal, Brendon J. Gurd
First published: 28 September 2017
Summary This study investigated whether VO2peak is reproducible across repeated tests before (PRE) and after (POST) training, and whether variability across tests impacts how individual responses are classified following 3 weeks of aerobic exercise training (cycle ergometry). Data from 45 young healthy adults (age: 20·1 ± 0·9 years; VO2peak, 42·0 ± 6·7 ml·min−1) from two previously published studies were utilized in the current analysis. Non-responders were classified as individuals who failed to demonstrate an increase or decrease in VO2peak that was greater than 2·0 times the typical error of measurement (107 ml·min−1) away from zero, while responders and adverse responders were above and below this cut-off, respectively.
VO2peak tests at PRE (three total) and POST (three total) were highly reproducible (PRE and POST average and single measures ICCs: range 0·938–0·992), with low coefficients of variation (PRE:4·9 ± 3·1%, POST: 4·8 ± 2·7%). However, a potential learning effect was observed in the VO2peak tests prior to training, as the initial pretraining test was significantly lower than the third (p = 0·010, PRE 1: 2 946 ± 924 ml·min−1, PRE 3: 3 042 ± 919 ml·min−1). This resulted in fewer individuals classified as adverse responders for Test 3 compared to any combination of tests that included Test 1, suggesting that a single ramp test at baseline may not be sufficient to accurately classify the VO2peak response in young recreationally active individuals. Thus, it is our recommendation that the initial VO2peak test be used as a familiarization visit and not included for analysis.
Grey and white matter differences in Chronic Fatigue Syndrome – A voxel-based morphometry study
Andreas Finkelmeyer, JiabaoHe, Laura Maclachlan, Stuart Watson, Peter Gallagher, Julia L. Newton, Andrew M. Blamire
Highlights VBM study of patients with Chronic Fatigue Syndrome without depression. Patients show increased grey matter in insular cortex and parts of the limbic system. Patients show decrease in white matter in midbrain and temporal lobe. Findings suggest potentially altered processing of interoceptive signals.
Objective Investigate global and regional grey and white matter volumes in patients with Chronic Fatigue Syndrome (CFS) using magnetic resonance imaging (MRI) and recent voxel-based morphometry (VBM) methods.
Forty-two patients with CFS and thirty healthy volunteers were scanned on a 3- Tesla MRI scanner. Anatomical MRI scans were segmented, normalized and submitted to a VBM analysis using randomisation methods. Group differences were identified in overall segment volumes and voxel-wise in spatially normalized grey matter (GM) and white matter (WM) segments.
Accounting for total intracranial volume, patients had larger GM volume and lower WM volume. The voxel-wise analysis showed increased GM volume in several structures including the amygdala and insula in the patient group. Reductions in WM volume in the patient group were seen primarily in the midbrain, pons and right temporal lobe.
Elevated GM volume in CFS is seen in areas related to processing of interoceptive signals and stress. Reduced WM volume in the patient group partially supports earlier findings of WM abnormalities in regions of the midbrain and brainstem.
Cellular Bioenergetics Is Impaired In Patients With Chronic Fatigue Syndrome.
Toma C, Brown A, Strassheim V, Elson J, Newton J, Manning P.
Chronic fatigue syndrome (CFS) is a highly debilitating disease of unknown aetiology. Abnormalities in bioenergetic function have been cited as one possible cause for CFS. Preliminary studies were performed to investigate cellular bioenergetic abnormalities in CFS patients. A series of assays were conducted using peripheral blood mononuclear cells (PBMCs) from CFS patients and healthy controls. These experiments investigated cellular patterns in oxidative phosphorylation (OXPHOS) and glycolysis. Results
showed consistently lower measures of OXPHOS parameters in PBMCs taken from CFS patients compared with healthy controls. Seven key parameters of OXPHOS were calculated: basal respiration, ATP production, proton leak, maximal respiration, reserve capacity, non-mitochondrial respiration, and coupling efficiency. While many of the parameters differed between the CFS and control cohorts, maximal respiration was determined to be the key parameter in mitochondrial function to differ between CFS and control PBMCs due to the consistency of its impairment in CFS patients found throughout the study (p ≤ 0.003). The lower maximal respiration in CFS PBMCs suggests that when the cells experience physiological stress they are less able to elevate their respiration rate to compensate for the increase in stress and are unable to fulfil cellular energy demands. The metabolic differences discovered highlight the inability of CFS patient PBMCs to fulfil cellular energetic demands both under basal conditions and when mitochondria are stressed during periods of high metabolic demand.
Source: PlosOne http://bit.ly/2iBDTCV
Epigenetic Modifications And Glucocorticoid Sensitivity Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
De Vega, Herrera, Vernon, McGowan
Despite a heterogeneous patient population, immune and hypothalamic-pituitaryadrenal (HPA) axis function differences, such as enhanced negative feedback to glucocorticoids, are recurring findings in ME/CFS studies. Epigenetic modifications, such as CpG methylation, are known to regulate long-term phenotypic differences and previous work by our group found DNA methylome differences in ME/CFS, however the relationship between DNA methylome modifications, clinical and functional characteristics associated with ME/CFS has not been examined.
We examined the DNA methylome in peripheral blood mononuclear cells (PBMCs) of a larger cohort of female ME/CFS patients using the Illumina HumanMethylation450 BeadChip Array. In parallel to the DNA methylome analysis, we investigated in vitro glucocorticoid sensitivity differences by stimulating PBMCs with phytohaemagglutinin and suppressed growth with dexamethasone. We explored DNA methylation differences using bisulfite pyrosequencing and statistical permutation. Linear regression was implemented to discover epigenomic regions associated with self-reported quality of life and network analysis of gene ontology terms to biologically contextualize results.
We detected 12,608 differentially methylated sites between ME/CFS patients and healthy controls predominantly localized to cellular metabolism genes, some of which were also related to self-reported quality of life health scores. Among ME/CFS patients, glucocorticoid sensitivity was associated with differential methylation at 13 loci.
Our results indicate DNA methylation modifications in cellular metabolism in ME/CFS despite a heterogeneous patient population, implicating these processes in immune and HPA axis dysfunction in ME/CFS. Modifications to epigenetic loci associated with differences in glucocorticoid sensitivity may be important as biomarkers for future clinical testing. Overall, these findings align with recent ME/CFS work that point towards impairment in cellular energy production in this patient population.
Source: http://bit.ly/2vdhr7w accessed Jul 31, 2017
Cytokine Signature Associated With Disease Severity In Chronic Fatigue Syndrome Patients
Authors Montoya, Holmes, Anderson, Maecker, Rosenberg-Hasson, Valencia. Chu, Younger, Tato & M. Davis Contributed by Mark M. Davis, June 28, 2017 (sent for review November 16, 2016; reviewed by Gordon Broderick, Ben Katz, and Anthony L. Komaroff)
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) devastates the lives of millions of people and has remained a mystery illness despite decades of research. It has long been suspected that inflammation is central to its pathogenesis. Although only two cytokines were found to be different (TGF-β higher and resistin lower) in ME/CFS patients compared with controls, 17 cytokines correlated with ME/CFS severity. Thirteen of these cytokines are proinflammatory and may contribute to many of the symptoms these patients experience for several years. Only CXCL9 (MIG) inversely correlated with fatigue duration.
Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.
Full text: http://m.pnas.org/content/early/2017/07/25/1710519114.
Dysregulation Of Cytokine Pathways Dysregulation of cytokine pathways in chronic fatigue syndrome and multiple sclerosis
Matthew Sorenson, Jacob Furst, Herbert Mathews & Leonard A. Jason
Published online: 07 Jun 2017
Background: Cytokine studies in chronic fatigue syndrome (CFS) have yielded mixed findings. Purpose: This investigation evaluated whether network analysis of cytokine production differs between patients with CFS and multiple sclerosis (MS) as compared to a reference group of healthy controls.
Methods: Three subgroups (N = 109) were included: 15 participants who met diagnostic criteria for CFS, 57 participants meeting criteria for MS, and 37 controls. Peripheral blood was obtained and production of a select cytokine profile was determined from stimulated and unstimulated mononuclear cells. Data were generated through the use of a multi-analyte bead suspension array. Pairwise associations were determined for each group, and these associations were used to create a graphical representation of the data. The graph was clustered using an eigenvector community algorithm and results visualized using edges to model the correlations by color and thickness to show direction and strength.
Results: The control and MS groups produced a three-neighborhood relationship regardless of cell condition. While producing a three-neighborhood relationship, the MS group differed significantly from the control group as it displayed stronger relationships among pro-inflammatory cytokines. In contrast, the CFS group displayed a three-neighborhood solution when unstimulated. However, when cells from the CFS group were stimulated, a two-neighborhood model was found that exhibited stronger inter-cytokine correlations. The model found in CFS was significantly different from that found in the control and MS groups.
Conclusion: CFS was characterized by a pattern of global immunologic activation using network analysis, fundamentally different from those found for either MS or control groups.
Source: http://bit.ly/2w4VSH0 Submitted by Prof. Leonard Jason
Chronic Fatigue Syndrome Prevalence Is Grossly Overestimated
Chronic fatigue syndrome prevalence is grossly overestimated using Oxford criteria compared to Centers for Disease Control (Fukuda) criteria in a U.S. population study –
James N. Baraniuk
Published online: 21 Jul 2017
Abstract: Background: Results from treatment studies using the low-threshold Oxford criteria for recruitment may have been overgeneralized to patients diagnosed by more stringent chronic fatigue syndrome (CFS) criteria.
Purpose: To compare the selectivity of Oxford and Fukuda criteria in a U.S. population.
Methods: Fukuda (Center for Disease Control (CDC)) criteria, as operationalized with the CFS Severity Questionnaire (CFSQ), were included in the nationwide rc2004 HealthStyles survey mailed to 6175 participants who were representative of the U.S. 2003 Census population. The 9 questionnaire items (CFS symptoms) were crafted into proxies for Oxford criteria (mild fatigue, minimal exclusions) and Fukuda criteria (fatigue plus ≥4 of 8 ancillary criteria at moderate or severe levels with exclusions). The comparative prevalence estimates of CFS were then determined. Severity scores for fatigue were plotted against the sum of severities for the eight ancillary criteria. The four quadrants of scatter diagrams assessed putative healthy controls, CFS, chronic idiopathic fatigue (CIF), and CFS-like with insufficient fatigue subjects.
Results: The Oxford criteria designated CFS in 25.5% of 2004 males and 19.9% of 1954 females. Based on quadrant analysis, 85% of Oxford-defined cases were inappropriately classified as CFS. Fukuda criteria identified CFS in 2.3% of males and 1.8% of females.
Discussion: CFS prevalence using Fukuda criteria and quadrant analysis was near the upper limits of previous epidemiology studies. The CFSQ may have utility for on-line and outpatient screening. The Oxford criteria were untenable because they inappropriately selected healthy subjects with mild fatigue and CIF and mislabeled them as CFS.
A Systematic Review and Meta-analysis of The Effect of Low Vitamin D on CognitionAlicia M. Goodwill, PhD; Cassandra Szoeke, PhD
J Am Geriatr Soc. 2017;65(10):2161-2168.
Background/Objective With an aging population and no cure for dementia on the horizon, risk factor modification prior to disease onset is an urgent health priority. Therefore, this review examined the effect of low vitamin D status or vitamin D supplementation on cognition in midlife and older adults without a diagnosis of dementia.
Design Systematic review and random effect meta-analysis.
Setting Observational (cross-sectional and longitudinal cohort) studies comparing low and high vitamin D status and interventions comparing vitamin D supplementation with a control group were included in the review and meta-analysis.
Participants Studies including adults and older adults without a dementia diagnosis were included.
Measurements Medline (PubMed), AMED, Psych INFO, and Cochrane Central databases were searched for articles until August 2016. The Newcastle-Ottawa Scale and Physiotherapy Evidence Database assessed methodological quality of all studies.
Results Twenty-six observational and three intervention studies (n = 19–9,556) were included in the meta-analysis. Low vitamin D was associated with worse cognitive performance (OR = 1.24, CI = 1.14–1.35) and cognitive decline (OR = 1.26, CI = 1.09–1.23); with cross-sectional yielding a stronger effect compared to longitudinal studies. Vitamin D supplementation showed no significant benefit on cognition compared with control (SMD = 0.21, CI = −0.05 to 0.46).
Short Sleep Duration Increases Metabolic Impact in Healthy Adults: A Population-Based Cohort Study
Han-Bing Deng, PhD Tony Tam, PhD
Address correspondence to: Xiang Qian Lao, PhD, Jockey Club School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, NT, Hong Kong. Telephone: 852 22528763; Fax: 852 26063500; Email: Benny Chung-Ying Zee, PhD Roger Yat-Nork Chung, PhD Xuefen Su, PhD Lei Jin, PhD
Ta-Chien Chan, PhD Ly-Yun Chang, PhD Eng-Kiong Yeoh, MBBS Xiang Qian Lao, PhD CHINA
Sleep, Volume 40, Issue 10, 1 October 2017, zsx130, https://doi.org/10.1093/sleep/zsx130
Published:22 July 2017
The metabolic impact of inadequate sleep has not been determined in healthy individuals outside laboratories. This study aims to investigate the impact of sleep duration on five metabolic syndrome components in a healthy adult cohort.
A total of 162121 adults aged 20–80 years (men 47.4%) of the MJ Health Database, who were not obese and free from major diseases, were recruited and followed up from 1996 to 2014. Sleep duration and insomnia symptoms were assessed by a self-administered questionnaire. Incident cases of five metabolic syndrome components were identified by follow-up medical examinations. Cox proportional hazard ratios (HRs) were calculated for three sleep duration categories “< 6 hours/day (short),” “6–8 hours/day (regular),” and “> 8 hours/day (long)” with adjustment for potential confounding factors. Analyses were stratified by insomnia symptoms to assess whether insomnia symptoms modified the association between sleep duration and metabolic syndrome.
Compared to regular sleep duration, short sleep significantly (p < .001) increased the risk for central obesity by 12% (adjusted HR 1.12 [1.07–1.17]), for elevated fasting glucose by 6% (adjusted HR 1.06 [1.03–1.09]), for high blood pressure by 8% (adjusted HR 1.08 [1.04–1.13]), for low high-density lipoprotein–cholesterol by 7% (adjusted HR 1.07 [1.03–1.11]), for hypertriglyceridemia by 9% (adjusted HR 1.09 [1.05–1.13]), and for metabolic syndrome by 9% (adjusted HR 1.09 [1.05–1.13]). Long sleep decreased the risk of hypertriglyceridemia (adjusted HR 0.89 [0.84–0.94]) and metabolic syndrome (adjusted HR 0.93 [0.88–0.99]). Insomnia symptoms did not modify the effects of sleep duration.
Sleep duration may be a significant determinant of metabolic health.
Many Doctors, Even Specialists, Don't Adhere to Fibromyalgia Diagnostic Criteria
By Lorraine L. Janeczko January 02, 2018
NEW YORK (Reuters Health) – Generalist doctors, and even many specialists, have relatively poor knowledge of the American College of Rheumatology 1990 and 2010 fibromyalgia diagnostic criteria, according to results of a survey conducted in Canada.
"Physicians do not have adequate and homogeneous knowledge of the fibromyalgia diagnostic criteria. Approximately half of physicians did not adhere to the criteria. Poor knowledge and adherence . . . may increase diagnosis delays and misdiagnoses. Knowledge translation strategies should be implemented to address this problem," lead author Dr. Dinesh Kumbhare of the University of Toronto and his coauthors write in Pain Medicine, online November 21.
"I think most physicians are aware of fibromyalgia, although many still 'don't believe in it' and communicate this (lack of belief) to their patients. Even among physicians who accept the science and existence of fibromyalgia, there is lack of understanding of it, which hampers their ability to effectively communicate about it with their patients," Dr. Eric L. Matteson, a professor of medicine at Mayo Clinic College of Medicine and Science in Rochester, Minnesota, told Reuters Health by email.
"In general, the results are unsurprising and reflect the lack of knowledge about this common pain condition. Many patients who are referred to me with chronic pain problems are wrongly diagnosed with fibromyalgia or are wrongly diagnosed as not having fibromyalgia," added Dr. Matteson, who was not involved in the study.
Dr. Kumbhare and his colleagues distributed a 37-item questionnaire to a convenience sample of 284 physicians who practice in urban clinical settings and diagnose chronic pain conditions: 100 family physicians, 69 anesthesiologists, 58 physical medicine and rehabilitation specialists, 29 rheumatologists, and 28 neurologists.
The questionnaire tested the physicians’ knowledge of the 1990 fibromyalgia classification criteria and the 2010 diagnostic criteria. The researchers assessed the homogeneity of the responses and whether specialist training affected the physicians’ knowledge.
Overall, 12% of the respondents used only the 1990 criteria in their practice, 27% used the 2010 criteria, 12% used both, and 49% used no criteria. Therefore, only 51% of respondents adhered to these sets of criteria in diagnosing fibromyalgia.
Doctors with specialist training were more familiar with the criteria, but their knowledge was not comprehensive. Even physicians categorized as having the “most specialist training” had mean scores of only 55.4% for the 1990 criteria and 72.4% for the 2010 criteria.
The authors suggest that doctors and medical students learn about the criteria and updates to them – and apply the criteria in daily practice. They specifically recommend continuing medical education seminars, dropdown menus that provide fibromyalgia diagnostic criteria in electronic medical records, and online training modules on fibromyalgia diagnosis. They also say medical and residency pain curricula should offer advanced courses on chronic pain and fibromyalgia diagnosis.
Dr. Matteson agreed. "The most important aspect of the survey is awareness-building. If the findings can be brought to the attention of educators and practitioners with resultant changes in practice, then they will influence patient care," he said.
Dr. Anne Louise Oaklander, an associate professor of neurology at Harvard Medical School and a neurologist at Massachusetts General Hospital, in Boston, told Reuters Health by email that the results did not surprise her: “Fibromyalgia isn’t a disease but, rather, a term agreed on by groups of physicians to describe a loose constellation of symptoms. The criteria for inclusion and exclusion are complex and have varied over the years; plus some of the features are impractical or difficult to apply or contradict medical experience."
"A minor weakness is that they assessed knowledge of earlier versions of the American College of Rheumatology diagnostic criteria (1990 and 2010) but not the latest changes to them in 2011 and 2016, which are the ones that doctors ideally should be using," said Dr. Oaklander, who was not involved in the study.
"Also, they included medical specialists other than rheumatologists, and I don’t think it’s realistic to expect doctors from other medical specialties to know the details developed by rheumatologists to guide rheumatologists," she concluded.
Dr. Kumbhare did not respond to requests for comment.
Pain Med 2017.
Reuters Health Information © 2017
Brain nerve 2018 Jan;70(1):41-54. doi: 10.11477/mf.1416200948.
[Neurologic Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review].
[Article in Japanese]
Komaroff AL1, Takahashi R, Yamamura T, Sawamura M.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by fatigue lasting for at least six months, post-exertional malaise, unrefreshing sleep, cognitive impairment and orthostatic intolerance. ME/CFS has been a controversial illness because it is defined exclusively by subjective complaints. However, recent studies of neuroimaging as well as analysis of blood markers, energy metabolism and mitochondrial function have revealed many objective biological abnormalities. Specifically, it is suspected that the symptoms of ME/CFS may be triggered by immune activation - either inside or outside the brain - through release of inflammatory cytokines. In this review, we summarize potentially important recent findings on ME/CFS, focusing on objective evidence.
Mass-spectrometric profiling of cerebrospinal fluid reveals metabolite biomarkers for CNS involvement in varicella zoster virus reactivation
- Maike Kuhn†,Kurt-Wolfram Sühs†,Manas K. Akmatov, Frank Klawonn,Junxi Wang,
- Thomas Skripuletz,Volkhard Kaever,Martin Stangel†Email author and
- Frank Pessler†Email author
Received: 11 October 2017 Accepted: 12 December 2017 Published: 17 January 2018
AbstractBackgroundVaricella zoster virus (VZV) reactivation spans the spectrum from uncomplicated segmental herpes zoster to life-threatening disseminated CNS infection. Moreover, in the absence of a small animal model for this human pathogen, studies of pathogenesis at the organismal level depend on analysis of human biosamples. Changes in cerebrospinal fluid (CSF) metabolites may reflect critical aspects of host responses and end-organ damage in neuroinfection and neuroinflammation. We therefore applied a targeted metabolomics screen of CSF to three clinically distinct forms of VZV reactivation and infectious and non-infectious disease controls in order to identify biomarkers for CNS involvement in VZV reactivation.
MethodsMetabolite profiles were determined by targeted liquid chromatography-mass spectrometry in CSF from patients with segmental zoster (shingles, n = 14), facial nerve zoster (n = 16), VZV meningitis/encephalitis (n = 15), enteroviral meningitis (n = 10), idiopathic Bell’s palsy (n = 11), and normal pressure hydrocephalus (n = 15).
ResultsConcentrations of 88 metabolites passing quality assessment clearly separated the three VZV reactivation forms from each other and from the non-infected samples. Internal cross-validation identified four metabolites (SM C16:1, glycine, lysoPC a C26:1, PC ae C34:0) that were particularly associated with VZV meningoencephalitis. SM(OH) C14:1 accurately distinguished facial nerve zoster from Bell’s palsy. Random forest construction revealed even more accurate classifiers (signatures comprising 2–4 metabolites) for most comparisons. Some of the most accurate biomarkers correlated only weakly with CSF leukocyte count, indicating that they do not merely reflect recruitment of inflammatory cells but, rather, specific pathophysiological mechanisms. Across all samples, only the sum of hexoses and the amino acids arginine, serine, and tryptophan correlated negatively with leukocyte count. Increased expression of the metabolites associated with VZV meningoencephalitis could be linked to processes relating to neuroinflammation/immune activation, neuronal signaling, and cell stress, turnover, and death (e.g., autophagy and apoptosis), suggesting that these metabolites might sense processes relating to end-organ damage.
ConclusionsThe results provide proof-of-concept for the value of CSF metabolites as (1) disease-associated signatures suggesting pathophysiological mechanisms, (2) degree and nature of neuroinflammation, and (3) biomarkers for diagnosis and risk stratification of VZV reactivation and, likely, neuroinfections due to other pathogens.