Empty mast cell syndrome: fallacy or fact?
Journal of Clinical Pathology vol 73 Issue 5
http://orcid.org/0000-0001-9102-278X Omar E Mohamed1,Richard L Baretto1, Ian Walker2,
Cathryn Melchior1, Jane Heslegrave1, Ruth Mckenzie2, Chidanand Hullur2, Anjali Ekbote1,
Mamidipudi Thirumala Krishna1,3
Abstract
Post-anaphylaxis mast cell anergy (PAMA), commonly referred to as ‘empty mast cell (MC) syndrome’, is a state of temporary loss of cutaneous MC reactivity in the immediate aftermath of anaphylaxis. Data relating to this condition are sparse and the incidence rate is currently unknown. PAMA has been described only in a few published case reports in the context of hymenoptera venom allergy and perioperative anaphylaxis. Best practice guidelines regarding optimal timing for performing skin tests postanaphylaxis are largely based on expert opinion, and allergy work-up has been recommended after 4–6 weeks postanaphylaxis to avoid false-negative results.
This article provides a review of clinical literature surrounding PAMA, critically evaluates intracellular events in MCs from in vitro data and hypothesises regarding plausible immune mechanisms. There are no published data to directly explain molecular mechanisms underlying this phenomenon. Although not evidence based, PAMA has been attributed to depletion of MC granules following anaphylaxis. It is also plausible that exposure to high allergen concentrations in anaphylaxis can induce a temporary shift in MCs towards dominance of inhibitory signalling pathways, thus contributing to a state of transient hyporesponsiveness observed in some patients. Other potential contributory factors for reduced MC reactivity include downregulation of FcεRI expression, cross-linking of FcεRI to the inhibitory, low-affinity IgG receptors and administration of pharmacotherapeutic agents for anaphylaxis treatment. It is likely that this interesting phenomenon can be explained by a combination of these proposed mechanisms in addition to other genetic/host factors that have not yet been identified.
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http://dx.doi.org/10.1136/jclinpath-2019-206157
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Paediatric patients with myalgic encephalomyelitis/chronic fatigue syndrome value understanding and help to move on with their lives
Katherine Rowe
First published:18 December 2019 ACTA Paediatrica
https://doi.org/10.1111/apa.15054
Abstract
Aim
The aim of this study was to document qualitative questionnaire feedback regarding management from a cohort observational study of young people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Methods
Between 1991 and 2009, 784 paediatric patients, age 6‐18 years, were diagnosed with ME/CFS following referral to a specialised clinic at the Royal Children's Hospital, Melbourne. Over a 14‐year period, feedback was requested on up to seven occasions.
Management included the following: symptom management and a self‐management lifestyle plan that included social, educational, physical and a pleasurable activity outside of home. They adjusted it by severity of illness, stage of education, family circumstances and life interests.
Results
Questionnaires were returned from 626 (80%) with 44% providing feedback more than once. They reported that their management plan allowed them to regain control over their lives. They cited early diagnosis, empathetic, informed physicians, self‐management strategies and educational liaison as helping them to function and remain socially engaged. Ongoing support, particularly assistance to navigate the education system, was essential for general well‐being and ability to cope.
Conclusion
Young people valued regaining the control over their lives that was lost through illness, support to maintain social contacts and assistance to achieve educational and/or life goals.
Key Notes
2020 Apr 10;15(4):e0231136. doi: 10.1371/journal.pone.0231136. eCollection 2020.PLoS one
The effect of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) severity on cellular bioenergetic function.
Tomas C1, Elson JL1,2, Strassheim V3, Newton JL1,3, Walker M1.
Abstract
Myalgic encephalomyelitis/ Chronic fatigue syndrome (ME/CFS) has been associated with abnormalities in mitochondrial function. In this study we have analysed previous bioenergetics data in peripheral blood mononuclear cells (PBMCs) using new techniques in order to further elucidate differences between ME/CFS and healthy control cohorts. We stratified our ME/CFS cohort into two individual cohorts representing moderately and severely affected patients in order to determine if disease severity is associated with bioenergetic function in PBMCs. Both ME/CFS cohorts showed reduced mitochondrial function when compared to a healthy control cohort. This shows that disease severity does not correlate with mitochondrial function and even those with a moderate form of the disease show evidence of mitochondrial dysfunction. Equations devised by another research group have enabled us to calculate ATP-linked respiration rates and glycolytic parameters. Parameters of glycolytic function were calculated by taking into account respiratory acidification. This revealed severely affected ME/CFS patients to have higher rates of respiratory acidification and showed the importance of accounting for respiratory acidification when calculating parameters of glycolytic function. Analysis of previously published glycolysis data, after taking into account respiratory acidification, showed severely affected patients have reduced glycolysis compared to moderately affected patients and healthy controls. Rates of ATP-linked respiration were also calculated and shown to be lower in both ME/CFS cohorts. This study shows that severely affected patients have mitochondrial and glycolytic impairments, which sets them apart from moderately affected patients who only have mitochondrial impairment. This may explain why these patients present with a more severe phenotype.
10.1371/journal.pone.0231136
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Journal of Cellular and Molecular medicine
Unravelling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Gender‐specific changes in the microRNA expression profiling in ME/CFS
Amanpreet K. Cheema,Leonor Sarria,Mina Bekheit,Fanny Collado, Eloy Almenar‐Pérez, Eva Martín‐Martínez, Jose Alegre, Jesus Castro‐Marrero, Mary A. Fletcher, Nancy G. Klimas
First published:14 April 2020
https://doi.org/10.1111/jcmm.15260
Funding information:
This study was supported by NIH awards 1R15NS087604‐01A1, 1R21AI124187‐01 and Presidential Faculty Research and Development Grant from Nova Southeastern University (all awarded to LN). We are grateful to all the participants who took part in the studies. The study used PBMC samples collected under CDMRP award W81XWH‐09‐2‐0071 (PI: NK), NIH awards 5R01NS090200‐02 (PI: MAF) and 5R01AR057853‐04 (PI: NK), UCV‐2019‐270‐001 (PI: EO) and Catalonia Association for Fibromyalgia, Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Environmental Sensitivities/Multiple Chemical Sensitivity (ACAF, www.fibromialgia.cat). The sponsors had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by either by the Department of Defense or National Institute of Health.
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Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells and extracellular vesicles in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Scientific Reports volume 10, Article number: 2064 (2020)
2099 Accesses 79 Altmetric Published: 07 February 2020
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multisystemic disease of unknown etiology, affecting thousands of individuals worldwide. Its diagnosis still relies on ruling out medical problems leading to unexplained fatigue due to a complete lack of disease-specific biomarkers. Our group and others have explored the potential value of microRNA profiles (miRNomes) as diagnostic tools for this disease. However, heterogeneity of participants, low numbers, the variety of samples assayed, and other pre-analytical variables, have hampered the identification of disease-associated miRNomes. In this study, our team has evaluated, for the first time, ME/CFS miRNomes in peripheral blood mononuclear cells (PBMCs) and extracellular vesicles (EVs) from severely ill patients recruited at the monographic UK ME biobank to assess, using standard operating procedures (SOPs), blood fractions with optimal diagnostic power for a rapid translation of a miR-based diagnostic method into the clinic. Our results show that routine creatine kinase (CK) blood values, plasma EVs physical characteristics (including counts, size and zeta-potential), and a limited number of differentially expressed PBMC and EV miRNAs appear significantly associated with severe ME/CFS (p < 0.05). Gene enrichment analysis points to epigenetic and neuroimmune dysregulated pathways, in agreement with previous reports. Population validation by a cost-effective approach limited to these few potentially discriminating variables is granted.
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Clinical Neurpophysiology Practice Research paper Vol 5 2020
Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography
C. (Linda) M.C.van CampenaFreek W.A.VerheugtbPeter C.RowecFrans C.Vissera
https://doi.org/10.1016/j.cnp.2020.01.003Get rights and content
Highlights
Doppler imaging to measure cerebral blood flow is feasible during tilt testing.
Cerebral blood flow in ME/CFS patients is reduced during tilt testing.
90% of ME/CFS patients show abnormal cerebral blood flow reduction on tilt testing.
Cerebral blood flow reduction correlates with symptoms of orthostatic intolerance.
Abstract
Objective
The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI.
Methods
429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms.
Results
End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P < .0005). Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P < .0005).
Conclusions
During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities.
Significance
This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients.
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An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients
by Daniel Missailidis 1,Sarah J. Annesley 1,Claire Y. Allan 1,Oana Sanislav 1,Brett A. Lidbury 2,
Department of Physiology, Anatomy, and Microbiology, La Trobe University, Melbourne, VIC 3086, Australia
National Centre for Epidemiology and Population Health, Research School of Population Health, Australian National University, Canberra, ACT 2601, Australia
Int. J. Mol. Sci. 2020, 21(3), 1074; https://doi.org/10.3390/ijms21031074
Received: 4 December 2019 / Revised: 2 February 2020 / Accepted: 4 February 2020 / Published: 6 February 2020
Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolizing patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signaling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters, and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to “normal” in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated
Keywords: myalgic encephalomyelitis; chronic fa
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In-vivo imaging of neuroinflammation in veterans with Gulf War illness
Brain,Behaviour and Immunity 4.2.2020
ZeynabAlshelha1Daniel S.Albrechta1CourtneyBerganaOluwaseunAkejubDaniel ClauwcLisaConboydRobert R.EdwardseMinhaeKimaYvonne C.LeefEkaterinaProtsenkoaVitalyNapadowaeKimberlySullivangMarco L.Loggiaa
a
Received 17 October 2019, Revised 27 January 2020, Accepted 30 January 2020, Available online 4 February 2020.
https://doi.org/10.1016/j.bbi.2020.01.020Get rights and content
Highlights
Gulf war illness (GWI) is a chronic condition characterised by musculoskeletal pain, cognitive problems and fatigue.
Levels of translocator protein (TSPO), a marker of neuroinflammation, are increased in the brain of veterans with GWI.
These results support a role for neuroinflammation in GWI.
Abstract
Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue. The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine bromide (PB) pills, and/or stressors during deployment have all been suspected to play some pathogenic role. Recent animal models of GWI have suggested that neuroinflammatory mechanisms may be implicated, including a dysregulated activation of microglia and astrocytes. However, neuroinflammation has not previously been directly observed in veterans with GWI. To measure GWI-related neuroinflammation in GW veterans, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the 18 kDa translocator protein (TSPO), a protein upregulated in activated microglia/macrophages and astrocytes.
Veterans with GWI (n = 15) and healthy controls (HC, n = 33, including a subgroup of healthy GW veterans, HCVET, n = 8), were examined using integrated [11C]PBR28 PET/MRI. Standardized uptake values normalized by occipital cortex signal (SUVR) were compared across groups and against clinical variables and circulating inflammatory cytokines (TNF-α, IL-6 and IL-1β). SUVR were validated against volume of distribution ratio (n = 13).
Whether compared to the whole HC group, or only the HCVET subgroup, veterans with GWI demonstrated widespread cortical elevations in [11C]PBR28 PET signal, in areas including precuneus, prefrontal, primary motor and somatosensory cortices. There were no significant group differences in the plasma levels of the inflammatory cytokines evaluated. There were also no significant correlations between [11C]PBR28 PET signal and clinical variables or circulating inflammatory cytokines.
Our study provides the first direct evidence of brain upregulation of the neuroinflammatory marker TSPO in veterans with GWI and supports the exploration of neuroinflammation as a therapeutic target for this disorder.
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020 Apr 1:102527. doi: 10.1016/j.autrev.2020.102527. [Epub ahead of print]
A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors.
Wirth K1, Scheibenbogen C2.
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system. We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia. Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis.
Copyright © 2020. Published by Elsevier B.V.
PMID:32247028 DOI:10.1016/j.autrev.2020.102527
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Inj J Mol Sci 2020 Feb 8;21(3). pii: E1142. doi: 10.3390/ijms21031142.
Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Missailidis D1, Sanislav O1, Allan CY1, Annesley SJ1, Fisher PR1.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood mononuclear cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase Target Of Rapamycin Complex 1 (TORC1). These differences were correlated with disease severity, as measured by the Richardson and Lidbury weighted standing test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here, we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and receiver operating characteristic (ROC) curve analysis. We found that results from three different tests-lymphocyte death rate, mitochondrial respiratory function and TORC1 activity-could each individually serve as a biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination, they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.
KEYWORDS:
ME/CFS; Seahorse respirometry; TORC1; biomarker; chronic fatigue syndrome; complex V; diagnosis; mitochondria; myalgic encephalomyelitis
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Brain Imaging Behav 2020 Apr;14(2):562-572. doi: 10.1007/s11682-018-0029-4.
Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy.
Mueller C1, Lin JC1, Sheriff S2, Maudsley AA2, Younger JW3.
Author information
Abstract
Previous neuroimaging studies have detected markers of neuroinflammation in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Magnetic Resonance Spectroscopy (MRS) is suitable for measuring brain metabolites linked to inflammation, but has only been applied to discrete regions of interest in ME/CFS. We extended the MRS analysis of ME/CFS by capturing multi-voxel information across the entire brain. Additionally, we tested whether MRS-derived brain temperature is elevated in ME/CFS patients. Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed fatigue and mood symptom questionnaires and whole-brain echo-planar spectroscopic imaging (EPSI). Choline (CHO), myo-inositol (MI), lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR), and compared between ME/CFS patients and controls using independent-samples t-tests. Brain temperature was similarly tested between groups. Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001). Metabolite ratios in seven regions were correlated with fatigue (p < 0.05). ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the cerebellum (all p < 0.05), which was not attributable to increased body temperature or differences in cerebral perfusion. Brain temperature increases converged with elevated LAC/CR in the right insula, right thalamus, and cerebellum (all p < 0.05). We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed regions. Our findings may indicate that ME/CFS involves neuroinflammation.
KEYWORDS:
Anterior cingulate; Brain temperature; Chronic fatigue syndrome; Magnetic resonance spectroscopy; Metabolites; Neuroinflammation
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J Translational Med 2020 Apr 19;18(1):173. doi: 10.1186/s12967-020-02341-9.
Altered muscle membrane potential and redox status differentiates two subgroups of patients with chronic fatigue syndrome.
Jammes Y1,2, Adjriou N1, Kipson N1, Criado C1, Charpin C2, Rebaudet S2, Stavris C2, Guieu R1, Fenouillet E1,3, Retornaz F4.
Abstract
BACKGROUND:
In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), altered membrane excitability often occurs in exercising muscles demonstrating muscle dysfunction regardless of any psychiatric disorder. Increased oxidative stress is also present in many ME/CFS patients and could affect the membrane excitability of resting muscles.
METHODS:
Seventy-two patients were examined at rest, during an incremental cycling exercise and during a 10-min post-exercise recovery period. All patients had at least four criteria leading to a diagnosis of ME/CFS. To explore muscle membrane excitability, M-waves were recorded during exercise (rectus femoris (RF) muscle) and at rest (flexor digitorum longus (FDL) muscle). Two plasma markers of oxidative stress (thiobarbituric acid reactive substance (TBARS) and oxidation-reduction potential (ORP)) were measured. Plasma potassium (K+) concentration was also measured at rest and at the end of exercise to explore K+ outflow.
RESULTS:
Thirty-nine patients had marked M-wave alterations in both the RF and FDL muscles during and after exercise while the resting values of plasma TBARS and ORP were increased and exercise-induced K+ outflow was decreased. In contrast, 33 other patients with a diagnosis of ME/CFS had no M-wave alterations and had lower baseline levels of TBARS and ORP. M-wave changes were inversely proportional to TBARS and ORP levels.
CONCLUSIONS:
Resting muscles of ME/CFS patients have altered muscle membrane excitability. However, our data reveal heterogeneity in some major biomarkers in ME/CFS patients. Measurement of ORP may help to improve the diagnosis of ME/CFS. Trial registration Ethics Committee "Ouest II" of Angers (May 17, 2019) RCB ID: number 2019-A00611-56.
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Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Not Due to Anti-mitochondrial Antibodies
Front. Med., 31 March 2020 | https://doi.org/10.3389/fmed.2020.00108
Isabell Nilsson1, Jeremy Palmer2, Eirini Apostolou1, Carl-Gerhard Gottfries3, Muhammad Rizwan1, Charlotte Dahle1 and Anders Rosén1*
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Risk Factors for Bites and Diseases Associated With Black-legged Ticks
A Meta-Analysis
Ilya R. Fischhoff; Felicia Keesing; Richard S. Ostfeld
Am J Epidemiol. 2019;188(9):1742-1750.
Abstract
The emergence and spread of Lyme disease and other infections associated with black-legged ticks is causing a public health crisis. No human vaccines are currently available, and both diagnosis and treatment are sometimes ineffectual, leading to advocacy for self-directed preventative measures. These recommendations are widely communicated to the public, but there is limited evidence for their efficacy. We undertook a systematic review and mixed-effects meta-regression analysis of factors purported to increase or decrease risk of black-legged tick bites and tick-borne disease. Published articles used in the study spanned the years 1984–2018. Variables associated with increased probability of tick-borne disease, with odds ratios significantly greater than 1, included deer abundance, high density of nymph-stage black-legged ticks, landscapes with interspersed herbaceous and forested habitat, low human population density, gardens, cat ownership, and race. Contrary to recommendations, use of landscape-related tick control measures, such as clearing brush, trimming branches, and having a dry barrier between lawn and woods, tended to increase risk. Pet ownership increased bite risk. Bite risk was highest for children aged 5 years or less, with a secondary peak in persons aged 50–70 years. Although some widely disseminated recommendations are supported by the research analyzed, others require further evaluation. Additional research is also needed to understand the mechanisms underlying significant relationships.
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International Journal for Molecular Sciences 2020 Feb 8;21(3):1142.
doi: 10.3390/ijms21031142.
Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Daniel Missailidis 1, Oana Sanislav 1, Claire Y Allan 1, Sarah J Annesley 1, Paul R Fisher 1
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood mononuclear cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase Target Of Rapamycin Complex 1 (TORC1). These differences were correlated with disease severity, as measured by the Richardson and Lidbury weighted standing test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here, we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and receiver operating characteristic (ROC) curve analysis. We found that results from three different tests-lymphocyte death rate, mitochondrial respiratory function and TORC1 activity-could each individually serve as a biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination, they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.
Keywords: ME/CFS; Seahorse respirometry; TORC1; biomarker; chronic fatigue syndrome; complex V; diagnosis; mitochondria; myalgic encephalomyelitis.
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Front Immunol. 2020; 11: 578.
Published online 2020 Apr 9. doi: 10.3389/fimmu.2020.00578
PMCID: PMC7161310 PMID: 32328064
Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset
Sophie Steiner,1 Sonya C. Becker,1† Jelka Hartwig,1 Franziska Sotzny,1 Sebastian Lorenz,1 Sandra Bauer,1 Madlen Löbel,2 Anna B. Stittrich,3,4 Patricia Grabowski,1 and Carmen Scheibenbogen1,3,*
Author information Article notes Copyright and License information Disclaimer
Abstract
Single nucleotide polymorphisms (SNP) in various genes have been described to be associated with susceptibility to autoimmune disease. In this study, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients and controls were genotyped for five immune gene SNPs in tyrosine phosphatase non-receptor type 22 (PTPN22, rs2476601), cytotoxic T-lymphocyte-associated protein 4 (CTLA4, rs3087243), tumor necrosis factor (TNF, rs1800629 and rs1799724), and interferon regulatory factor 5 (IRF5, rs3807306), which are among the most important risk variants for autoimmune diseases. Analysis of 305 ME/CFS patients and 201 healthy controls showed significant associations of the PTPN22 rs2476601 and CTLA4 rs3087243 autoimmunity-risk alleles with ME/CFS. The associations were only found in ME/CFS patients, who reported an acute onset of disease with an infection (PTPN22 rs2476601: OR 1.63, CI 1.04–2.55, p = 0.016; CTLA4 rs3087243: OR 1.53, CI 1.17–2.03, p = 0.001), but not in ME/CFS patients without infection-triggered onset (PTPN22 rs2476601: OR 1.09, CI 0.56–2.14, p = 0.398; CTLA4 rs3087243: OR 0.89, CI 0.61–1.30, p = 0.268). This finding provides evidence that autoimmunity might play a role in ME/CFS with an infection-triggered onset. Both genes play a key role in regulating B and T cell activation.
Keywords: single nucleotide polymorphism (SNP), tyrosine phosphatase non-receptor type 22 (PTPN22), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), interferon regulatory factor 5 (IRF5), tumor necrosis factor (TNF), myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), autoimmunity
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A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques
Rebekah Maksoud ,Stanley du Preez,Natalie Eaton-Fitch,Kiran Thapaliya,Leighton Barnden,
Hélène Cabanas,Donald Staines,Sonya Marshall-Gradisnik
Background
Myalgic encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a multi-system illness characterised by a diverse range of debilitating symptoms including autonomic and cognitive dysfunction. The pathomechanism remains elusive, however, neurological and cognitive aberrations are consistently described. This systematic review is the first to collect and appraise the literature related to the structural and functional neurological changes in ME/CFS patients as measured by neuroimaging techniques and to investigate how these changes may influence onset, symptom presentation and severity of the illness.
Methods
A systematic search of databases Pubmed, Embase, MEDLINE (via EBSCOhost) and Web of Science (via Clarivate Analytics) was performed for articles dating between December 1994 and August 2019. Included publications report on neurological differences in ME/CFS patients compared with healthy controls identified using neuroimaging techniques such as magnetic resonance imaging, positron emission tomography and electroencephalography. Article selection was further refined based on specific inclusion and exclusion criteria. A quality assessment of included publications was completed using the Joanna Briggs Institute checklist.
Results
A total of 55 studies were included in this review. All papers assessed neurological or cognitive differences in adult ME/CFS patients compared with healthy controls using neuroimaging techniques. The outcomes from the articles include changes in gray and white matter volumes, cerebral blood flow, brain structure, sleep, EEG activity, functional connectivity and cognitive function. Secondary measures including symptom severity were also reported in most studies.
Conclusions
The results suggest widespread disruption of the autonomic nervous system network including morphological changes, white matter abnormalities and aberrations in functional connectivity. However, these findings are not consistent across studies and the origins of these anomalies remain unknown. Future studies are required confirm the potential neurological contribution to the pathology of ME/CFS.
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Front. Med., 29 April 2020 | https://doi.org/10.3389/fmed.2020.00162
Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study
Ingrid G. Rekeland1, Alexander Fosså2, Asgeir Lande3, Irini Ktoridou-Valen1, Kari Sørland1, Mari Holsen4, Karl J. Tronstad5, Kristin Risa1, Kine Alme1, Marte K. Viken3,6, Benedicte A. Lie3,6, Olav Dahl5, Olav Mella1,5 and Øystein Fluge1,5*
Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600–700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles.
Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1–2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients.
Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted.
Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02444091.
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Brain Behav Immun. 2018 Oct;73:520-532. doi: 10.1016/j.bbi.2018.06.017. Epub 2018 Jun 20.
Sustained Stimulation of β 2- And β 3-adrenergic Receptors Leads to Persistent Functional Pain and Neuroinflammation
Xin Zhang 1, Jane E Hartung 2, Andrey V Bortsov 3, Seungtae Kim 4, Sandra C O'Buckley 3, Julia Kozlowski 3, Andrea G Nackley 5
Functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical syndromes, our lab has shown that sustained 14-day delivery of the COMT inhibitor OR486 in rodents results in pain at multiple body sites and pain-related volitional behaviors. The onset of COMT-dependent functional pain is mediated by peripheral β2- and β3-adrenergic receptors (β2- and β3ARs) through the release of the pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Here, we first sought to investigate the role of β2- and β3ARs and downstream mediators in the maintenance of persistent functional pain. We then aimed to characterize the resulting persistent inflammation in neural tissues (neuroinflammation), characterized by activated glial cells and phosphorylation of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK). Separate groups of rats were implanted with subcutaneous osmotic mini-pumps to deliver OR486 (15 mg/kg/day) or vehicle for 14 days. The β2AR antagonist ICI118551 and β3AR antagonist SR59230A were co-administrated subcutaneously with OR486 or vehicle either on day 0 or day 7. The TNFα inhibitor Etanercept, the p38 inhibitor SB203580, or the ERK inhibitor U0126 were delivered intrathecally following OR486 cessation on day 14. Behavioral responses, pro-inflammatory cytokine levels, glial cell activation, and MAPK phosphorylation were measured over the course of 35 days. Our results demonstrate that systemic delivery of OR486 leads to mechanical hypersensitivity that persists for at least 3 weeks after OR486 cessation. Corresponding increases in spinal TNFα, IL-1β, and IL-6 levels, microglia and astrocyte activation, and neuronal p38 and ERK phosphorylation were observed on days 14-35. Persistent functional pain was alleviated by systemic delivery of ICI118551 and SR59230A beginning on day 0, but not day 7, and by spinal delivery of Etanercept or SB203580 beginning on day 14. These results suggest that peripheral β2- and β3ARs drive persistent COMT-dependent functional pain via increased activation of immune cells and production of pro-inflammatory cytokines, which promote neuroinflammation and nociceptor activation. Thus, therapies that resolve neuroinflammation may prove useful in the management of functional pain syndromes.
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ESC Heart Fail . 2020 Jun;7(3):1064-1071. doi: 10.1002/ehf2.12633. Epub 2020 Mar 10.
Peripheral Endothelial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Nadja Scherbakov 1 2 3 4, Marvin Szklarski 5, Jelka Hartwig 5, Franziska Sotzny 5, Sebastian Lorenz 5, Antje Meyer 1 3 4, Patricia Grabowski 5, Wolfram Doehner 1 2 3 4, Carmen Scheibenbogen 1 5
Aims: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem disease. Evidence for disturbed vascular regulation comes from various studies showing cerebral hypoperfusion and orthostatic intolerance. The peripheral endothelial dysfunction (ED) has not been sufficiently investigated in patients with ME/CFS. The aim of the present study was to examine peripheral endothelial function in patients with ME/CFS.
Methods and results: Thirty-five patients [median age 40 (range 18-70) years, mean body mass index 23.8 ± 4.2 kg/m2 , 31% male] with ME/CFS were studied for peripheral endothelial function assessed by peripheral arterial tonometry (EndoPAT2000). Clinical diagnosis of ME/CFS was based on Canadian Criteria. Nine of these patients with elevated antibodies against β2-adrenergic receptor underwent immunoadsorption, and endothelial function was measured at baseline and 3, 6, and 12 months follow-up. ED was defined by reactive hyperaemia index ≤1.81. Twenty healthy subjects of similar age and body mass index were used as a control group. Peripheral ED was found in 18 of 35 patients (51%) with ME/CFS and in 4 healthy subjects (20%, P < 0.05). Patients with ED, in contrast to patients with normal endothelial function, reported more severe disease according to Bell score (31 ± 12 vs. 40 ± 16, P = 0.04), as well as more severe fatigue-related symptoms (8.62 ± 0.87 vs. 7.75 ± 1.40, P = 0.04) including a higher demand for breaks [9.0 (interquartile range 7.0-10.0) vs. 7.5 (interquartile range 6.0-9.25), P = 0.04]. Peripheral ED showed correlations with more severe immune-associated symptoms (r = -0.41, P = 0.026), such as sore throat (r = -0.38, P = 0.038) and painful lymph nodes (r = -0.37, P = 0.042), as well as more severe disease according to Bell score (r = 0.41, P = 0.008) and symptom score (r = -0.59, P = 0.005). There were no differences between the patient group with ED and the patient group with normal endothelial function regarding demographic, metabolic, and laboratory parameters. Further, there was no difference in soluble vascular cell adhesion molecule and soluble intercellular adhesion molecule levels. At baseline, peripheral ED was observed in six patients who underwent immunoadsorption. After 12 months, endothelial function had improved in five of these six patients (reactive hyperaemia index 1.58 ± 0.15 vs. 2.02 ± 0.46, P = 0.06).
Conclusions: Peripheral ED is frequent in patients with ME/CFS and associated with disease severity and severity of immune symptoms. As ED is a risk factor for cardiovascular disease, it is important to elucidate if peripheral ED is associated with increased cardiovascular morbidity and mortality in ME/CFS.
Keywords: Cardiovascular risk factor; Chronic fatigue syndrome; Immune score; Peripheral endothelial dysfunction; Reactive hyperaemia index.
© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.
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Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Philipp Schreiner,* Thomas Harrer,† Carmen Scheibenbogen,‡ Stephanie Lamer,§ Andreas Schlosser,§ Robert K. Naviaux,{ and Bhupesh K. Prusty*,
ImmunoHorizons 2020, 4 (4) 201-215
ABSTRACT Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disorder with many possible triggers. Human herpesvirus (HHV)–6 and HHV-7 are two infectious triggers for which evidence has been growing. To understand possible causative role of HHV-6 in ME/CFS, metabolic and antiviral phenotypes of U2-OS cells were studied with and without chromosomally integrated HHV-6 and with or without virus reactivation using the histone deacetylase inhibitor trichostatin-A. Proteomic analysis was conducted by pulsed stable isotope labeling by amino acids in cell culture analysis. Antiviral properties that were induced by HHV-6 transactivation were studied in virus-naive A549 cells challenged by infection with influenza-A (H1N1) or HSV-1. Mitochondria were fragmented and 1-carbon metabolism, dUTPase, and thymidylate synthase were strongly induced by HHV-6 reactivation, whereas superoxide dismutase 2 and proteins required for mitochondrial oxidation of fatty acid, amino acid, and glucose metabolism, Received for publication January 21, 2020. Accepted for publication April 5, 2020
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A systematic review of metabolomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID)
Journal of Translational Medicine volume 18, Article number: 198 (2020) Cite this article
Abstract
Background
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID) is a complex illness that has an unknown aetiology. It has been proposed that metabolomics may contribute to the illness pathogenesis of CFS/ME/SEID. In metabolomics, the systematic identification of measurable changes in small molecule metabolite products have been identified in cases of both monogenic and heterogenic diseases. Therefore, the aim of this systematic review was to evaluate if there is any evidence of metabolomics contributing to the pathogenesis of CFS/ME/SEID.
Methods
PubMed, Scopus, EBSCOHost (Medline) and EMBASE were searched using medical subject headings terms for Chronic Fatigue Syndrome, metabolomics and metabolome to source papers published from 1994 to 2020. Inclusion and exclusion criteria were used to identify studies reporting on metabolites measured in blood and urine samples from CFS/ME/SEID patients compared with healthy controls. The Joanna Briggs Institute Checklist was used to complete a quality assessment for all the studies included in this review.
Results
11 observational case control studies met the inclusion criteria for this review. The primary outcome of metabolite measurement in blood samples of CFS/ME/SEID patients was reported in ten studies. The secondary outcome of urine metabolites was measured in three of the included studies. No studies were excluded from this review based on a low-quality assessment score, however there was inconsistency in the scientific research design of the included studies. Metabolites associated with the amino acid pathway were the most commonly impaired with significant results in seven out of the 10 studies. However, no specific metabolite was consistently impaired across all of the studies. Urine metabolite results were also inconsistent.
Conclusion
The findings of this systematic review reports that a lack of consistency with scientific research design provides little evidence for metabolomics to be clearly defined as a contributing factor to the pathogenesis of CFS/ME/SEID. Further research using the same CFS/ME/SEID diagnostic criteria, metabolite analysis method and control of the confounding factors that influence metabolite levels are required.
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2020 Apr 7;8(2):E88. doi: 10.3390/healthcare8020088.
The Development of a Consistent Europe-Wide Approach to Investigating the Economic Impact of Myalgic Encephalomyelitis (ME/CFS): A Report From the European Network on ME/CFS (EUROMENE)
Derek F H Pheby 1, Diana Araja 2, Uldis Berkis 3, Elenka Brenna 4, John Cullinan 5, Jean-Dominique de Korwin 6 7, Lara Gitto 8, Dyfrig A Hughes 9, Rachael M Hunter 10, Dominic Trepel 11 12, Xia Wang-Steverding 13
We have developed a Europe-wide approach to investigating the economic impact of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), facilitating acquisition of information on the economic burden of ME/CFS, and international comparisons of economic costs between countries. The economic burden of ME/CFS in Europe appears large, with productivity losses most significant, giving scope for substantial savings through effective prevention and treatment. However, economic studies of ME/CFS, including cost-of-illness analyses and economic evaluations of interventions, are problematic due to different, arbitrary case definitions, and unwillingness of doctors to diagnose it. We therefore lack accurate incidence and prevalence data, with no obvious way to estimate costs incurred by undiagnosed patients. Other problems include, as for other conditions, difficulties estimating direct and indirect costs incurred by healthcare systems, patients and families, and heterogeneous healthcare systems and patterns of economic development across countries. We have made recommendations, including use of the Fukuda (CDC-1994) case definition and Canadian Consensus Criteria (CCC), a pan-European common symptom checklist, and implementation of prevalence-based cost-of-illness studies in different countries using an agreed data list. We recommend using purchasing power parities (PPP) to facilitate international comparisons, and EuroQol-5D as a generic measure of health status and multi-attribute utility instrument to inform future economic evaluations in ME/CFS.
Keywords: ME/CFS; cost-of-illness studies; economic evaluation; economic impact; healthcare systems.
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2020 Mar 5.
Trans Biomed Eng: doi: 10.1109/TBME.2020.2978801. Online ahead of print.
Characterization of Cortisol Dysregulation in Fibromyalgia and Chronic Fatigue Syndromes: A State-Space Approach
Divesh Deepak Pednekar, Md Rafiul Amin, Hamid Fekri Azgomi, Kirstin Aschbacher, Leslie J Crofford, Rose T Faghih
Objective: Fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) are complicated medical disorders, with little known etiologies. The purpose of this research is to characterize FMS and CFS by studying the variations in cortisol secretion patterns, timings, amplitudes, the number of underlying pulses, as well as infusion and clearance rates of cortisol.
Methods: Using a physiological state-space model with plausible constraints, we estimate the hormonal secretory events and the physiological system parameters (i.e., infusion and clearance rates).
Results: Our results show that the clearance rate of cortisol is lower in FMS patients as compared to their matched healthy individuals based on a simplified cortisol secretion model. Moreover, the number, magnitude, and energy of hormonal secretory events are lower in FMS patients. During early morning hours, the magnitude and energy of the hormonal secretory events are higher in CFS patients.
Conclusion: Due to lower cortisol clearance rate, there is a higher accumulation of cortisol in FMS patients as compared to their matched healthy subjects. As the FMS patient accumulates higher cortisol residues, internal inhibitory feedback regulates the hormonal secretory events. Therefore, the FMS patients show a lower number, magnitude, and energy of hormonal secretory events. Though CFS patients have the same number of secretory events, they secrete lower quantities during early morning hours. When we compare the results for CFS patients against FMS patients, we observe different cortisol alteration patterns.
Significance: Characterizing CFS and FMS based on the cortisol alteration will help us to develop novel methods for treating these disorders.
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Eng Med Biol Soc. 2019 Jul;2019:6896-6901. doi: 10.1109/EMBC.2019.8857427.
A System Theoretic Investigation of Cortisol Dysregulation in Fibromyalgia Patients With Chronic Fatigue
Divesh Deepak Pednekar, Md Rafiul Amin, Hamid Fekri Azgomi, Kirstin Aschbacher, Leslie J Crofford, Rose T Faghih
Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome (CFS) are complex medical conditions with similar symptoms such as anxiety, fatigue, depression, headaches, muscle aches and joint pain. The etiology of both these syndromes is unknown. The objective of this study is to characterize FMS, both in the presence and in the absence of CFS, by analyzing variations in cortisol secretion patterns, timings, amplitudes, and the number of the underlying pulses as well as infusion and clearance rates. The comparison is performed against matched healthy control subjects. We estimate the hormonal secretory events by deconvolving cortisol data using a two-step coordinate descent approach. The first step implements a sparse recovery approach to infer the amplitudes and the timings of the cortisol secretion events from limited cortisol hormone data. The main advantage of this method is estimating the cortisol secretory events using a system theoretic approach. The second step is to estimate the physiological system parameters (i.e. infusion and clearance rates). This approach has been verified on healthy individuals previously. Our results show that the clearance rate of cortisol by the liver is relatively lower in patients as compared to the matched healthy individuals. This suggests that there is a relatively higher accumulation of serum cortisol in patients when compared to matched healthy subjects.
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ORIGINAL RESEARCH ARTICLE
Front. Neurosci., 26 June 2020 | https://doi.org/10.3389/fnins.2020.00688
Cognitive Function Declines Following Orthostatic Stress in Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
(Linda) M. C. van Campen1*, Peter C. Rowe2, Freek W. A. Verheugt3 and Frans C. Visser1
Methods and Results: Eligible participants were consecutive individuals satisfying criteria for ME/CFS who underwent HUT because of OI. The 2- and 3-back tests were performed before the start of HUT and within 5 min after completion of HUT. We measured the percentage of correct responses and raw reaction times before and after HUT for both the 2- and 3-back tests. We studied 128 ME/CFS patients who underwent HUT and had a complete set of N-back data before and after HUT. Compared to pre-tilt responses, the percentage of correct responses on the 2-back test decreased post-HUT from 77(18) to 62(21) and of the 3-back test from 57(17) to 41(17) (both p < 0.0001). The raw reaction time of the 2-back test increased post-HUT from 783(190) to 941(234) m/s and of the 3-back test from 950(170) to 1102(176) (both p < 0.0001). There was no difference in the N-back test data for subgroups dichotomized based on disease severity, the presence of co-morbid fibromyalgia, or the presence of postural orthostatic tachycardia syndrome.
Conclusion: As measured by the N-back test, working memory remains impaired in adults with ME/CFS following a 30-min head-up tilt test.
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• Published: 05 June 2020
Health-related quality of life in Norwegian adolescents living with chronic fatigue syndrome
Wenche Ann Similä, Vidar Halsteinli, Ingrid B. Helland, Christer Suvatne, Hanna Elmi & Torstein Baade Rø
Health and Quality of Life Outcomes volume 18, Article number: 170 (2020)
Abstract
Purpose
The primary aim was to measure health related quality of life (HRQoL) in a Norwegian cohort of adolescents with Chronic Fatigue Syndrome (CFS/ME). A secondary aim was to identify factors before diagnosis, at time of diagnosis and after diagnosis that were associated with HRQoL.
Methods
In this cross-sectional population-based study, HRQoL was measured by Pediatric Quality of Life Inventory™ Generic Core scale version 4.0 (PedsQL4.0) in 63 adolescents with CFS/ME. In addition, fatigue was measured by PedsQL Multidimensional Fatigue scale (PedsQL-MFS), depressive symptoms were measured by the Short Mood and Feelings Questionnaire (SMFQ), and disruption in school activities was measured by The De Paul Pediatric Health Questionnaire (DPHQ-N). Data were also collected from medical records and patient interviews.
Results
Age at diagnosis was 15 (2) years (mean (SD)), and four out of five participants were female. Time from diagnosis to reply was 39 (22) months. Adolescents with CFS/ME reported PedsQL4.0 score 50 (17), and boys reported a better score than girls (64 vs 47, 95% Confidence Interval (CI) for difference (− 27; − 6)). There were positive associations between overall HRQoL and support from a schoolteacher, school attendance or participation in leisure activities. There were negative associations between overall HRQoL and delayed school progression, having been to rehabilitation stay and depressive symptoms.
Conclusion
HRQoL in adolescents diagnosed with CFS/ME was low. The associations between reported HRQoL, healthcare previously provided, support from a schoolteacher, school attendance and participation in leisure activity may provide information of value when developing refined strategies for healthcare among adolescents with CFS/ME. Possible causal relationships must however be explored in future studies.
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Systematic Review of the Epidemiological Burden of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Across Europe: Current Evidence and EUROMENE Research Recommendations for Epidemiology
by Fernando Estévez-López 1,*,Kathleen Mudie 2,‡,Xia Wang-Steverding 3,‡,Inger Johanne Bakken 4,Andrejs Ivanovs 5,Jesús Castro-Marrero 6,Luis Nacul 2,Jose Alegre 6,Paweł Zalewski 7,Joanna Słomko 7,Elin Bolle Strand 8,9,Derek Pheby 10,Evelina Shikova 11,Lorenzo Lorusso 12,Enrica Capelli 13,Slobodan Sekulic 14,Carmen Scheibenbogen 15,Nuno Sepúlveda 2,16,Modra Murovska 17,† andEliana Lacerda 2,†,§ on behalf of The European Network on ME/CFS (EUROMENE)
Abstract
This review aimed at determining the prevalence and incidence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Europe. We conducted a primary search in Scopus, PubMed and Web of Science for publications between 1994 and 15 June 2019 (PROSPERO: CRD42017078688). Additionally, we performed a backward-(reference lists) and forward-(citations) search of the works included in this review. Grey literature was addressed by contacting all members of the European Network on ME/CFS (EUROMENE). Independent reviewers searched, screened and selected studies, extracted data and evaluated the methodological and reporting quality. For prevalence, two studies in adults and one study in adolescents were included. Prevalence ranged from 0.1% to 2.2%. Two studies also included incidence estimates. In conclusion, studies on the prevalence and incidence of ME/CFS in Europe were scarce. Our findings point to the pressing need for well-designed and statistically powered epidemiological studies. To overcome the shortcomings of the current state-of-the-art, EUROMENE recommends that future research is better conducted in the community, reviewing the clinical history of potential cases, obtaining additional objective information (when needed) and using adequate ME/CFS case definitions; namely, the Centers for Disease Control & Prevention−1994, Canadian Consensus Criteria, or Institute of Medicine criteria.
Journal of Clinical Pathology vol 73 Issue 5
http://orcid.org/0000-0001-9102-278X Omar E Mohamed1,Richard L Baretto1, Ian Walker2,
Cathryn Melchior1, Jane Heslegrave1, Ruth Mckenzie2, Chidanand Hullur2, Anjali Ekbote1,
Mamidipudi Thirumala Krishna1,3
Abstract
Post-anaphylaxis mast cell anergy (PAMA), commonly referred to as ‘empty mast cell (MC) syndrome’, is a state of temporary loss of cutaneous MC reactivity in the immediate aftermath of anaphylaxis. Data relating to this condition are sparse and the incidence rate is currently unknown. PAMA has been described only in a few published case reports in the context of hymenoptera venom allergy and perioperative anaphylaxis. Best practice guidelines regarding optimal timing for performing skin tests postanaphylaxis are largely based on expert opinion, and allergy work-up has been recommended after 4–6 weeks postanaphylaxis to avoid false-negative results.
This article provides a review of clinical literature surrounding PAMA, critically evaluates intracellular events in MCs from in vitro data and hypothesises regarding plausible immune mechanisms. There are no published data to directly explain molecular mechanisms underlying this phenomenon. Although not evidence based, PAMA has been attributed to depletion of MC granules following anaphylaxis. It is also plausible that exposure to high allergen concentrations in anaphylaxis can induce a temporary shift in MCs towards dominance of inhibitory signalling pathways, thus contributing to a state of transient hyporesponsiveness observed in some patients. Other potential contributory factors for reduced MC reactivity include downregulation of FcεRI expression, cross-linking of FcεRI to the inhibitory, low-affinity IgG receptors and administration of pharmacotherapeutic agents for anaphylaxis treatment. It is likely that this interesting phenomenon can be explained by a combination of these proposed mechanisms in addition to other genetic/host factors that have not yet been identified.
View Full Text
http://dx.doi.org/10.1136/jclinpath-2019-206157
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Paediatric patients with myalgic encephalomyelitis/chronic fatigue syndrome value understanding and help to move on with their lives
Katherine Rowe
First published:18 December 2019 ACTA Paediatrica
https://doi.org/10.1111/apa.15054
Abstract
Aim
The aim of this study was to document qualitative questionnaire feedback regarding management from a cohort observational study of young people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Methods
Between 1991 and 2009, 784 paediatric patients, age 6‐18 years, were diagnosed with ME/CFS following referral to a specialised clinic at the Royal Children's Hospital, Melbourne. Over a 14‐year period, feedback was requested on up to seven occasions.
Management included the following: symptom management and a self‐management lifestyle plan that included social, educational, physical and a pleasurable activity outside of home. They adjusted it by severity of illness, stage of education, family circumstances and life interests.
Results
Questionnaires were returned from 626 (80%) with 44% providing feedback more than once. They reported that their management plan allowed them to regain control over their lives. They cited early diagnosis, empathetic, informed physicians, self‐management strategies and educational liaison as helping them to function and remain socially engaged. Ongoing support, particularly assistance to navigate the education system, was essential for general well‐being and ability to cope.
Conclusion
Young people valued regaining the control over their lives that was lost through illness, support to maintain social contacts and assistance to achieve educational and/or life goals.
Key Notes
- A cohort observational study of 784 young people with myalgic encephalomyelitis/chronic fatigue syndrome provided feedback across a 14‐year period regarding helpful strategies and ways to improve management.
- Early diagnosis, empathetic informed physicians, assistance with symptom control, self‐management strategies, educational liaison and advocacy enabled them to regain control, remain socially engaged and function optimally.
- Doctors and teachers awareness of helpful strategies could significantly reduce distress with this illness.
2020 Apr 10;15(4):e0231136. doi: 10.1371/journal.pone.0231136. eCollection 2020.PLoS one
The effect of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) severity on cellular bioenergetic function.
Tomas C1, Elson JL1,2, Strassheim V3, Newton JL1,3, Walker M1.
Abstract
Myalgic encephalomyelitis/ Chronic fatigue syndrome (ME/CFS) has been associated with abnormalities in mitochondrial function. In this study we have analysed previous bioenergetics data in peripheral blood mononuclear cells (PBMCs) using new techniques in order to further elucidate differences between ME/CFS and healthy control cohorts. We stratified our ME/CFS cohort into two individual cohorts representing moderately and severely affected patients in order to determine if disease severity is associated with bioenergetic function in PBMCs. Both ME/CFS cohorts showed reduced mitochondrial function when compared to a healthy control cohort. This shows that disease severity does not correlate with mitochondrial function and even those with a moderate form of the disease show evidence of mitochondrial dysfunction. Equations devised by another research group have enabled us to calculate ATP-linked respiration rates and glycolytic parameters. Parameters of glycolytic function were calculated by taking into account respiratory acidification. This revealed severely affected ME/CFS patients to have higher rates of respiratory acidification and showed the importance of accounting for respiratory acidification when calculating parameters of glycolytic function. Analysis of previously published glycolysis data, after taking into account respiratory acidification, showed severely affected patients have reduced glycolysis compared to moderately affected patients and healthy controls. Rates of ATP-linked respiration were also calculated and shown to be lower in both ME/CFS cohorts. This study shows that severely affected patients have mitochondrial and glycolytic impairments, which sets them apart from moderately affected patients who only have mitochondrial impairment. This may explain why these patients present with a more severe phenotype.
10.1371/journal.pone.0231136
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Journal of Cellular and Molecular medicine
Unravelling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Gender‐specific changes in the microRNA expression profiling in ME/CFS
Amanpreet K. Cheema,Leonor Sarria,Mina Bekheit,Fanny Collado, Eloy Almenar‐Pérez, Eva Martín‐Martínez, Jose Alegre, Jesus Castro‐Marrero, Mary A. Fletcher, Nancy G. Klimas
First published:14 April 2020
https://doi.org/10.1111/jcmm.15260
Funding information:
This study was supported by NIH awards 1R15NS087604‐01A1, 1R21AI124187‐01 and Presidential Faculty Research and Development Grant from Nova Southeastern University (all awarded to LN). We are grateful to all the participants who took part in the studies. The study used PBMC samples collected under CDMRP award W81XWH‐09‐2‐0071 (PI: NK), NIH awards 5R01NS090200‐02 (PI: MAF) and 5R01AR057853‐04 (PI: NK), UCV‐2019‐270‐001 (PI: EO) and Catalonia Association for Fibromyalgia, Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Environmental Sensitivities/Multiple Chemical Sensitivity (ACAF, www.fibromialgia.cat). The sponsors had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by either by the Department of Defense or National Institute of Health.
SECTIONS
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Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells and extracellular vesicles in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Scientific Reports volume 10, Article number: 2064 (2020)
2099 Accesses 79 Altmetric Published: 07 February 2020
Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multisystemic disease of unknown etiology, affecting thousands of individuals worldwide. Its diagnosis still relies on ruling out medical problems leading to unexplained fatigue due to a complete lack of disease-specific biomarkers. Our group and others have explored the potential value of microRNA profiles (miRNomes) as diagnostic tools for this disease. However, heterogeneity of participants, low numbers, the variety of samples assayed, and other pre-analytical variables, have hampered the identification of disease-associated miRNomes. In this study, our team has evaluated, for the first time, ME/CFS miRNomes in peripheral blood mononuclear cells (PBMCs) and extracellular vesicles (EVs) from severely ill patients recruited at the monographic UK ME biobank to assess, using standard operating procedures (SOPs), blood fractions with optimal diagnostic power for a rapid translation of a miR-based diagnostic method into the clinic. Our results show that routine creatine kinase (CK) blood values, plasma EVs physical characteristics (including counts, size and zeta-potential), and a limited number of differentially expressed PBMC and EV miRNAs appear significantly associated with severe ME/CFS (p < 0.05). Gene enrichment analysis points to epigenetic and neuroimmune dysregulated pathways, in agreement with previous reports. Population validation by a cost-effective approach limited to these few potentially discriminating variables is granted.
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Clinical Neurpophysiology Practice Research paper Vol 5 2020
Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography
C. (Linda) M.C.van CampenaFreek W.A.VerheugtbPeter C.RowecFrans C.Vissera
https://doi.org/10.1016/j.cnp.2020.01.003Get rights and content
Highlights
Doppler imaging to measure cerebral blood flow is feasible during tilt testing.
Cerebral blood flow in ME/CFS patients is reduced during tilt testing.
90% of ME/CFS patients show abnormal cerebral blood flow reduction on tilt testing.
Cerebral blood flow reduction correlates with symptoms of orthostatic intolerance.
Abstract
Objective
The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI.
Methods
429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms.
Results
End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P < .0005). Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P < .0005).
Conclusions
During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities.
Significance
This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients.
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An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients
by Daniel Missailidis 1,Sarah J. Annesley 1,Claire Y. Allan 1,Oana Sanislav 1,Brett A. Lidbury 2,
Department of Physiology, Anatomy, and Microbiology, La Trobe University, Melbourne, VIC 3086, Australia
National Centre for Epidemiology and Population Health, Research School of Population Health, Australian National University, Canberra, ACT 2601, Australia
Int. J. Mol. Sci. 2020, 21(3), 1074; https://doi.org/10.3390/ijms21031074
Received: 4 December 2019 / Revised: 2 February 2020 / Accepted: 4 February 2020 / Published: 6 February 2020
Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolizing patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signaling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters, and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to “normal” in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated
Keywords: myalgic encephalomyelitis; chronic fa
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In-vivo imaging of neuroinflammation in veterans with Gulf War illness
Brain,Behaviour and Immunity 4.2.2020
ZeynabAlshelha1Daniel S.Albrechta1CourtneyBerganaOluwaseunAkejubDaniel ClauwcLisaConboydRobert R.EdwardseMinhaeKimaYvonne C.LeefEkaterinaProtsenkoaVitalyNapadowaeKimberlySullivangMarco L.Loggiaa
a
Received 17 October 2019, Revised 27 January 2020, Accepted 30 January 2020, Available online 4 February 2020.
https://doi.org/10.1016/j.bbi.2020.01.020Get rights and content
Highlights
Gulf war illness (GWI) is a chronic condition characterised by musculoskeletal pain, cognitive problems and fatigue.
Levels of translocator protein (TSPO), a marker of neuroinflammation, are increased in the brain of veterans with GWI.
These results support a role for neuroinflammation in GWI.
Abstract
Gulf War Illness (GWI) is a chronic disorder affecting approximately 30% of the veterans who served in the 1991 Gulf War. It is characterised by a constellation of symptoms including musculoskeletal pain, cognitive problems and fatigue. The cause of GWI is not definitively known but exposure to neurotoxicants, the prophylactic use of pyridostigmine bromide (PB) pills, and/or stressors during deployment have all been suspected to play some pathogenic role. Recent animal models of GWI have suggested that neuroinflammatory mechanisms may be implicated, including a dysregulated activation of microglia and astrocytes. However, neuroinflammation has not previously been directly observed in veterans with GWI. To measure GWI-related neuroinflammation in GW veterans, we conducted a Positron Emission Tomography (PET) study using [11C]PBR28, which binds to the 18 kDa translocator protein (TSPO), a protein upregulated in activated microglia/macrophages and astrocytes.
Veterans with GWI (n = 15) and healthy controls (HC, n = 33, including a subgroup of healthy GW veterans, HCVET, n = 8), were examined using integrated [11C]PBR28 PET/MRI. Standardized uptake values normalized by occipital cortex signal (SUVR) were compared across groups and against clinical variables and circulating inflammatory cytokines (TNF-α, IL-6 and IL-1β). SUVR were validated against volume of distribution ratio (n = 13).
Whether compared to the whole HC group, or only the HCVET subgroup, veterans with GWI demonstrated widespread cortical elevations in [11C]PBR28 PET signal, in areas including precuneus, prefrontal, primary motor and somatosensory cortices. There were no significant group differences in the plasma levels of the inflammatory cytokines evaluated. There were also no significant correlations between [11C]PBR28 PET signal and clinical variables or circulating inflammatory cytokines.
Our study provides the first direct evidence of brain upregulation of the neuroinflammatory marker TSPO in veterans with GWI and supports the exploration of neuroinflammation as a therapeutic target for this disorder.
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020 Apr 1:102527. doi: 10.1016/j.autrev.2020.102527. [Epub ahead of print]
A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors.
Wirth K1, Scheibenbogen C2.
Abstract
Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system. We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia. Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis.
Copyright © 2020. Published by Elsevier B.V.
PMID:32247028 DOI:10.1016/j.autrev.2020.102527
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Inj J Mol Sci 2020 Feb 8;21(3). pii: E1142. doi: 10.3390/ijms21031142.
Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
Missailidis D1, Sanislav O1, Allan CY1, Annesley SJ1, Fisher PR1.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood mononuclear cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase Target Of Rapamycin Complex 1 (TORC1). These differences were correlated with disease severity, as measured by the Richardson and Lidbury weighted standing test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here, we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and receiver operating characteristic (ROC) curve analysis. We found that results from three different tests-lymphocyte death rate, mitochondrial respiratory function and TORC1 activity-could each individually serve as a biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination, they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.
KEYWORDS:
ME/CFS; Seahorse respirometry; TORC1; biomarker; chronic fatigue syndrome; complex V; diagnosis; mitochondria; myalgic encephalomyelitis
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Brain Imaging Behav 2020 Apr;14(2):562-572. doi: 10.1007/s11682-018-0029-4.
Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy.
Mueller C1, Lin JC1, Sheriff S2, Maudsley AA2, Younger JW3.
Author information
Abstract
Previous neuroimaging studies have detected markers of neuroinflammation in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Magnetic Resonance Spectroscopy (MRS) is suitable for measuring brain metabolites linked to inflammation, but has only been applied to discrete regions of interest in ME/CFS. We extended the MRS analysis of ME/CFS by capturing multi-voxel information across the entire brain. Additionally, we tested whether MRS-derived brain temperature is elevated in ME/CFS patients. Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed fatigue and mood symptom questionnaires and whole-brain echo-planar spectroscopic imaging (EPSI). Choline (CHO), myo-inositol (MI), lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR), and compared between ME/CFS patients and controls using independent-samples t-tests. Brain temperature was similarly tested between groups. Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001). Metabolite ratios in seven regions were correlated with fatigue (p < 0.05). ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the cerebellum (all p < 0.05), which was not attributable to increased body temperature or differences in cerebral perfusion. Brain temperature increases converged with elevated LAC/CR in the right insula, right thalamus, and cerebellum (all p < 0.05). We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed regions. Our findings may indicate that ME/CFS involves neuroinflammation.
KEYWORDS:
Anterior cingulate; Brain temperature; Chronic fatigue syndrome; Magnetic resonance spectroscopy; Metabolites; Neuroinflammation
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J Translational Med 2020 Apr 19;18(1):173. doi: 10.1186/s12967-020-02341-9.
Altered muscle membrane potential and redox status differentiates two subgroups of patients with chronic fatigue syndrome.
Jammes Y1,2, Adjriou N1, Kipson N1, Criado C1, Charpin C2, Rebaudet S2, Stavris C2, Guieu R1, Fenouillet E1,3, Retornaz F4.
Abstract
BACKGROUND:
In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), altered membrane excitability often occurs in exercising muscles demonstrating muscle dysfunction regardless of any psychiatric disorder. Increased oxidative stress is also present in many ME/CFS patients and could affect the membrane excitability of resting muscles.
METHODS:
Seventy-two patients were examined at rest, during an incremental cycling exercise and during a 10-min post-exercise recovery period. All patients had at least four criteria leading to a diagnosis of ME/CFS. To explore muscle membrane excitability, M-waves were recorded during exercise (rectus femoris (RF) muscle) and at rest (flexor digitorum longus (FDL) muscle). Two plasma markers of oxidative stress (thiobarbituric acid reactive substance (TBARS) and oxidation-reduction potential (ORP)) were measured. Plasma potassium (K+) concentration was also measured at rest and at the end of exercise to explore K+ outflow.
RESULTS:
Thirty-nine patients had marked M-wave alterations in both the RF and FDL muscles during and after exercise while the resting values of plasma TBARS and ORP were increased and exercise-induced K+ outflow was decreased. In contrast, 33 other patients with a diagnosis of ME/CFS had no M-wave alterations and had lower baseline levels of TBARS and ORP. M-wave changes were inversely proportional to TBARS and ORP levels.
CONCLUSIONS:
Resting muscles of ME/CFS patients have altered muscle membrane excitability. However, our data reveal heterogeneity in some major biomarkers in ME/CFS patients. Measurement of ORP may help to improve the diagnosis of ME/CFS. Trial registration Ethics Committee "Ouest II" of Angers (May 17, 2019) RCB ID: number 2019-A00611-56.
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Metabolic Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Not Due to Anti-mitochondrial Antibodies
Front. Med., 31 March 2020 | https://doi.org/10.3389/fmed.2020.00108
Isabell Nilsson1, Jeremy Palmer2, Eirini Apostolou1, Carl-Gerhard Gottfries3, Muhammad Rizwan1, Charlotte Dahle1 and Anders Rosén1*
- 1Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- 2The Medical School, The University Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
- 3The Gottfries Clinic AB, Mölndal, Sweden
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Risk Factors for Bites and Diseases Associated With Black-legged Ticks
A Meta-Analysis
Ilya R. Fischhoff; Felicia Keesing; Richard S. Ostfeld
Am J Epidemiol. 2019;188(9):1742-1750.
Abstract
The emergence and spread of Lyme disease and other infections associated with black-legged ticks is causing a public health crisis. No human vaccines are currently available, and both diagnosis and treatment are sometimes ineffectual, leading to advocacy for self-directed preventative measures. These recommendations are widely communicated to the public, but there is limited evidence for their efficacy. We undertook a systematic review and mixed-effects meta-regression analysis of factors purported to increase or decrease risk of black-legged tick bites and tick-borne disease. Published articles used in the study spanned the years 1984–2018. Variables associated with increased probability of tick-borne disease, with odds ratios significantly greater than 1, included deer abundance, high density of nymph-stage black-legged ticks, landscapes with interspersed herbaceous and forested habitat, low human population density, gardens, cat ownership, and race. Contrary to recommendations, use of landscape-related tick control measures, such as clearing brush, trimming branches, and having a dry barrier between lawn and woods, tended to increase risk. Pet ownership increased bite risk. Bite risk was highest for children aged 5 years or less, with a secondary peak in persons aged 50–70 years. Although some widely disseminated recommendations are supported by the research analyzed, others require further evaluation. Additional research is also needed to understand the mechanisms underlying significant relationships.
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International Journal for Molecular Sciences 2020 Feb 8;21(3):1142.
doi: 10.3390/ijms21031142.
Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Daniel Missailidis 1, Oana Sanislav 1, Claire Y Allan 1, Sarah J Annesley 1, Paul R Fisher 1
- PMID: 32046336 PMCID: PMC7037777 DOI: 10.3390/ijms21031142
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood mononuclear cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase Target Of Rapamycin Complex 1 (TORC1). These differences were correlated with disease severity, as measured by the Richardson and Lidbury weighted standing test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here, we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and receiver operating characteristic (ROC) curve analysis. We found that results from three different tests-lymphocyte death rate, mitochondrial respiratory function and TORC1 activity-could each individually serve as a biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination, they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.
Keywords: ME/CFS; Seahorse respirometry; TORC1; biomarker; chronic fatigue syndrome; complex V; diagnosis; mitochondria; myalgic encephalomyelitis.
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Front Immunol. 2020; 11: 578.
Published online 2020 Apr 9. doi: 10.3389/fimmu.2020.00578
PMCID: PMC7161310 PMID: 32328064
Autoimmunity-Related Risk Variants in PTPN22 and CTLA4 Are Associated With ME/CFS With Infectious Onset
Sophie Steiner,1 Sonya C. Becker,1† Jelka Hartwig,1 Franziska Sotzny,1 Sebastian Lorenz,1 Sandra Bauer,1 Madlen Löbel,2 Anna B. Stittrich,3,4 Patricia Grabowski,1 and Carmen Scheibenbogen1,3,*
Author information Article notes Copyright and License information Disclaimer
Abstract
Single nucleotide polymorphisms (SNP) in various genes have been described to be associated with susceptibility to autoimmune disease. In this study, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients and controls were genotyped for five immune gene SNPs in tyrosine phosphatase non-receptor type 22 (PTPN22, rs2476601), cytotoxic T-lymphocyte-associated protein 4 (CTLA4, rs3087243), tumor necrosis factor (TNF, rs1800629 and rs1799724), and interferon regulatory factor 5 (IRF5, rs3807306), which are among the most important risk variants for autoimmune diseases. Analysis of 305 ME/CFS patients and 201 healthy controls showed significant associations of the PTPN22 rs2476601 and CTLA4 rs3087243 autoimmunity-risk alleles with ME/CFS. The associations were only found in ME/CFS patients, who reported an acute onset of disease with an infection (PTPN22 rs2476601: OR 1.63, CI 1.04–2.55, p = 0.016; CTLA4 rs3087243: OR 1.53, CI 1.17–2.03, p = 0.001), but not in ME/CFS patients without infection-triggered onset (PTPN22 rs2476601: OR 1.09, CI 0.56–2.14, p = 0.398; CTLA4 rs3087243: OR 0.89, CI 0.61–1.30, p = 0.268). This finding provides evidence that autoimmunity might play a role in ME/CFS with an infection-triggered onset. Both genes play a key role in regulating B and T cell activation.
Keywords: single nucleotide polymorphism (SNP), tyrosine phosphatase non-receptor type 22 (PTPN22), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), interferon regulatory factor 5 (IRF5), tumor necrosis factor (TNF), myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), autoimmunity
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A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques
Rebekah Maksoud ,Stanley du Preez,Natalie Eaton-Fitch,Kiran Thapaliya,Leighton Barnden,
Hélène Cabanas,Donald Staines,Sonya Marshall-Gradisnik
- Published: April 30, 2020
- https://doi.org/10.1371/journal.pone.0232475
Background
Myalgic encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a multi-system illness characterised by a diverse range of debilitating symptoms including autonomic and cognitive dysfunction. The pathomechanism remains elusive, however, neurological and cognitive aberrations are consistently described. This systematic review is the first to collect and appraise the literature related to the structural and functional neurological changes in ME/CFS patients as measured by neuroimaging techniques and to investigate how these changes may influence onset, symptom presentation and severity of the illness.
Methods
A systematic search of databases Pubmed, Embase, MEDLINE (via EBSCOhost) and Web of Science (via Clarivate Analytics) was performed for articles dating between December 1994 and August 2019. Included publications report on neurological differences in ME/CFS patients compared with healthy controls identified using neuroimaging techniques such as magnetic resonance imaging, positron emission tomography and electroencephalography. Article selection was further refined based on specific inclusion and exclusion criteria. A quality assessment of included publications was completed using the Joanna Briggs Institute checklist.
Results
A total of 55 studies were included in this review. All papers assessed neurological or cognitive differences in adult ME/CFS patients compared with healthy controls using neuroimaging techniques. The outcomes from the articles include changes in gray and white matter volumes, cerebral blood flow, brain structure, sleep, EEG activity, functional connectivity and cognitive function. Secondary measures including symptom severity were also reported in most studies.
Conclusions
The results suggest widespread disruption of the autonomic nervous system network including morphological changes, white matter abnormalities and aberrations in functional connectivity. However, these findings are not consistent across studies and the origins of these anomalies remain unknown. Future studies are required confirm the potential neurological contribution to the pathology of ME/CFS.
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Front. Med., 29 April 2020 | https://doi.org/10.3389/fmed.2020.00162
Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study
Ingrid G. Rekeland1, Alexander Fosså2, Asgeir Lande3, Irini Ktoridou-Valen1, Kari Sørland1, Mari Holsen4, Karl J. Tronstad5, Kristin Risa1, Kine Alme1, Marte K. Viken3,6, Benedicte A. Lie3,6, Olav Dahl5, Olav Mella1,5 and Øystein Fluge1,5*
- 1Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
- 2Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- 3Department of Medical Genetics, Oslo University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway
- 4Clinical Research Unit, Haukeland University Hospital, Bergen, Norway
- 5Department of Biomedicine, University of Bergen, Bergen, Norway
- 6Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway
Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600–700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles.
Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1–2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients.
Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted.
Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02444091.
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Brain Behav Immun. 2018 Oct;73:520-532. doi: 10.1016/j.bbi.2018.06.017. Epub 2018 Jun 20.
Sustained Stimulation of β 2- And β 3-adrenergic Receptors Leads to Persistent Functional Pain and Neuroinflammation
Xin Zhang 1, Jane E Hartung 2, Andrey V Bortsov 3, Seungtae Kim 4, Sandra C O'Buckley 3, Julia Kozlowski 3, Andrea G Nackley 5
- PMID: 29935309 PMCID: PMC6129429 DOI: 10.1016/j.bbi.2018.06.017
Functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical syndromes, our lab has shown that sustained 14-day delivery of the COMT inhibitor OR486 in rodents results in pain at multiple body sites and pain-related volitional behaviors. The onset of COMT-dependent functional pain is mediated by peripheral β2- and β3-adrenergic receptors (β2- and β3ARs) through the release of the pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Here, we first sought to investigate the role of β2- and β3ARs and downstream mediators in the maintenance of persistent functional pain. We then aimed to characterize the resulting persistent inflammation in neural tissues (neuroinflammation), characterized by activated glial cells and phosphorylation of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK). Separate groups of rats were implanted with subcutaneous osmotic mini-pumps to deliver OR486 (15 mg/kg/day) or vehicle for 14 days. The β2AR antagonist ICI118551 and β3AR antagonist SR59230A were co-administrated subcutaneously with OR486 or vehicle either on day 0 or day 7. The TNFα inhibitor Etanercept, the p38 inhibitor SB203580, or the ERK inhibitor U0126 were delivered intrathecally following OR486 cessation on day 14. Behavioral responses, pro-inflammatory cytokine levels, glial cell activation, and MAPK phosphorylation were measured over the course of 35 days. Our results demonstrate that systemic delivery of OR486 leads to mechanical hypersensitivity that persists for at least 3 weeks after OR486 cessation. Corresponding increases in spinal TNFα, IL-1β, and IL-6 levels, microglia and astrocyte activation, and neuronal p38 and ERK phosphorylation were observed on days 14-35. Persistent functional pain was alleviated by systemic delivery of ICI118551 and SR59230A beginning on day 0, but not day 7, and by spinal delivery of Etanercept or SB203580 beginning on day 14. These results suggest that peripheral β2- and β3ARs drive persistent COMT-dependent functional pain via increased activation of immune cells and production of pro-inflammatory cytokines, which promote neuroinflammation and nociceptor activation. Thus, therapies that resolve neuroinflammation may prove useful in the management of functional pain syndromes.
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ESC Heart Fail . 2020 Jun;7(3):1064-1071. doi: 10.1002/ehf2.12633. Epub 2020 Mar 10.
Peripheral Endothelial Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Nadja Scherbakov 1 2 3 4, Marvin Szklarski 5, Jelka Hartwig 5, Franziska Sotzny 5, Sebastian Lorenz 5, Antje Meyer 1 3 4, Patricia Grabowski 5, Wolfram Doehner 1 2 3 4, Carmen Scheibenbogen 1 5
- PMID: 32154656 PMCID: PMC7261521 DOI: 10.1002/ehf2.12633
Aims: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem disease. Evidence for disturbed vascular regulation comes from various studies showing cerebral hypoperfusion and orthostatic intolerance. The peripheral endothelial dysfunction (ED) has not been sufficiently investigated in patients with ME/CFS. The aim of the present study was to examine peripheral endothelial function in patients with ME/CFS.
Methods and results: Thirty-five patients [median age 40 (range 18-70) years, mean body mass index 23.8 ± 4.2 kg/m2 , 31% male] with ME/CFS were studied for peripheral endothelial function assessed by peripheral arterial tonometry (EndoPAT2000). Clinical diagnosis of ME/CFS was based on Canadian Criteria. Nine of these patients with elevated antibodies against β2-adrenergic receptor underwent immunoadsorption, and endothelial function was measured at baseline and 3, 6, and 12 months follow-up. ED was defined by reactive hyperaemia index ≤1.81. Twenty healthy subjects of similar age and body mass index were used as a control group. Peripheral ED was found in 18 of 35 patients (51%) with ME/CFS and in 4 healthy subjects (20%, P < 0.05). Patients with ED, in contrast to patients with normal endothelial function, reported more severe disease according to Bell score (31 ± 12 vs. 40 ± 16, P = 0.04), as well as more severe fatigue-related symptoms (8.62 ± 0.87 vs. 7.75 ± 1.40, P = 0.04) including a higher demand for breaks [9.0 (interquartile range 7.0-10.0) vs. 7.5 (interquartile range 6.0-9.25), P = 0.04]. Peripheral ED showed correlations with more severe immune-associated symptoms (r = -0.41, P = 0.026), such as sore throat (r = -0.38, P = 0.038) and painful lymph nodes (r = -0.37, P = 0.042), as well as more severe disease according to Bell score (r = 0.41, P = 0.008) and symptom score (r = -0.59, P = 0.005). There were no differences between the patient group with ED and the patient group with normal endothelial function regarding demographic, metabolic, and laboratory parameters. Further, there was no difference in soluble vascular cell adhesion molecule and soluble intercellular adhesion molecule levels. At baseline, peripheral ED was observed in six patients who underwent immunoadsorption. After 12 months, endothelial function had improved in five of these six patients (reactive hyperaemia index 1.58 ± 0.15 vs. 2.02 ± 0.46, P = 0.06).
Conclusions: Peripheral ED is frequent in patients with ME/CFS and associated with disease severity and severity of immune symptoms. As ED is a risk factor for cardiovascular disease, it is important to elucidate if peripheral ED is associated with increased cardiovascular morbidity and mortality in ME/CFS.
Keywords: Cardiovascular risk factor; Chronic fatigue syndrome; Immune score; Peripheral endothelial dysfunction; Reactive hyperaemia index.
© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.
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Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Philipp Schreiner,* Thomas Harrer,† Carmen Scheibenbogen,‡ Stephanie Lamer,§ Andreas Schlosser,§ Robert K. Naviaux,{ and Bhupesh K. Prusty*,
ImmunoHorizons 2020, 4 (4) 201-215
ABSTRACT Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disorder with many possible triggers. Human herpesvirus (HHV)–6 and HHV-7 are two infectious triggers for which evidence has been growing. To understand possible causative role of HHV-6 in ME/CFS, metabolic and antiviral phenotypes of U2-OS cells were studied with and without chromosomally integrated HHV-6 and with or without virus reactivation using the histone deacetylase inhibitor trichostatin-A. Proteomic analysis was conducted by pulsed stable isotope labeling by amino acids in cell culture analysis. Antiviral properties that were induced by HHV-6 transactivation were studied in virus-naive A549 cells challenged by infection with influenza-A (H1N1) or HSV-1. Mitochondria were fragmented and 1-carbon metabolism, dUTPase, and thymidylate synthase were strongly induced by HHV-6 reactivation, whereas superoxide dismutase 2 and proteins required for mitochondrial oxidation of fatty acid, amino acid, and glucose metabolism, Received for publication January 21, 2020. Accepted for publication April 5, 2020
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A systematic review of metabolomic dysregulation in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID)
Journal of Translational Medicine volume 18, Article number: 198 (2020) Cite this article
Abstract
Background
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID) is a complex illness that has an unknown aetiology. It has been proposed that metabolomics may contribute to the illness pathogenesis of CFS/ME/SEID. In metabolomics, the systematic identification of measurable changes in small molecule metabolite products have been identified in cases of both monogenic and heterogenic diseases. Therefore, the aim of this systematic review was to evaluate if there is any evidence of metabolomics contributing to the pathogenesis of CFS/ME/SEID.
Methods
PubMed, Scopus, EBSCOHost (Medline) and EMBASE were searched using medical subject headings terms for Chronic Fatigue Syndrome, metabolomics and metabolome to source papers published from 1994 to 2020. Inclusion and exclusion criteria were used to identify studies reporting on metabolites measured in blood and urine samples from CFS/ME/SEID patients compared with healthy controls. The Joanna Briggs Institute Checklist was used to complete a quality assessment for all the studies included in this review.
Results
11 observational case control studies met the inclusion criteria for this review. The primary outcome of metabolite measurement in blood samples of CFS/ME/SEID patients was reported in ten studies. The secondary outcome of urine metabolites was measured in three of the included studies. No studies were excluded from this review based on a low-quality assessment score, however there was inconsistency in the scientific research design of the included studies. Metabolites associated with the amino acid pathway were the most commonly impaired with significant results in seven out of the 10 studies. However, no specific metabolite was consistently impaired across all of the studies. Urine metabolite results were also inconsistent.
Conclusion
The findings of this systematic review reports that a lack of consistency with scientific research design provides little evidence for metabolomics to be clearly defined as a contributing factor to the pathogenesis of CFS/ME/SEID. Further research using the same CFS/ME/SEID diagnostic criteria, metabolite analysis method and control of the confounding factors that influence metabolite levels are required.
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2020 Apr 7;8(2):E88. doi: 10.3390/healthcare8020088.
The Development of a Consistent Europe-Wide Approach to Investigating the Economic Impact of Myalgic Encephalomyelitis (ME/CFS): A Report From the European Network on ME/CFS (EUROMENE)
Derek F H Pheby 1, Diana Araja 2, Uldis Berkis 3, Elenka Brenna 4, John Cullinan 5, Jean-Dominique de Korwin 6 7, Lara Gitto 8, Dyfrig A Hughes 9, Rachael M Hunter 10, Dominic Trepel 11 12, Xia Wang-Steverding 13
- PMID: 32272608
- DOI: 10.3390/healthcare8020088
We have developed a Europe-wide approach to investigating the economic impact of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), facilitating acquisition of information on the economic burden of ME/CFS, and international comparisons of economic costs between countries. The economic burden of ME/CFS in Europe appears large, with productivity losses most significant, giving scope for substantial savings through effective prevention and treatment. However, economic studies of ME/CFS, including cost-of-illness analyses and economic evaluations of interventions, are problematic due to different, arbitrary case definitions, and unwillingness of doctors to diagnose it. We therefore lack accurate incidence and prevalence data, with no obvious way to estimate costs incurred by undiagnosed patients. Other problems include, as for other conditions, difficulties estimating direct and indirect costs incurred by healthcare systems, patients and families, and heterogeneous healthcare systems and patterns of economic development across countries. We have made recommendations, including use of the Fukuda (CDC-1994) case definition and Canadian Consensus Criteria (CCC), a pan-European common symptom checklist, and implementation of prevalence-based cost-of-illness studies in different countries using an agreed data list. We recommend using purchasing power parities (PPP) to facilitate international comparisons, and EuroQol-5D as a generic measure of health status and multi-attribute utility instrument to inform future economic evaluations in ME/CFS.
Keywords: ME/CFS; cost-of-illness studies; economic evaluation; economic impact; healthcare systems.
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2020 Mar 5.
Trans Biomed Eng: doi: 10.1109/TBME.2020.2978801. Online ahead of print.
Characterization of Cortisol Dysregulation in Fibromyalgia and Chronic Fatigue Syndromes: A State-Space Approach
Divesh Deepak Pednekar, Md Rafiul Amin, Hamid Fekri Azgomi, Kirstin Aschbacher, Leslie J Crofford, Rose T Faghih
- PMID: 32149617 DOI: 10.1109/TBME.2020.2978801
Objective: Fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) are complicated medical disorders, with little known etiologies. The purpose of this research is to characterize FMS and CFS by studying the variations in cortisol secretion patterns, timings, amplitudes, the number of underlying pulses, as well as infusion and clearance rates of cortisol.
Methods: Using a physiological state-space model with plausible constraints, we estimate the hormonal secretory events and the physiological system parameters (i.e., infusion and clearance rates).
Results: Our results show that the clearance rate of cortisol is lower in FMS patients as compared to their matched healthy individuals based on a simplified cortisol secretion model. Moreover, the number, magnitude, and energy of hormonal secretory events are lower in FMS patients. During early morning hours, the magnitude and energy of the hormonal secretory events are higher in CFS patients.
Conclusion: Due to lower cortisol clearance rate, there is a higher accumulation of cortisol in FMS patients as compared to their matched healthy subjects. As the FMS patient accumulates higher cortisol residues, internal inhibitory feedback regulates the hormonal secretory events. Therefore, the FMS patients show a lower number, magnitude, and energy of hormonal secretory events. Though CFS patients have the same number of secretory events, they secrete lower quantities during early morning hours. When we compare the results for CFS patients against FMS patients, we observe different cortisol alteration patterns.
Significance: Characterizing CFS and FMS based on the cortisol alteration will help us to develop novel methods for treating these disorders.
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Eng Med Biol Soc. 2019 Jul;2019:6896-6901. doi: 10.1109/EMBC.2019.8857427.
A System Theoretic Investigation of Cortisol Dysregulation in Fibromyalgia Patients With Chronic Fatigue
Divesh Deepak Pednekar, Md Rafiul Amin, Hamid Fekri Azgomi, Kirstin Aschbacher, Leslie J Crofford, Rose T Faghih
- PMID: 31947425
Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome (CFS) are complex medical conditions with similar symptoms such as anxiety, fatigue, depression, headaches, muscle aches and joint pain. The etiology of both these syndromes is unknown. The objective of this study is to characterize FMS, both in the presence and in the absence of CFS, by analyzing variations in cortisol secretion patterns, timings, amplitudes, and the number of the underlying pulses as well as infusion and clearance rates. The comparison is performed against matched healthy control subjects. We estimate the hormonal secretory events by deconvolving cortisol data using a two-step coordinate descent approach. The first step implements a sparse recovery approach to infer the amplitudes and the timings of the cortisol secretion events from limited cortisol hormone data. The main advantage of this method is estimating the cortisol secretory events using a system theoretic approach. The second step is to estimate the physiological system parameters (i.e. infusion and clearance rates). This approach has been verified on healthy individuals previously. Our results show that the clearance rate of cortisol by the liver is relatively lower in patients as compared to the matched healthy individuals. This suggests that there is a relatively higher accumulation of serum cortisol in patients when compared to matched healthy subjects.
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ORIGINAL RESEARCH ARTICLE
Front. Neurosci., 26 June 2020 | https://doi.org/10.3389/fnins.2020.00688
Cognitive Function Declines Following Orthostatic Stress in Adults With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
(Linda) M. C. van Campen1*, Peter C. Rowe2, Freek W. A. Verheugt3 and Frans C. Visser1
- 1Stichting CardioZorg, Hoofddorp, Netherlands
- 2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- 3Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands
Methods and Results: Eligible participants were consecutive individuals satisfying criteria for ME/CFS who underwent HUT because of OI. The 2- and 3-back tests were performed before the start of HUT and within 5 min after completion of HUT. We measured the percentage of correct responses and raw reaction times before and after HUT for both the 2- and 3-back tests. We studied 128 ME/CFS patients who underwent HUT and had a complete set of N-back data before and after HUT. Compared to pre-tilt responses, the percentage of correct responses on the 2-back test decreased post-HUT from 77(18) to 62(21) and of the 3-back test from 57(17) to 41(17) (both p < 0.0001). The raw reaction time of the 2-back test increased post-HUT from 783(190) to 941(234) m/s and of the 3-back test from 950(170) to 1102(176) (both p < 0.0001). There was no difference in the N-back test data for subgroups dichotomized based on disease severity, the presence of co-morbid fibromyalgia, or the presence of postural orthostatic tachycardia syndrome.
Conclusion: As measured by the N-back test, working memory remains impaired in adults with ME/CFS following a 30-min head-up tilt test.
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• Published: 05 June 2020
Health-related quality of life in Norwegian adolescents living with chronic fatigue syndrome
Wenche Ann Similä, Vidar Halsteinli, Ingrid B. Helland, Christer Suvatne, Hanna Elmi & Torstein Baade Rø
Health and Quality of Life Outcomes volume 18, Article number: 170 (2020)
Abstract
Purpose
The primary aim was to measure health related quality of life (HRQoL) in a Norwegian cohort of adolescents with Chronic Fatigue Syndrome (CFS/ME). A secondary aim was to identify factors before diagnosis, at time of diagnosis and after diagnosis that were associated with HRQoL.
Methods
In this cross-sectional population-based study, HRQoL was measured by Pediatric Quality of Life Inventory™ Generic Core scale version 4.0 (PedsQL4.0) in 63 adolescents with CFS/ME. In addition, fatigue was measured by PedsQL Multidimensional Fatigue scale (PedsQL-MFS), depressive symptoms were measured by the Short Mood and Feelings Questionnaire (SMFQ), and disruption in school activities was measured by The De Paul Pediatric Health Questionnaire (DPHQ-N). Data were also collected from medical records and patient interviews.
Results
Age at diagnosis was 15 (2) years (mean (SD)), and four out of five participants were female. Time from diagnosis to reply was 39 (22) months. Adolescents with CFS/ME reported PedsQL4.0 score 50 (17), and boys reported a better score than girls (64 vs 47, 95% Confidence Interval (CI) for difference (− 27; − 6)). There were positive associations between overall HRQoL and support from a schoolteacher, school attendance or participation in leisure activities. There were negative associations between overall HRQoL and delayed school progression, having been to rehabilitation stay and depressive symptoms.
Conclusion
HRQoL in adolescents diagnosed with CFS/ME was low. The associations between reported HRQoL, healthcare previously provided, support from a schoolteacher, school attendance and participation in leisure activity may provide information of value when developing refined strategies for healthcare among adolescents with CFS/ME. Possible causal relationships must however be explored in future studies.
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Systematic Review of the Epidemiological Burden of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Across Europe: Current Evidence and EUROMENE Research Recommendations for Epidemiology
by Fernando Estévez-López 1,*,Kathleen Mudie 2,‡,Xia Wang-Steverding 3,‡,Inger Johanne Bakken 4,Andrejs Ivanovs 5,Jesús Castro-Marrero 6,Luis Nacul 2,Jose Alegre 6,Paweł Zalewski 7,Joanna Słomko 7,Elin Bolle Strand 8,9,Derek Pheby 10,Evelina Shikova 11,Lorenzo Lorusso 12,Enrica Capelli 13,Slobodan Sekulic 14,Carmen Scheibenbogen 15,Nuno Sepúlveda 2,16,Modra Murovska 17,† andEliana Lacerda 2,†,§ on behalf of The European Network on ME/CFS (EUROMENE)
Abstract
This review aimed at determining the prevalence and incidence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Europe. We conducted a primary search in Scopus, PubMed and Web of Science for publications between 1994 and 15 June 2019 (PROSPERO: CRD42017078688). Additionally, we performed a backward-(reference lists) and forward-(citations) search of the works included in this review. Grey literature was addressed by contacting all members of the European Network on ME/CFS (EUROMENE). Independent reviewers searched, screened and selected studies, extracted data and evaluated the methodological and reporting quality. For prevalence, two studies in adults and one study in adolescents were included. Prevalence ranged from 0.1% to 2.2%. Two studies also included incidence estimates. In conclusion, studies on the prevalence and incidence of ME/CFS in Europe were scarce. Our findings point to the pressing need for well-designed and statistically powered epidemiological studies. To overcome the shortcomings of the current state-of-the-art, EUROMENE recommends that future research is better conducted in the community, reviewing the clinical history of potential cases, obtaining additional objective information (when needed) and using adequate ME/CFS case definitions; namely, the Centers for Disease Control & Prevention−1994, Canadian Consensus Criteria, or Institute of Medicine criteria.
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