Category: Pathophysiology

Oxidative Stress is a Convincing Contributor to Idiopathic Chronic Fatigue

Abstract:

The linkage between oxidative stress and idiopathic chronic fatigue (ICF) has not been explored in detail. This study thoroughly compared the serum levels of biomarkers for oxidative stress and antioxidants from 103 subjects with ICF (20 men and 83 women) to those of 82 healthy volunteers (27 men and 55 women).

Oxidative parameters, which included reactive oxygen species (ROS), malondialdehyde (MDA) and F2-isoprotan, and tumor necrosis factor-alpha (TNF-α) were significantly elevated, while antioxidant parameters, which included total antioxidant activity (TAC), catalase, superoxide dismutase, SOD and GSH activity, were decreased compared to those of healthy subjects (by approximately 1.2- to 2.3-fold, p < 0.05 or 0.01).

Our results confirmed that oxidative stress is a key contributor in the pathophysiology of ICF, and firstly explored the features of oxidative stress parameters in ICF subjects compared to a healthy population.

Source: Lee JS, Kim HG, Lee DS, Son CG. Oxidative Stress is a Convincing Contributor to Idiopathic Chronic Fatigue. Sci Rep. 2018;8(1):12890. Published 2018 Aug 27. doi:10.1038/s41598-018-31270-3 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110864/ (Full article)

Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and meta-analysis

Abstract:

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition with no reliable diagnostic biomarkers. Studies have shown evidence of autonomic dysfunction in patients with ME/CFS, but results have been equivocal. Heart rate (HR) parameters can reflect changes in autonomic function in healthy individuals; however, this has not been thoroughly evaluated in ME/CFS.

METHODS: A systematic database search for case-control literature was performed. Meta-analysis was performed to determine differences in HR parameters between ME/CFS patients and controls.

RESULTS: Sixty-four articles were included in the systematic review. HR parameters assessed in ME/CFS patients and controls were grouped into ten categories: resting HR (RHR), maximal HR (HRmax), HR during submaximal exercise, HR response to head-up tilt testing (HRtilt), resting HR variability (HRVrest), HR variability during head-up tilt testing (HRVtilt), orthostatic HR response (HROR), HR during mental task(s) (HRmentaltask), daily average HR (HRdailyaverage), and HR recovery (HRR) Meta-analysis revealed RHR (MD ± 95% CI = 4.14 ± 1.38, P < .001), HRtilt (SMD ± 95% CI = 0.92 ± 0.24, P < .001), HROR (0.50 ± 0.27, P < .001), and the ratio of low frequency power to high frequency power of HRVrest (0.39 ± 0.22, P < .001) were higher in ME/CFS patients compared to controls, while HRmax (MD ± 95% CI = -13.81 ± 4.15, P < .001), HR at anaerobic threshold (SMD ± 95% CI = -0.44 ± 0.30, P = 0.005) and the high frequency portion of HRVrest (-0.34 ± 0.22, P = .002) were lower in ME/CFS patients.

CONCLUSIONS: The differences in HR parameters identified by the meta-analysis indicate that ME/CFS patients have altered autonomic cardiac regulation when compared to healthy controls. These alterations in HR parameters may be symptomatic of the condition.

Source: Nelson MJ, Bahl JS, Buckley JD, Thomson RL, Davison K. Evidence of altered cardiac autonomic regulation in myalgic encephalomyelitis/chronic fatigue syndrome: A systematic review and meta-analysis. Medicine (Baltimore). 2019 Oct;98(43):e17600. doi: 10.1097/MD.0000000000017600. https://www.ncbi.nlm.nih.gov/pubmed/31651868 (Full article)

Neuroinflammation disorders exacerbated by environmental stressors

Abstract:

Neuroinflammation is a condition characterized by the elaboration of proinflammatory mediators within the central nervous system. Neuroinflammation has emerged as a dominant theme in contemporary neuroscience due to its association with neurodegenerative disease states such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.

While neuroinflammation often is associated with damage to the CNS, it also can occur in the absence of neurodegeneration, e.g., in association with systemic infection. The “acute phase” inflammatory response to tissue injury or infections instigates neuroinflammation-driven “sickness behavior,” i.e. a constellation of symptoms characterized by loss of appetite, fever, muscle pain, fatigue and cognitive problems. Typically, sickness behavior accompanies an inflammatory response that resolves quickly and serves to restore the body to homeostasis. However, recurring and sometimes chronic sickness behavior disorders can occur in the absence of an underlying cause or attendant neuropathology.

Here, we review myalgic enchepalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Illness (GWI), and chemobrain as examples of such disorders and propose that they can be exacerbated and perhaps initiated by a variety of environmental stressors. Diverse environmental stressors may disrupt the hypothalamic pituitary adrenal (HPA) axis and contribute to the degree and duration of a variety of neuroinflammation-driven diseases.

Source: O’Callaghan JP, Miller DB. Neuroinflammation disorders exacerbated by environmental stressors. Metabolism. 2019 Nov;100S:153951. doi: 10.1016/j.metabol.2019.153951. https://www.ncbi.nlm.nih.gov/pubmed/31610852

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: From Pathophysiological Insights to Novel Therapeutic Opportunities

Abstract:

Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is a common and disabling condition with a paucity of effective and evidence-based therapies reflecting a major unmet need. Cognitive behavioural therapy and graded exercise are of modest benefit for only some ME/CFS patients, and many sufferers report aggravation of symptoms of fatigue with exercise.

The presence of a multiplicity of pathophysiological abnormalities, in at least the subgroup of people with ME/CFS diagnosed with the current international consensus “Fukuda” criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics.

In this paper, these pathways are summarised, and data regarding promising therapeutic options that target these pathways are highlighted; they include coenzyme Q10, melatonin, curcumin, molecular hydrogen and N-acetylcysteine. These data are promising yet preliminary, suggesting hopeful avenues to address this major unmet burden of illness.

Copyright © 2019. Published by Elsevier Ltd.

Source: Morris G, Puri BK, Walker AJ, Maes M, Carvalho AF, Walder K, Mazza C, Berk M. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: From Pathophysiological Insights to Novel Therapeutic Opportunities. Pharmacol Res. 2019 Sep 8:104450. doi: 10.1016/j.phrs.2019.104450. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31509764

Phylogenetic Tree-based Microbiome Association Test

Abstract:

MOTIVATION: Ecological patterns of the human microbiota exhibit high inter-subject variation, with few operational taxonomic units (OTUs) shared across individuals. To overcome these issues, non-parametric approaches, such as the Mann-Whitney U-test and Wilcoxon rank-sum test, have often been used to identify OTUs associated with host diseases. However, these approaches only use the ranks of observed relative abundances, leading to information loss, and are associated with high false-negative rates. In this study, we propose a phylogenetic tree-based microbiome association test (TMAT) to analyze the associations between microbiome OTU abundances and disease phenotypes. Phylogenetic trees illustrate patterns of similarity among different OTUs, and TMAT provides an efficient method for utilizing such information for association analyses. The proposed TMAT provides test statistics for each node, which are combined to identify mutations associated with host diseases.

RESULTS: Power estimates of TMAT were compared with existing methods using extensive simulations based on real absolute abundances. Simulation studies showed that TMAT preserves the nominal type-1 error rate, and estimates of its statistical power generally outperformed existing methods in the considered scenarios. Furthermore, TMAT can be used to detect phylogenetic mutations associated with host diseases, providing more in-depth insight into bacterial pathology.

AVAILABILITY: The 16S rRNA amplicon sequencing metagenomics datasets for colorectal carcinoma and myalgic encephalomyelitis/chronic fatigue syndrome are available from the European Nucleotide Archive (ENA) database under project accession number PRJEB6070 and PRJEB13092, respectively. TMAT was implemented in the R package. Detailed information is available at http://healthstat.snu.ac.kr/software/tmat.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

© The Author(s) (2019). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Source: Kim KJ, Park J, Park SC, Won S. Phylogenetic Tree-based Microbiome Association Test. Bioinformatics. 2019 Sep 3. pii: btz686. doi: 10.1093/bioinformatics/btz686. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31504188

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology that is recognized by the World Health Organization (WHO) and the United States Center for Disease Control and Prevention (US CDC) as a disorder of the brain. The disease predominantly affects adults, with a peak age of onset of between 20 and 45 years with a female to male ratio of 3:1. Although the clinical features of the disease have been well established within diagnostic criteria, the diagnosis of ME/CFS is still of exclusion, meaning that other medical conditions must be ruled out.

The pathophysiological mechanisms are unclear but the neuro-immuno-endocrinological pattern of CFS patients gleaned from various studies indicates that these three pillars may be the key point to understand the complexity of the disease. At the moment, there are no specific pharmacological therapies to treat the disease, but several studies’ aims and therapeutic approaches have been described in order to benefit patients’ prognosis, symptomatology relief, and the recovery of pre-existing function.

This review presents a pathophysiological approach to understanding the essential concepts of ME/CFS, with an emphasis on the population, clinical, and genetic concepts associated with ME/CFS.

Source: Cortes Rivera M, Mastronardi C, Silva-Aldana CT, Arcos-Burgos M, Lidbury BA. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review. Diagnostics (Basel). 2019 Aug 7;9(3). pii: E91. doi: 10.3390/diagnostics9030091. https://www.ncbi.nlm.nih.gov/pubmed/31394725

Suggested pathology of systemic exertion intolerance disease: Impairment of the E3 subunit or crossover of swinging arms of the E2 subunit of the pyruvate dehydrogenase complex decreases regeneration of cofactor dihydrolipoic acid of the E2 subunit

Abstract:

Systemic Exertion Intolerance Disease (SEID) or myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) has an unknown aetiology, with no known treatment and a prevalence of approximately 22 million individuals (2%) in Western countries. Although strongly suspected, the role of lactate in pathology is unknown, nor has the nature of the two most central symptoms of the condition – post exertional malaise and fatigue. The proposed mechanism of action of pyruvate dehydrogenase complex (PDC) plays a central role in maintaining energy production with cofactors alpha-lipoic acid (LA) and its counterpart dihydrolipoic acid (DHLA), its regeneration suggested as the new rate limiting factor.

Decreased DHLA regeneration due to impairment of the E3 subunit or crossover of the swinging arms of the E2 subunit of PDC have been suggested as a cause of ME/CFS/SEID resulting in instantaneous fluctuations in lactate levels and instantaneous offset of the DHLA/LA ratio and defining the condition as an LA deficiency with chronic instantaneous hyperlactataemia with explicit stratification of symptoms. While instantaneous hyperlactataemia has been suggested to account for the PEM, the fatigue was explained by the downregulated throughput of pyruvate and consequently lower production of ATP with the residual enzymatic efficacy of the E3 subunit or crossover of the E2 as a proposed explanation of the fatigue severity. Functional diagnostics and visualization of instantaneous elevations of lactate and DHLA has been suggested.

Novel treatment strategies have been implicated to compensate for chronic PDC impairment and hyperlactataemia. This hypothesis potentially influences the current understanding and treatment methods for any type of hyperlactataemia, fatigue, ME/CFS/SEID, and conditions associated with PDC impairment.

Copyright © 2019. Published by Elsevier Ltd.

Source: Bohne VJB, Bohne Ø.Suggested pathology of systemic exertion intolerance disease: Impairment of the E3 subunit or crossover of swinging arms of the E2 subunit of the pyruvate dehydrogenase complex decreases regeneration of cofactor dihydrolipoic acid of the E2 subunit. Med Hypotheses. 2019 Sep;130:109260. doi: 10.1016/j.mehy.2019.109260. Epub 2019 Jun 14. https://www.ncbi.nlm.nih.gov/pubmed/31383326

Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

The underlying molecular basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”) and variably presenting, multi-system symptoms, ME/CFS is a complex disease which demands concerted biomedical investigation from disparate fields of expertise.

ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is largely comprised of disturbances to immunological and inflammatory pathways, autonomic and neurologic systems, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiome disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift affecting each of these systems.

Due to the variability of non-overlapping symptom presentation or precipitating events such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.

Source: Missailidis, D.; Annesley, S.; Fisher, P. Pathological Mechanisms Underlying Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Preprints 2019, 2019070196 (doi: 10.20944/preprints201907.0196.v1). https://www.preprints.org/manuscript/201907.0196/v1

Red blood cell biomechanics in Chronic Fatigue Syndrome

INTRODUCTION:

Chronic Fatigue Syndrome (CFS) is a multi-systemic illness of unknown etiology, affecting millions worldwide [1], with the capacity to persist for several years. It is characterized by persistent or relapsing unexplained fatigue of at least 6 months’ duration that is not alleviated by rest. CFS can be debilitating, and its clinical definition includes a broad cluster of symptoms and signs that give it its distinct character, and its diagnosis is based on these characteristic symptom patterns including cognitive impairment, post-exertional malaise, unrefreshing sleep, headache, hypersensitivity to noise, light or certain food items. Although an abnormal profile of circulating proinflammatory cytokines, and the presence of chronic oxidative and nitrosative stresses have been identified and correlated with severity in CFS [2], there are no reliable molecular or cellular biomarkers of the disease.

Read the rest of this article HERE.

Source: Saha, Amit & R. Schmidt, Brendan & Kumar, Arun & Saadat, Amir & C. Suja, Vineeth & Nguyen, Vy & K. Do, Justin & Ho, Wendy & Nemat-Gorgani, Mohsen & Shaqfeh, Eric & Ramasubrmanian, Anand & Davis, Ronald. (2019). Red Blood Cell Biomechanics in Chronic Fatigue Syndrome. Summer Biomechanics, Bioengineering and Biotransport Conference. June 25 -28, Seven Springs, PA, USA

Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases

Abstract:

Post-exertional malaise (PEM) is a cardinal predictive symptom in the definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). If the cases overexert themselves they have what is termed “payback” resulting in a worsening of symptoms or relapse which can last for days, weeks or even months. The aim was to assess the changes in biochemistry associated with the cases self-reported PEM scores over a 7-day period and the frequency of reporting over a 12-month period.

Forty-seven ME/CFS cases and age/sex-matched controls had a clinical examination, completed questionnaires; were subjected to standard serum biochemistry; had their serum and urine metabolomes analyzed in an observational study. Thirty-five of the 46 ME/CFS cases reported PEM in the last 7-days and these were allocated to the PEM group.

The principal biochemical change related to the 7-day severity of PEM was the fall in the purine metabolite, hypoxanthine. This decrease correlated with alterations in the glucose:lactate ratio highly suggestive of a glycolytic anomaly. Increased excretion of urine metabolites within the 7-day response period indicated a hypermetabolic event was occurring. Increases in urine excretion of methylhistidine (muscle protein degradation), mannitol (intestinal barrier deregulation) and acetate were noted with the hypermetabolic event.

These data indicate hypoacetylation was occurring, which may also be related to deregulation of multiple cytoplasmic enzymes and DNA histone regulation. These findings suggest the primary events associated with PEM were due to hypoacetylation and metabolite loss during the acute PEM response.

Source: Neil R. McGregor, Christopher W. Armstrong , Donald P. Lewis and Paul R. Gooley. Post-Exertional Malaise Is Associated with Hypermetabolism, Hypoacetylation and Purine Metabolism Deregulation in ME/CFS Cases. Diagnostics 2019, 9(3), 70; https://doi.org/10.3390/diagnostics9030070 https://www.mdpi.com/2075-4418/9/3/70/htm (Full article)