Cell-based blood biomarkers for ME/CFS

Posted on 03/01/2020 by wames

Cell-based blood biomarkers for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, by Daniel Missailidis, Oana Sanislav, Claire Y Allan, Sarah J Annesley, Paul R Fisher in Int. J. Mol. Sci. 2020, 21(3), 1142; [doi.org/10.3390/ijms21031142]

 

Research 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 monocytic 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 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 biomarker with better than 90% sensitivity but only modest specificity vis a vis 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.

 

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Associations of occupational stress, workplace violence & organizational support on chronic fatigue symptoms among nurses

Posted on 02/27/2020 by wames

Associations of occupational stress, workplace violence and organizational support on chronic fatigue symptoms among nurses, by Dr Mengyao Li, Dr Qianyi Shu, Dr Hao Huang, Dr Wen Bo, Dr Lulu Wang, Dr Hui Wu in Jan 14312 03 February 2020[https://doi.org/10.1111/jan.14312]

 

Research abstract:

Aims:
Chronic fatigue syndrome is an agnogenic disease worldwide. Nurses are at a high risk of chronic fatigue syndrome. However, no research has been done to examine the associations of workplace violence, organizational support and occupational stress with chronic fatigue syndrome among Chinese nurses. This study aimed to examine effects of these factors on chronic fatigue syndrome in this occupational group.

Design:
Cross‐sectional. All participants voluntarily completed a questionnaire survey.

Methods:
The study was conducted in Liaoning province from December 2017 to January 2018. Self‐administered questionnaires were distributed to 1200 nurses, including Effort‐Reward‐Imbalance, Workplace Violence Scale, Survey of Perceived Organizational Support, together with age, gender, marital status, education levels, physical activities, job rank, monthly income and weekly working hours. Complete responses were obtained from 1080 (90%) participants. Chronic fatigue syndrome was diagnosed by doctors according to the Centers for Disease Control and Prevention criteria. Multivariable logistic regression was performed to examine these independent risk factors.

Results:
The prevalence of chronic fatigue syndrome was 6.76%. The results of logistic regression analysis showed that nurses who experienced serious higher levels of overcommitment, workplace violence and less organizational support were more likely to be classified as chronic fatigue syndrome.

Conclusion:
There was a high prevalence of chronic fatigue syndrome. Lower workplace violence, more organizational support and lower overcommitment could be effective resources for reducing chronic fatigue syndrome.

Impact:
Workplace violence, organizational support and occupational stress were related to chronic fatigue syndrome, which helped to explain why Chinese nurses suffered higher prevalance of chronic fatigue syndrome. Overcommitment explained chronic fatigue syndrome better than Effort/Reward Ratio, so intrinsic stress played a more critical role than extrinsic stress in chronic fatigue syndrome. Chinese nurses suffered serious sleep disorders and impairment of concentration and memory. These symptoms might also attributed to serious occupational stress, unsafe and unsupportive working environment. Creating a safe and supportive working environment, relieving intrinsic occupational stress should be considered as an institutional strategy to early prevent chronic fatigue syndrome.

Read full paper

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Carnitine conjugation profiling in a selected cohort of patients with CFS

Posted on 02/26/2020 by wames

Carnitine conjugation profiling in a selected cohort of patients with CFS, by L Du Plessis. MSc BioChem Dissertation 2019, North West University, South Africa.  21648859

 

Research abstract:

Chronic fatigue syndrome (CFS) is classified by the World Health Organisation (WHO) as a non-communicable disease. Fatigue is a symptom commonly experienced by many individuals and is also a symptom associated with a wide variety of diseases, but once this fatigue becomes long lasting, persistent and debilitating, a case of CFS is considered.

Research of CFS dates back to the nineteen hundreds, but unfortunately, no definite underlying cause or one single positive treatment has been identified. Diagnosis also poses a difficult task due to different criteria available, but also because of the lack in confidence of diagnosing doctors in making a positive diagnosis, because this disease is still poorly understood.

Recent studies and research found promising evidence that mitochondrial dysfunction may be considered as a possible underlying cause of CFS. Because mitochondria are responsible for the release of energy in cells, the connection between mitochondrial dysfunction and the underlying energy deficiency in CFS patients may indicate a good starting point for further investigation. L-carnitine plays an important role in energy metabolism and could possibly be used as potential biomarkers for energy related diseases such as CFS.

The first part of the study focused on method development and validation. A pre-existing high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method coupled with electrospray ionisation (ESI) was further developed and validated to simultaneously quantify

The second part of the study included application of the developed and validated method to urine samples of controls and possible CFS patients. All carnitines of interest could be detected and identified with this method, although the longer chain aclylcarnitines posed some difficulty. The aim of this study was to identify altered acylcarnitine profiles associated with possible CFS patients compared to control samples. At the end, principal component analysis (PCA) statistical analysis could not differentiate between the two groups, but two acylcarnitines were identified by the Mann Whitney test to have significant p-values, namely octanoylcarnitine (C8) and decanoylcarnitine (C10).

Although the method can be applied for acylcarnitine identification in urine samples, it is advised to pay attention to detecting the long chain acylcarnitines more efficiently in order to get the whole profile for comparison.

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A critical review to investigate CFS as Sleep Disorder

Posted on 02/25/2020 by wames

A critical review to investigate Chronic Fatigue Syndrome as Sleep Disorder
Aman Gupta, Ramesh C Deka and Shruti Gupta in EC Neurology 12:1 (2020): 01-10

 

Review abstract:

Introduction: Chronic fatigue syndrome is associated with marked fatigue and sleep disturbance specifically the non-restorative sleep. This has led to a though process among the Scientists to rule out possibility of association of CFS with Sleep Disorders. Researchers have tried to investigate the causal relationship between the two by virtue of multiple experiments, however consensus on the same still lacks.

Methods and Results: In current review, critical analysis of individual studies was conducted evaluating credibility of experiments leading to a final opinion pertaining to Chronic Fatigue Syndrome association with Sleep Pathology. Possible overlaps among different mechanisms were also identified to provide robust conclusion.

Conclusion: Current review suggests that Chronic Fatigue Syndrome and Sleep Disorders can be more of comorbid rather than having a causal relationship. Hence there is a mix type of evidence which tries to build relationship between the two but definite conclusion clearly demonstrating CFS as a sleep disorder cannot be reached.

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Biomedical insights that inform the diagnosis of ME/CFS

Posted on 02/24/2020 by wames

Biomedical insights that inform the diagnosis of ME/CFS, by Brett A Lidbury, & Paul R Fisher, in Diagnostics 2020, 10(2), 92; [doi.org/10.3390/diagnostics10020092] (This article belongs to the Special Issue Biomedical Insights that Inform the Diagnosis of ME/CFS)

 

Editorial announcing the publication of a new book:

Prof Brett A Lidbury

It is well known that myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS), whether considered as separate diseases or as the one chronic syndrome, continue to generate debate. Discussions on language, definitions and theoretical parameters continue, but whatever your position, one can now agree that ME and/or CFS (referred to hereafter as ME/CFS) is a disease with a physiological basis, rooted in biochemical and molecular dysfunction in the cells of sick individuals, and not attitudes that can be alleviated by psychological therapies. As a result, biomedical imperatives must now become the focus of research enquiry in order to find clinically translatable answers as soon as possible.

Prof Paul R Fisher

 

This book is intended as a landmark volume to mark this shift in thinking and to consolidate recent fundamental discoveries and biomedical insights as pathways towards tangible diagnostics, and eventual ME/CFS treatments.

Australian researchers, with their collaborators locally and abroad, have been at the forefront of discovery in the biomedical realm, and this book draws together fundamental and applied insights that have emerged from scientific and clinical enquiry.

The consolidation of up-to-date insights into ME/CFS was catalysed by a conference (https://www.emerge.org.au/symposium#.XbIv2iVS-3c) in March 2019 (Geelong, Australia), hosted by Emerge Australia, and several chapters in this volume are based on presentations from this meeting.

Section I—Reviews, Commentaries and Opinions

Section II—Research Results—Biomedical Insights and Diagnostics

Read full editorial – a pdf

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IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS

Posted on 02/24/2020 by wames

IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS, by Jelka Hartwig, Franziska Sotzny, Sandra Bauer, Harald Heidecke, Gabriela Riemekasten, Duska Dragund, Christian Meisel, Claudia Dames, Patricia Grabowski, Carmen Scheibenbogen in Brain, Behavior, & Immunity – Health, 5 February 2020, [doi.org/10.1016/j.bbih.2020.100047]

Highlights:

  • IgG physiologically stimulates β2 AdR signaling.
  • β2 AdR activation by IgG is attenuated in ME/CFS patients.
  • First evidence that IgG from ME/CFS patients differentially modulates β2 AdR ligand signaling.

Abstract:

β2 AdR

Background:
There is emerging evidence of a network of natural autoantibodies against GPCR which is dysregulated in various diseases. β2 adrenergic and M3 and M4 cholinergic receptor (β2 AdR and M3/4 mAChR) antibodies were found to be elevated in a subset of ME/CFS patients.

Methods:
We comparatively analyzed the effects of polyclonal IgG on β2 AdR signaling and immune cell function in vitro. 16 IgG fractions were isolated from serum of 5 ME/CFS patients with elevated (CFS AABhigh) and 5 with normal levels (CFS AABnorm) of β2 AdR autoantibodies, and from 6 healthy controls (HC). The effect of each IgG on β-arrestin recruitment and cAMP production in β2 AdR and M3/4R reporter cell lines was studied. Further effect of each IgG on human monocyte cytokine production and on T cell proliferation in vitro was analyzed. In addition, studies on cytokine production in β2 AdR wild type and knockout mice splenocytes incubated with IgG fractions were performed.

Results:
We found that IgGs from HC could stimulate β-arrestin recruitment and cAMP production in β2 AdR reporter cell lines whereas IgGs from CFS AABhigh had no effect. The IgG-mediated activation of β2 AdR was confirmed in β2 AdR wt and ko mice. In accordance with previous studies IgG fractions from HC inhibited LPS-induced TNFα and stimulated LPS-induced IL-10 production of monocytes.

Further IgG fractions from HC enhanced proliferation of T-cells stimulated with anti-CD3/CD28. IgG fractions from CFS AABhigh patients had no significant effect on both cytokine production and T cell proliferation, while IgGs from CFS AABnorm had an intermediate effect. We could also observe that IgG can modulate the signaling of β2 AdR ligands isoprenline and propranolol.

Conclusions:
We provide evidence that IgG can activate β2 AdR. The β2 AdR activation by IgG is attenuated in ME/CFS patients. A dysregulation of β2 AdR function could explain many symptoms of ME/CFS.

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Investigation into cognitive behavioural therapy for CFS/ME

Posted on 02/20/2020 by wames

Investigation into cognitive behavioural therapy for Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis, by Catherine E Clark . DClinPsych Thesis, Canterbury Christ Church, April 2019

 

Thesis abstract:

Background:

In the UK, CBT is currently recommended as an intervention for CFS/ME. Physical and psychological outcomes of CBT for CFS/ME vary across studies, as does the CBT model adopted. There is some evidence to suggest that some participants experience improved psychological and physical outcomes post CBT. However, the specific nature of these changes and the factors facilitating them is not well understood. This was therefore the focus of the current study.

Methodology:

Semi-structured interviews were conducted with 13 service users who had engaged in CBT aimed at improved management of their condition. Interviews were analysed using a grounded theory methodology, in order to build a theory of participants’ experiences.

Results:

The theory suggests that CBT led to participants feeling more able to cope with CFS/ME. This was due to both a shift in perspective arising from the therapy room and taking a more adaptive approach to daily life. The theory also suggested that participants experienced increased acceptance of the condition, which facilitated further adaptive changes.

Discussion:

Findings extend existing literature in suggesting that CBT aimed to improve management of CFS/ME may result in improved coping and reduced distress, independently of changes in fatigue. Clinical and research implications are discussed.

Thesis summary:

Section A is a systematic review exploring service users’ and their families’ experiences of psycho-social interventions for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). A thematic analysis was completed on the qualitative literature to explore the experience of interventions, the intervention components perceived as helpful and unhelpful and facilitators and barriers to benefitting from interventions. Resulting themes are discussed and study methodologies critiqued. Clinical and research implications are discussed.

Section B presents the results of a grounded theory study of cognitive behavioural therapy (CBT) for CFS/ME, specifically focused on the changes experienced by service users and the therapy components and conditions perceived to facilitate these. Semi-structured interviews were conducted with 13 service users recruited via a specialist CFS/ME service.

In contrast to the NICE guidelines, the model of CBT delivered in this service was not one of ‘reconditioning’ in which service users are supported to increase their activity; instead the goal was better adjustment to CFS/ME to improve quality of life. A theorised model of the therapeutic process is discussed, in which CBT led to participants feeling more able to cope with CFS/ME and experience increased acceptance of the condition. Clinical and research implications are discussed.

Read full thesis

 

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An isolated complex V inefficiency & dysregulated mitochondrial function in immortalized lymphocytes from ME/CFS patients

Posted on 02/20/2020 by wames

An isolated complex V inefficiency and dysregulated mitochondrial function in immortalized lymphocytes from ME/CFS patients, by Daniel Missailidis, Sarah J Annesley, Claire Y Allan, Oana Sanislav, Brett A Lidbury, Donald P Lewis and Paul R Fisher in J. Mol. Sci. 2020, 21(3), 1074; [doi.org/10.3390/ijms21031074]

 

Research 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.

 

A short guide to mitochondria and complex V (you’ll need to sign in)

Mitochondria-Powering the Cell-Science Video

“The Cellular Equivalent of Chronic Fatigue” Found in ME/CFS – the work of Paul Fisher

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News & views in ME/CFS: the role of co-morbidity & novel treatments

Posted on 02/19/2020 by wames

News and views in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): The role of co-morbidity and novel treatments, by F Comhaire, JP Deslypere in Medical Hypotheses Vol 134, January 2020, 109444 [doi.org/10.1016/j.mehy.2019.109444]

 

Research abstract:

Though affecting many thousands of patients, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) should be considered an orphan disease, since the cause remains elusive and no treatment is available that can provide complete cure.

There is reasonable insight into the pathogenesis of signs and symptoms, and treatments specifically directed to immunological, inflammatory and metabolic processes offer relief to an increasing number of patients. Particular attention is given to the importance of co-morbidity requiring appropriate therapy.

Promising results are obtained by treatment with Metformin, or possibly Momordica charantia extract, which will correct insulin resistance, with Meldonium improving the transportation of glucose into the mitochondria, with sodium dichloroacetate activating pyruvate dehydrogenase, and with nutraceutical support reducing oxidative and inflammatory impairment.

Extract from materials & methods:

Sixty four (64) consecutive patients participated in a prospective pragmatic open-label trial. They had been diagnosed to suffer from ME/CFS by certified expert university centres, and consulted at the private clinic of one of the authors (FC). All patients underwent a thorough and systematic evaluation at intake. This included history taking and completion of the fatigue severity score (FSS) [12], propaedeutic physical examination, echography, blood analysis including immunological and endocrinological tests with postprandial C-peptide measurement [13] and essays for the detection of infections, NeuroSPECT fusion imaging of cerebral blood supply [14] and quantitative electro-encephalography (sLORETA) [15].

Patients were offered the option to start a treatment trial with a nutraceutical composed of sodium dichloroacetate, Vitamin B1, Alpha lipoic acid, and Ubiquinone Q10 as described earlier [4]. Six weeks after the intake consultation, patients came back to discuss the results of the examinations, to report on their experience with the nutraceutical, and to complete the FSS once again.

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Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells & extracellular vesicles in ME/CFS

Posted on 02/17/2020 by wames

Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells and extracellular vesicles in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome by Eloy Almenar-Pérez, Leonor Sarría, Lubov Nathanson & Elisa Oltra in Scientific Reports vol 10, no: 2064 (2020)

 

Research 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.

 

Comment: MEA Summary Review: Assessing diagnostic value of microRNAs from PMBC’s and EV’s in ME/CFS  11 February 2020

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