Central sensitization: a pathogenic mechanism in complex undefined diseases

Central sensitization: A pathogenic mechanism in complex undefined diseases, by Joaquim Fernández-Solà, in Neuropsychiatry (London) 2019: 9(6), 2485–2490

 

Abstract:

There is a common perception that complex undefined diseases manifested with diverse combination of symptoms and a difficult clinical diagnosis have a possible common physiological mechanism of disease production.

Physical or cognitive fatigue, widespread pain without arthritis, sleep, mood and autonomic disturbances as well as multiple intolerance involving drug, food, chemical agents, electromagnetic fields or other environmental factors may be included in this category.

Along last three decades, the existence of central sensitivity as a well established common pathogenic mechanism involved in abnormal symptom development emerged in diverse areas as pain, fatigue, food and environmental intolerance, as well as in the global chronic disease epidemic. The common fact of all of these disorders is a deregulation of the central control mechanisms at the limbic brain system. This may relate to amplification of pain and fatigue perception and disturbance of environmental tolerance and control of circadian rhythms and mood.

This deregulation causes amplification of central somatosensory perception, but also a decrease of nociceptive inhibitory outputs. The final result is a chronic condition with central hyperexcitability and systemic disabling symptoms highly difficult to manage.

This article comments on the current significance to evaluate central sensitization symptoms and to consider these mechanisms in the development of complex diseases, as well as in the global chronic disease epidemic. We propose to include central sensitization to structuring a multidisciplinary concept addressed to improve scientific comprehension and clinical management of diseases, as well as future research directions on this field.

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An investigation into the modulation of T cell phenotypes by amitriptyline & nortriptyline

An investigation into the modulation of T cell phenotypes by amitriptyline and nortriptyline, by JonathanRoyds, Melissa J Conroy, Margaret R Dunne, Connail McCrory, Joanne Lysaght in European Neuropsychopharmacology, Dec 2019[doi.org/10.1016/j.euroneuro.2019.12.106]

 

Research abstract:
Amitriptyline is prescribed for treating the symptoms of neuroinflammatory disorders including neuropathic pain and fibromyalgia. As amitriptyline has evidence of modulating the neuroimmune interface; the effects of amitriptyline treatment on T-cell phenotype and function were examined in vitro. Peripheral blood mononuclear cells (PBMCs) were isolated and treated with amitriptyline, nortriptyline and a combination of both drugs. Toxicity for T-cells was assessed by Annexin V/Propidium Iodide staining. Activation status and cytokine expression by T-cells post treatment was assessed by flow cytometry.

The levels of secreted cytokines, chemokines and neurotrophins were measured by ELISA in the supernatants. There was no significant increase in T-cell death following 24 or 48 h compared to controls. There were significantly lower frequencies of CD8+ T-cells after treatment with amitriptyline, nortriptyline and a combination of both compared to a Vehicle Control(VC)(p<0.001). The frequencies of naive CD8+CD45RA+ cells were significantly lower after amitriptyline, nortriptyline and a combination of both (p<0001).

The frequencies of CD27+CD4+(p<0.05) and CD27+CD8+(p<0.01) T-cells were also significantly lower following combination drug treatment. Significantly lower frequencies of IFN-γ-producing CD8+ T-cells were observed with all treatment combinations(p<0.05) and frequencies of IL-17-producing CD4+ and CD8+ T-cells were significantly lower following amitriptyline treatment (p<0.05).

Frequencies of Natural Killer T-cells were significantly higher following treatment with nortriptyline (p<0.05). Significantly higher levels of IL-16 (p<0.001) and lower levels of TNF-β (p<0.05) were observed in supernatants. This data indicates that both amitriptyline and nortriptyline modulate the phenotype and function of T-cells and this may have clinical relevance in the pathologies of its off-label applications.

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Register your interest today in taking part in ME/CFS genome-wide research!

The ME/CFS Biomedical Partnership Genome-wide association study

The ME/CFS Biomedical Partnership is working on a funding application to be made in early 2020 to the MRC/NIHR for a genome-wide association study.

 

How can we help?

They need to demonstrate to the funders that they can recruit 20,000 people to participate so they are asking people to sign up to a mailing list to keep updated on the application progress. Additionally, UK residents can log their potential interest in being involved in the research itself and they need as many people as possible to do this.

Sign up here: https://mebiomed.org.uk/get-involved/

What is a genome-wide association study?

A genome-wide association study (GWAS) is a very large genetic study that seeks to uncover some of the biological roots of ME/CFS. By probing small DNA differences among people, a GWAS can help to pinpoint the genetic causes of disease and then can help to guide drug development.

This design has previously provided helpful in identifying genes together with molecular and cellular pathways to contribute to disease risk. Read more about the science of GWAS.

The ME/CFS Biomedical Partnership website: https://mebiomed.org.uk/

More information: https://mecfsresearchreview.me/2020/01/08/sign-up-your-support-could-help-win-funding-for-a-game-changing-me-cfs-study/

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WAMES helpline holiday hours 2019-2020

WAMES helpline hours

The WAMES helpline is run by volunteers and will be closed over the festive period.

 

Support bricksWe apologise that due to extra pressures on the team in January, the closure will last longer than usual. Feel free to email queries and we will reply as soon as possible.

helpline@wames.org.uk  0290 2051 5061

  • 23 December – 12 January  closed
  • 13 January onwards 10-7pm

 

For emotional support, the Samaritans can be contacted 24 hours a day, 7 days a week.

English – 116 123 – free number (24 hours a day, 7 days a week)

Cymraeg – 0808 164 0123 – free number (check times on the website)

 

Children and young people up to age 25 can also contact Meic by phone, email, SMS text and instant messaging.

  • 8am to midnight, 7 days a week
  • FREEPHONE: 0808 80 23456
  • SMS TEXT: 84001
  • IM/Webchat: www.meic.cymru
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Minireview for CFS & its medical attention recently

Minireview for Chronic Fatigue Syndrome and its medical attention recently, by Chang-Gue Son in J Korean Med. 2019;40(4):84-90 [http://dx.doi.org/10.13048/jkm.19043]

 

Review abstract:

Objectives: Chronic fatigue syndrome (CFS) is a debilitating illness impairing seriously quality of life, while CFS would be an optimized target disorder of Korean medicine. This study aims to present the recent information especially in aspect of medical policy and new diagnosis criteria for CFS.

Methods: The literature survey was conducted using the terms of “chronic fatigue syndrome”, “myalgic encephalomyelitis” and “fibromyalgia” in PubMed database and Google database in its entirety from January 2011 to February 2019. The in-depth review was made focusing on the changes in policy and medical perspective for CFS.

Results: Recently large medical attentions and researches for CFS have been existed worldwide. By supporting of USA government, IOM made a report which leaded to a turning point in clinical practices and research in 2015. This report recommended a new name of CFS to systemic exertion intolerance disease (SEID), and new diagnostic criteria focusing on post-exertional malaise, unrefreshing sleep, cognitive impairment and orthostatic intolerance. The medical perspective also was changed into “a serious, chronic, complex, systemic disease” from a psychological-like disorder, and then UAS and EU governments sharply increased the research grants.

Conclusions: This study provided practitioners in Korean medicine (KM) a core information about the recent changes in CFS-related perspectives. This review would be helpful for KM-derived researches or therapeutics development for CFS.

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Transient receptor potential melastatin 2 channels are overexpressed in ME/CFS patients

Transient receptor potential melastatin 2 channels are overexpressed in myalgic encephalomyelitis/chronic fatigue syndrome patients, by Cassandra Balinas, Helene Cabanas, Donald Staines, Sonya Marshall-Gradisnik in Journal of Translational Medicine Vol 17, #1, p 401, December 3, 2019

 

Research abstract:

Background:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is hallmarked by a significant reduction in natural killer (NK) cell cytotoxicity, a mechanism tightly regulated by calcium (Ca2+). Interestingly, interleukin-2 (IL-2) increases NK cell cytotoxicity. Transient receptor potential melastatin 2 (TRPM2) ion channels are fundamental for Ca2+ signalling in NK cells.

This pilot investigation aimed to characterise TRPM2 and CD38 surface expression in vitro on NK cells in ME/CFS patients. This investigation furthermore examined the pharmaceutical effect of 8-bromoadenosine phosphoribose (8-Br-ADPR) and N6-Benzoyladenosine-3′,5′-cyclic monophosphate (N6-Bnz-cAMP) on TRPM2 and CD38 surface expression and NK cell cytotoxicity between ME/CFS and healthy control (HC) participants.

Methods:
Ten ME/CFS patients (43.45  p/m  12.36) and 10 HCs (43  p/m  12.27) were age and sex-matched. Isolated NK cells were labelled with fluorescent antibodies to determine baseline and drug-treated TRPM2 and CD38 surface expression on NK cell subsets. Following IL-2 stimulation, NK cell cytotoxicity was measured following 8-Br-ADPR and N6-Bnz-cAMP drug treatments by flow cytometry.

Results:
Baseline TRPM2 and CD38 surface expression was significantly higher on NK cell subsets in ME/CFS patients compared with HCs. Post IL-2 stimulation, TRPM2 and CD38 surface expression solely decreased on the CD56DimCD16+ subset. 8-Br-ADPR treatment significantly reduced TRPM2 surface expression on the CD56BrightCD16Dim/− subset within the ME/CFS group. Baseline cell cytotoxicity was significantly reduced in ME/CFS patients, however no changes were observed post drug treatment in either group.

Conclusion:
Overexpression of TRPM2 on NK cells may function as a compensatory mechanism to alert a dysregulation in Ca2+ homeostasis to enhance NK cell function in ME/CFS, such as NK cell cytotoxicity. As no improvement in NK cell cytotoxicity was observed within the ME/CFS group, an impairment in the TRPM2 ion channel may be present in ME/CFS patients, resulting in alterations in [Ca2+]i mobilisation and influx, which is fundamental in driving NK cell cytotoxicity. Differential expression of TRPM2 between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in ME/CFS.

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Paediatric CFS patients’ & parents’ perceptions of recovery

Paediatric chronic fatigue syndrome patients’ and parents’ perceptions of recovery, by Matthew Robert Harland, Roxanne Morin Parslow, Nina Anderson, Danielle Byrne, Esther Crawley in BMJ Paediatrics Open Vol 3, #1, Dec 2, 2019

 

Research abstract:

What is known about the subject?

  • Little is known about how to define recovery in the paediatric chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) population.

What this study adds?

  • Children and their parents struggle to define what would constitute a complete recovery as CFS/ME has become a ‘new normal’.
  • There is wide variation in definitions of recovery between individuals.
  • Recovery definitions go beyond symptom reduction and focus on returning to or achieving the same activity as peers, without payback and with flexibility in routine.

Objectives:
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is common in children and adolescents; however, little is known about how we should define recovery. This study aims to explore perceptions of recovery held by paediatric patients with CFS/ME and their parents.

Methods:
Children with CFS/ME and their parents were recruited through a single specialist paediatric CFS/ME service. Data were collected through semistructured interviews with children and parents. The interview questions explored how participants would know if they/their child had recovered from CFS/ME. Thematic analysis was used to identify patterns within the data.

Results:
Twenty-one children with CFS/ME, twenty mothers and two fathers were interviewed. Some children found it hard to define recovery as the illness had become a ‘new normal’. Others thought recovery would indicate returning to pre-morbid levels of activity or achieving the same activity level as peers (socialising, education and leisure activities). Increased flexibility in routines and the absence of payback after activities were important. The interviews highlighted the concept of recovery as highly individual with wide variation in symptoms experienced, type and level of activity that would signify recovery. Parents describe how changes in mood and motivation would signify their child’s recovery, but children did not reflect on this.

Conclusion:
Some parents and children struggle to define what would constitute complete recovery. However, signs of recovery were more easily identifiable. Definitions of recovery went far beyond symptom reduction and were focused towards rebuilding lives.

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A laboratory approach for characterizing chronic fatigue: what does metabolomics tell us?

A laboratory approach for characterizing chronic fatigue: What does metabolomics tell us? by Elardus Erasmus, Shayne Mason, Mari van Reenen, Francois E
Steffens, B Chris Vorster, Carolus J Reinecke in Metabolomics Vol 15, p 158, November 27, 2019

 

Research abstract:

Introduction:
Manifestations of fatigue range from chronic fatigue up to a severe syndrome and myalgic encephalomyelitis. Fatigue grossly affects the functional status and quality of life of affected individuals, prompting the World Health Organization to recognize it as a chronic non-communicable condition.

Objectives:
Here, we explore the potential of urinary metabolite information to complement clinical criteria of fatigue, providing an avenue towards an objective measure of fatigue in patients presenting with the full spectrum of fatigue levels.

Methods:
The experimental group consisted of 578 chronic fatigue female patients. The measurement design was composed of (1) existing clinical fatigue scales, (2) a hepatic detoxification challenge test, and (3) untargeted proton nuclear magnetic resonance (1H-NMR) procedure to generate metabolomics data. Data analysed via an in-house Matlab script that combines functions from a Statistics and a PLS Toolbox.

Results:
Multivariate analysis of the original 459 profiled 1H-NMR bins for the low (control) and high (patient) fatigue groups indicated complete separation following the detoxification experimental challenge. Important bins identified from the 1H-NMR spectra provided quantitative metabolite information on the detoxification challenge for the fatigue groups.

Conclusions:
Untargeted 1H-NMR metabolomics proved its applicability as a global profiling tool to reveal the impact of toxicological interventions in chronic fatigue patients. No clear potential biomarker emerged from this study, but the quantitative profile of the phase II biotransformation products provide a practical visible effect directing to up-regulation of crucial phase II enzyme systems in the high fatigue group in response to a high xenobiotic-load.

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Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with ME/CFS

Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome by Alaa Ghali, Carole Lacout, Maria Ghali, Aline Gury, Anne-Berengere Beucher, Pierre Lozac’h, Christian Lavigne & Geoffrey Urbanski (France) in Nature Scientific Reports vol 9, Article number: 18817 (2019) Published Dec 11, 2019

 

Research abstract:

Elevated blood lactate after moderate exercise was reported in some of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

We hypothesised that blood lactate could be also elevated in resting conditions. We aimed investigating the frequency of elevated lactate at rest in ME/CFS patients, and comparing characteristics of ME/CFS patients with and without elevated lactate.

Patients fulfilling international consensus criteria for ME/CFS who attended the internal medicine department of University hospital Angers-France between October 2011 and December 2017 were included retrospectively. All patients were systematically hospitalised for an aetiological workup and overall assessment. We reviewed their medical records for data related to the assessment: clinical characteristics, comorbidities, fatigue features, post-exertional malaise (PEM) severity, and results of 8 lactate measurements at rest. Patients having ≥1 lactate measurement ≥2 mmol/L defined elevated lactate group.

The study included 123 patients. Elevated (n = 55; 44.7%) and normal (n = 68; 55.3%) lactate groups were comparable except for PEM, which was more severe in the elevated lactate group after adjusting for age at disease onset, sex, and comorbidities (OR 2.47, 95% CI: 1.10–5.55).

ME/CFS patients with elevated blood lactate at rest may be at higher risk for more severe PEM. This finding may be of interest in ME/CFS management.

From the conclusion:

At the best of our knowledge, this is the first study that reports elevated blood lactate in resting conditions in a significant proportion of patients with ME/CFS. Patients who showed abnormal elevation of blood lactate at rest displayed more frequent severe PEM than those with normal lactate concentrations.

This finding brings supplementary evidence for mitochondrial dysfunction in ME/CFS patients, and may contribute to a better understanding the illness.

Subtyping ME/CFS patients adds to the growing body of evidence that ME/CFS is heterogeneous, and allows identifying patients with more risk for severe PEM who must adhere more closely to pacing strategies in order to avoid PEM occurrence and prevent disease exacerbation.

Furthermore, our study allowed describing clinical and biological characteristics of a French population with MPE/CFS. Shedding light on these characteristics may improve knowledge and raise awareness of this public health issue.

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ME/CFS patients exhibit altered T cell metabolism & cytokine associations

Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations, by Alexandra H Mandarano, Jessica Maya, Ludovic Giloteaux, Daniel L Peterson, Marco Maynard, C Gunnar Gottschalk, and Maureen R Hanson in J Clin Invest. 2019. [First published December 12, 2019] https://doi.org/10.1172/JCI132185

 

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease.

ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and post-exertional malaise. There is little known about the metabolism of specific immune cells in ME/CFS patients.

To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 ME/CFS patients and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism, and plasma cytokines.

We found that ME/CFS CD8+ T cells have reduced mitochondrial membrane potential compared to healthy controls. Both CD4+ and CD8+ T cells from ME/CFS patients had reduced glycolysis at rest, while CD8+ T cells also had reduced glycolysis following activation. ME/CFS patients had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from healthy control subjects.

Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.

 

Video: Dr Alexandra Mandarano explains the research in this paper.

NIH press release: Study finds differences in energy use by immune
cells in ME/CFS

Dr. Hanson and her colleagues did not see significant differences in mitochondrial respiration, the cell’s primary energy-producing method, between healthy and ME/CFS cells at rest or after activation. However, results suggest that glycolysis, a less efficient method of energy production, may be disrupted in ME/CFS. Compared to healthy cells, CD4 and CD8 cells from people with ME/CFS had decreased levels of glycolysis at rest. In addition, ME/CFS CD8 cells had lower levels of glycolysis after activation.

“Our work demonstrates the importance of looking at particular types of immune cells that have different jobs to do, rather than looking at them all mixed together, which can hide problems specific to particular cells,” said Dr. Hanson. “Additional studies focusing on specific cell types will be important to unravel what’s gone wrong with immune defenses in ME/CFS.”

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