Research review: Potential implications of TRPM7 in ME/CFS

Posted on 10/21/2021 by wames

Potential implications of mammalian Transient Receptor Potential Melastatin 7 in the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: a review, by  Stanley Du Preez, Helene Cabanas, Donald Staines and Sonya Marshall-Gradisnik in Int. J. Environ. Res. Public Health 2021, 18(20), 10708  [doi.org/10.3390/ijerph182010708] 2 October 2021 (This article belongs to the Special Issue Chronic Fatigue Syndrome: Medical, Nursing and Public Health Management)

 

Research abstract:

The transient receptor potential (TRP) superfamily of ion channels is involved in the molecular mechanisms that mediate neuroimmune interactions and activities. Recent advancements in neuroimmunology have identified a role for TRP cation channels in several neuroimmune disorders including amyotropic lateral sclerosis, multiple sclerosis, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

ME/CFS is a debilitating disorder with an obscure aetiology, hence considerable examination of its pathobiology is warranted. Dysregulation of TRP melastatin (TRPM) subfamily members and calcium signalling processes are implicated in the neurological, immunological, cardiovascular, and metabolic impairments inherent in ME/CFS.

In this review, we present TRPM7 as a potential candidate in the pathomechanism of ME/CFS, as TRPM7 is increasingly recognized as a key mediator of physiological and pathophysiological mechanisms affecting neurological, immunological, cardiovascular, and metabolic processes. A focused examination of the biochemistry of TRPM7, the role of this protein in the aforementioned systems, and the potential of TRPM7 as a molecular mechanism in the pathophysiology of ME/CFS will be discussed in this review.

TRPM7 is a compelling candidate to examine in the pathobiology of ME/CFS as TRPM7 fulfils several key roles in multiple organ systems, and there is a paucity of literature reporting on its role in ME/CFS.

Excerpt from 4. Conclusions

Of particular interest is elucidating the role of TRPM7 in NK cell function in both healthy individuals and ME/CFS patients. Specifically, identifying the importance of TRPM7 in Ca2+ and kinase signalling cascades, as well as regulating intracellular Mg2+ homeostasis and metabolism, in NK cells may serve to facilitate the identification of additional diagnostic and treatment targets to relieve the burden of illness in ME/CFS.

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Diagnostic test research: Autoantibodies & receptors correlate with symptom severity, autonomic dysfunction & disability in ME/CFS

Posted on 10/19/2021 by wames

Autoantibodies to vasoregulative G-Protein-Coupled receptors correlate with symptom severity, autonomic dysfunction and disability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Helma Freitag, Marvin Szklarski, Sebastian Lorenz, Franziska Sotzny, Sandra Bauer, Aurélie Philippe, Claudia Kedor, Patricia Grabowski, Tanja Lange, Gabriela Riemekasten, Harald Heidecke and Carmen Scheibenbogen in J. Clin. Med. 2021, 10(16), 3675; 19 August 2021  (This article belongs to the Special Issue Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Diagnosis and Treatment)

 

Research abstract:

Background:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an acquired complex disease with patients suffering from the cardinal symptoms of fatigue, post-exertional malaise (PEM), cognitive impairment, pain and autonomous dysfunction. ME/CFS is triggered by an infection in the majority of patients. Initial evidence for a potential role of natural regulatory autoantibodies (AAB) to beta-adrenergic (AdR) and muscarinic acetylcholine receptors (M-AChR) in ME/CFS patients comes from a few studies.

Methods:

Here, we analyzed the correlations of symptom severity with levels of AAB to vasoregulative AdR, AChR and Endothelin-1 type A and B (ETA/B) and Angiotensin II type 1 (AT1) receptor in a Berlin cohort of ME/CFS patients (n = 116) by ELISA. The severity of disease, symptoms and autonomic dysfunction were assessed by questionnaires.

Results:

We found levels of most AABs significantly correlated with key symptoms of fatigue and muscle pain in patients with infection-triggered onset. The severity of cognitive impairment correlated with AT1-R- and ETA-R-AAB and severity of gastrointestinal symptoms with alpha1/2-AdR-AAB. In contrast, the patients with non-infection-triggered ME/CFS showed fewer and other correlations.

Conclusion:

Correlations of specific AAB against G-protein-coupled receptors (GPCR) with symptoms provide evidence for a role of these AAB or respective receptor pathways in disease pathomechanism.

Excerpts from: 4. Discussion

There is increasing evidence for a role of vascular dysfunction in ME/CFS that shows associations with key symptoms [11]. In this study, we found several remarkable correlations of vasoregulative AAB with clinical symptoms in ME/CFS.

In conclusion, our study provides evidence that AAB and/or the receptor pathways of AdR, AChR as well as AT1-R and ET-R play a role in ME/CFS due to the association with symptom severity. Thus, it is conceivable that various symptoms of ME/CFS, including fatigue, muscle pain, cognitive impairment and autonomic dysregulation, could be mediated or aggravated by these AAB.

Further studies are required to decipher the mechanism and binding specificity of these GPCR-AAB, and their effect of on vascular function in ME/CFS, and how this may be translated into therapeutic concepts. In the case of dysfunctional AAB, therapies targeting AAB, such as immunoadsorption or rituximab, would be warranted and were shown to be effective in a subset of ME/CFS patients (reviewed in [5]).

Further specific targeting of dysfunctional or regulative AAB may be developed as treatment strategies in ME/CFS.

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Research: Neurochemical abnormalities in CFS

Posted on 10/14/2021 by wames

Neurochemical abnormalities in chronic fatigue syndrome: a pilot magnetic resonance spectroscopy study at 7 Tesla, by Beata R Godlewska, Stephen Williams, Uzay E Emir, Chi Chen, Ann L Sharpley, Ana Jorge Goncalves, Monique I Andersson, William Clarke, Brian Angus, Philip J Cowen in Psychopharmacology, October 5, 2021

 

Research abstract: 

Rationale

Chronic fatigue syndrome (CFS) is a common and burdensome illness with a poorly understood pathophysiology, though many of the characteristic symptoms are likely to be of brain origin. The use of high-field proton magnetic resonance spectroscopy (MRS) enables the detection of a range of brain neurochemicals relevant to aetiological processes that have been linked to CFS, for example, oxidative stress and mitochondrial dysfunction.

Methods

We studied 22 CFS patients and 13 healthy controls who underwent MRS scanning at 7 T with a voxel placed in the anterior cingulate cortex. Neurometabolite concentrations were calculated using the unsuppressed water signal as a reference.

Results

Compared to controls, CFS patients had lowered levels of glutathione, total creatine and myo-inositol in anterior cingulate cortex. However, when using N-acetylaspartate as a reference metabolite, only myo-inositol levels continued to be significantly lower in CFS participants.

Conclusions

The changes in glutathione and creatine are consistent with the presence of oxidative and energetic stress in CFS patients and are potentially remediable by nutritional intervention. A reduction in myo-inositol would be consistent with glial dysfunction. However, the relationship of the neurochemical abnormalities to the causation of CFS remains to be established, and the current findings require prospective replication in a larger sample.

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Legal challenge to NICE ME/CFS Guideline delay

Posted on 10/14/2021 by wames

Legal challenge to NICE ‘pause in publication’

 

On the 1st October a legal action was launched against NICE, claiming the failure to publish the final guideline for ME/CFS was unlawful – that NICE failed to follow it’s own rules – and it should be published by Wed 6 October.

When NICE failed to publish, instead insisting they would aim to make a decision following the 18 October Roundtable discussion, the legal team obtained legal aid to begin the process of applying to take NICE to a Judicial Review.

Who is behind the legal action?

A child diagnosed with post-viral CFS/ME in December 2013 ‘was given treatments according to the current NICE guidelines: CBT where he was instructed not to talk about his symptoms but just push through them and Graded Exercise Therapy [GET] which was a continual gradual increase in activity, regardless of the state he was in. This treatment caused him significant harm… [his] post-exertional malaise [PEM] was ignored… [He] is worried that if he seeks treatment from the NHS he will be further subject to the harmful regimen specified in the NHS by the current NICE guidance.’

The 2021 unpublished  guideline no longer recommends the treatments many say has harmed them, so that is not the focus of the legal action.

Barrister Valerie Elliot Smith says:

“It’s important to remember that this action is concerned with a judicial review of due process, not of the scientific evidence.”

Why is NICE accused of acting unlawfully?

The accusation is based on two principles:

1. Procedural impropriety

“NICE has adopted its manual of methods and procedures for developing its guidelines. It has followed those procedures scrupulously to this point. However, NICE has broken out of its prescribed procedures and now intends to repudiate its procedures and engage in politics. This is a fundamental betrayal of NICE’s constitutional role and prescribed methods. The Claimant intends to ask the court to intervene to prevent this unlawful use of NICE’s powers.”

2. Irrationality

“… In this case it is contended that NICE have acted irrationally in that they have ceased to have regard to scientific evidence, but instead are being materially influenced by irrelevant factors such as whether those who may have commercial interests need to be persuaded to support a change which will adversely affect those interests.”

NICE’s defence

NICE’s lawyers replied late on Wed 6th October to deny the claims because:

  • they have wide discretion
  • ‘NICE guidelines are not binding. They inform the judgement of bodies providing NHS services and their clinicians, nothing more.’
  • ‘The Manual does not expressly provide circumstances justifying a pause in publication of guidelines, but nor does it expressly exclude this possibility’
  • ‘the express purpose of the meeting is to gain support for the Guideline’.

The Lawyers fail to explain why it was necessary to pause publication if all they intend to do is to gather support for the guideline. The unanswered question is whether they are open to making changes before finally publishing. The ME community knows the guideline is not perfect but believes it is a more ‘evidence based’ document than the 2007 guideline. The Royal Colleges and NHS England have said they want some reversal to the treatment recommendations so they can continue to deliver controversial treatments to people with ME.

Should the UK Government intervene?

Steve Topple, in his online article in ‘the Canary’ says the government could intervene if an MP raises the issue formally via an “urgent question” in parliament because:

  • Under the Health and Social Care Act 2012. NICE has an agreement with the Department of Health and Social Care (DHSC) its work is commissioned by ministers or by NHS England several years in advance and the development of individual pieces of guidance can take between 6 months to 2 years.
  • the DHSC secretary of state (currently Sajid Javid) is “accountable to parliament” for NICE and its “performance”. And the DHSC permanent secretary (currently Chris Wormals is responsible for making sure “arrangements are in place” to address significant problems and bring concerns about the activities of NICE to the DHSC board and give assurances that appropriate action has been taken.

Next steps:

Lawyer Peter Todd is preparing papers to file and serve proceedings in the High Court after the Round Table discussion.  Ian Wise QC is being instructed to settle the statement of facts and grounds. 

More information:

Letter before action to NICE

Letter of response from NICE legal team

Valerie Eliot Smith: NICE developments: preparatory action for a judicial review of the decision to pause publication of the new guideline for “ME/CFS”

Steve Topple: NICE will now face court over the ME guidelines debacle, in the Canary

See also

NICE publishes ME/CFS guideline: evidence says GET & CBT cannot cure!

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Dr Muirhead: “the medical profession have massively underestimated hidden disease”

Posted on 10/12/2021 by wames

What long COVID awareness means for people with chronic illnesses

 

Dr Nina Muirhead is quoted in an article by Rachel Charlton-Dailey on the Verywell Health website, September 29, 2021

 

Hopeful for more acceptance and understanding

There is hope in the chronic illness community that interest in long COVID will also trickle down into more acceptance and a better understanding of other illnesses.

“Whilst it feels frustrating…I think that the wave of interest in long COVID will pull up all the little boats of chronic conditions,” Nina Muirhead, MRCS, DOHNS, director of Doctors with M.E., tells Verywell.

Muirhead hopes that long COVID will make “patient experts more culturally acceptable.”

What Is a Patient Expert?
Patient experts are those who have significant knowledge of their disease and treatment in addition to self-management skills. Medical teams will sometimes lean on patient experts as educators for other patients and as a person to provide feedback on care delivery.

“Doctors can’t be expected to know everything,” Muirhead says. But at the same time, once they’ve done all the tests and ruled out what they think a patient’s options might be, healthcare providers shouldn’t “turn around and tell the patient they’re making up [their condition],” she adds.

As a doctor who has a chronic illness herself, Muirhead acknowledges she is in a unique position.

“It was only by being on the patient side that I realized the medical profession have massively underestimated hidden disease,” she says. “I was completely ignorant to the knowledge gap between where I stood, and where [the patient] sat.”

Though it has been difficult for disabled and chronically ill people to see long COVID garner attention and resources their illnesses have never received, the prevailing sentiment is one of goodwill.

Read the full article for more views from a researcher about long COVID and other people with ME.

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Research review: ME/CFS: a neurological entity?

Posted on 10/05/2021 by wames

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A neurological entity?, by Inigo Murga Gandasegui, Larraitz Aranburu Laka, Pascual-Angel Gargiulo, Juan-Carlos Gomez-Esteban, Jose-Vicente Lafuente Sanchez in Medicina Vol 57, #10, p 1030, Sep 27, 2021 [doi.org/10.3390/medicina57101030]

 

Review abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disorder of unknown physiopathology with multisystemic repercussions, framed in ICD-11 under the heading of neurology (8E49). There is no specific test to support its clinical diagnosis.

Our objective is to review the evidence in neuroimaging and dysautonomia evaluation in order to support the neurological involvement and to find biomarkers serving to identify and/or monitor the pathology. The symptoms typically appear acutely, although they can develop progressively over years; an essential trait for diagnosis is ‘central’ fatigue together with physical and/or mental exhaustion after a small effort.

Neuroimaging reveals various morphological, connectivity, metabolic, and functional alterations of low specificity, which can serve to complement the neurological study of the patient. The COMPASS-31 questionnaire is a useful tool to triage patients under suspect of dysautonomia, at which point they may be redirected for deeper evaluation.

Recently, alterations in heart rate variability, the Valsalva maneuver, and the tilt table test, together with the presence of serum autoantibodies against adrenergic, cholinergic, and serotonin receptors were shown in a subgroup of patients. This approach provides a way to identify patient phenotypes. Broader studies are needed to establish the level of sensitivity and specificity necessary for their validation.

Neuroimaging contributes scarcely to the diagnosis, and this depends on the identification of specific changes. On the other hand, dysautonomia studies, carried out in specialized units, are highly promising in order to support the diagnosis and to identify potential biomarkers. ME/CFS orients towards a functional pathology that mainly involves the autonomic nervous system, although not exclusively.

5. Conclusions
The neurobiopathological substrate of ME/CFS is unknown. There currently is no neuroimaging finding or specific laboratory test to establish the diagnosis. Changes reported in volumetry, cerebral blood flow, anatomy, and functional connectivity, at rest as well as in response to stimuli reveal the existence of brain dysfunctions, whose meaning is yet to be determined. The interpretation of findings is complicated by the lack of a consensual study protocol.

The available evidence on the involvement of the autonomic nervous system
(sympathetic/parasympathetic imbalance) indicates that the neurologist plays an essential role in the clinical evaluation of the syndrome and highlights the potential benefits of dysautonomia units for a better understanding of these dysfunctional pathologies.

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IAfME expands & relaunches as World ME Alliance

Posted on 10/05/2021 by wames

International Alliance for ME becomes the World ME Alliance

As a founding member of IAfME, WAMES is excited to be part of the development and launch of the World ME Alliance.

The Alliance is the only organisation in the world to bring together national ME/CFS organisations to advocate for better recognition and treatments for Myalgic Encephalomyelitis at an international level, with a particular aim of targeting the World Health Organization to bring greater focus to all post-viral illness.

Bringing myalgic encephalomyelitis out of the shadows

 

In addition, the World ME Alliance website and events will create a dedicated space for national ME/CFS organisation leaders to share the knowledge, experience and challenges they face in their countries.

This re-launch comes at an important time for ME/CFS globally. Long Covid has shone a light on post-viral disease that has long been missing. Other developments around ME/CFS, such as new guidance published in Mayo Clinic Proceedings and the UK’s much-anticipated National Institute for Health and Care Excellence guideline, will have an impact that reverberates around many countries.

Sonya Chowdhury, chair of the World ME Alliance, tells us:

“Our new website, name, logo and brand will help place us at the fore of international discussions around ME/CFS and other post-viral illnesses.

ME/CFS is a global health crisis, with hundreds of thousands more now being diagnosed with this illness and other post-viral illnesses in the wake of Covid-19.

By working collaboratively, we can expose the devastating impact of these illnesses, and begin to do justice to those desperately in need of research and care.”

The Alliance is currently made up of member organisations from countries including the UK, South Africa, Canada, Spain, Wales, New Zealand and the US. As part of its next steps, it is looking to expand this and bring in more organisations to help shape its future.

Find out more:

www.worldmealliance.org    Read in a variety of languages, including Welsh

Twitter: @WorldMEAlliance

Sian Leary, Communications Officer  sian@worldmealliance.org

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Research: A comprehensive examination of severely ill ME/CFS patients

Posted on 10/01/2021 by wames

A comprehensive examination of severely ill ME/CFS patients, by Chia-Jung Chang, Li-Yuan Hung, Andreas M. Kogelnik, David Kaufman, Raeka S Aiyar, Angela M Chu, Julie Wilhelmy, Peng Li, Linda Tannenbaum, Wenzhong Xiao, Ronald W Davis in Healthcare Vol 9, #10, p 1290, Sep 29, 2021 [doi.org/10.3390/healthcare9101290]

 

Research abstract:

One in four myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients are estimated to be severely affected by the disease, and these house-bound or bedbound patients are currently understudied. Here, we report a comprehensive examination of the symptoms and clinical laboratory tests of a cohort of severely ill patients and healthy controls.

The greatly reduced quality of life of the patients was negatively correlated with clinical depression. The most troublesome symptoms included fatigue (85%), pain (65%), cognitive impairment (50%), orthostatic intolerance (45%), sleep disturbance (35%), post-exertional malaise (30%), and neurosensory disturbance (30%). Sleep profiles and cognitive tests revealed distinctive impairments.

Lower morning cortisol level and alterations in its diurnal rhythm were observed in the patients, and antibody and antigen measurements showed no evidence for acute infections by common viral or bacterial pathogens. These results highlight the urgent need of developing molecular diagnostic tests for ME/CFS.

 

In addition, there was a striking similarity in symptoms between long COVID and ME/CFS, suggesting that studies on the mechanism and treatment of ME/CFS may help prevent and treat long COVID and vice versa.

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Hypothesis: Radiation exposure & mitochondrial insufficiency in CIFDS

Posted on 09/30/2021 by wames

Radiation exposure and mitochondrial insufficiency in chronic fatigue and immune dysfunction syndrome by Andrej Rusin, Megan Li, Alan Cocchetto, Colin Seymour, Carmel Mothersill, in Medical Hypotheses, Vol 154, Sep 2021, 110647 [doi.org/10.1016/j.mehy.2021.110647]

 

Research abstract:

Chronic fatigue and Immune Dysfunction Syndrome (CFIDS) is a heterogeneous disease that may be promoted by various environmental stressors, including viral infection, toxin uptake, and ionizing radiation exposure.

Previous studies have identified mitochondrial dysfunction in CFIDS patients, including modulation of mitochondrial respiratory chain activity, deletions in the mitochondrial genome, and upregulation of reactive oxygen species (ROS).

This paper focuses on radiation effects and hypothesizes that CFIDS is primarily caused by stressor-induced mitochondrial metabolic insufficiency, which results in decreased energy production and anabolic metabolites required for normal cellular metabolism. Furthermore, tissues neighbouring or distant from directly perturbed tissues compensate for this dysfunction, which causes symptoms associated with CFIDS.

This hypothesis is justified by reviewing the links between radiation exposure and CFIDS, cancer, immune dysfunction, and induction of oxidative stress.

Moreover, the relevance of mitochondria in cellular responses to radiation and metabolism are discussed and putative mitochondrial biomarkers for CFIDS are introduced. Implications for diagnosis are then described, including a potential urine assay and PCR test for mitochondrial genome mutations.

Finally, future research needs are offered with an emphasis on where rapid progress may be made to assist the afflicted.

Full paper behind paywall

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Research: ME/CFS is not influenced by the presence or absence of joint hypermobility

Posted on 09/30/2021 by wames

The presentation of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is not influenced by the presence or absence of joint hypermobility, by Sarah K Vogel, Isabelle R Primavera, Colleen L Marden, Marissa AK Flaherty, Richard L Violand, Peter C Rowe in the Journal of Pediatrics Sep 16, 2021 [DOI:https://doi.org/10.1016/j.jpeds.2021.09.014]

 

Research abstract:

Objective
To examine demographic and clinical characteristics of individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with and without joint hypermobility We hypothesized that JH+ patients would have an earlier onset of ME/CFS symptoms as well as increased severity, greater number of co-morbid conditions, and lower health related quality of life.

Study design
From an observational cohort study of 55 individuals meeting the Fukuda criteria for ME/CFS, we compared groups using a Beighton score cut-off of 4 or higher to indicate JH. Chart data were collected to examine the age and type of onset of ME/CFS, and the presence of comorbid conditions. The impact on quality of life was assessed through questionnaires that included the Peds QL, Functional Disability Inventory, Peds QL Multidimensional Fatigue Scale, and Anxiety Subscale of the Symptom Checklist 90.

Results
There was no significant difference between groups in mean (SD) age at onset of ME/CFS (13.3 [3.3] years vs 13.3 [2.3] years; P = .92), sex, frequency, and severity of ME/CFS symptoms, orthostatic intolerance symptoms, or comorbid conditions. There was no significant difference between groups in measures of health-related quality of life using a Beighton score cut-off of 4 or a cut-off of 5 to define joint hypermobility.

Conclusions
Despite being a risk factor for the development of ME/CFS, JH as defined in this study was not associated with other clinical characteristics of the illness.

The full paper is behind a paywall.

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