»We could have our first transferable factor in #MECFS blood«
Big news from Prusty Lab at University of Würzburg! But they need financial resources to continue their great work. Now we all can help them out together!
Retweets appreciated! #GOfundMECFShttps://bit.ly/gofundmecfs
Version 1 : Received: 2 February 2020 / Approved: 3 February 2020 / Online: 3 February 2020 (10:36:05 CET)
How to cite: Missailidis, D.; Sanislav, O.; Allan, C.; Annesley, S.; Fisher, P. Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Preprints2020, 2020020029 (doi: 10.20944/preprints202002.0029.v1). Missailidis, D.; Sanislav, O.; Allan, C.; Annesley, S.; Fisher, P. Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Preprints 2020, 2020020029 (doi: 10.20944/preprints202002.0029.v1).
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 vís a vís healthy controls. However, in combination they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS.
A 34-year-old woman suffered from significant chronic pain, depression, non-restorative sleep, chronic fatigue, severe morning stiffness, leg cramps, irritable bowel syndrome, hypersensitivity to cold, concentration difficulties, and forgetfulness. Blood tests were negative for rheumatic disorders. The patient was diagnosed with Fibromyalgia syndrome (FMS). Due to the lack of effectiveness of pharmacological therapies in FMS, she approached a novel metabolic proposal for the symptomatic remission. Its core idea is supporting serotonin synthesis by allowing a proper absorption of tryptophan assumed with food, while avoiding, or at least minimizing the presence of interfering non-absorbed molecules, such as fructose and sorbitol. Such a strategy resulted in a rapid improvement of symptoms after only few days on diet, up to the remission of most symptoms in 2 months. Depression, widespread chronic pain, chronic fatigue, non-restorative sleep, morning stiffness, and the majority of the comorbidities remitted. Energy and vitality were recovered by the patient as prior to the onset of the disease, reverting the occupational and social disabilities. The patient episodically challenged herself breaking the dietary protocol leading to its negative test and to the evaluation of its benefit. These breaks correlated with the recurrence of the symptoms, supporting the correctness of the biochemical hypothesis underlying the diet design toward remission of symptoms, but not as a final cure. We propose this as a low risk and accessible therapeutic protocol for the symptomatic remission in FMS with virtually no costs other than those related to vitamin and mineral salt supplements in case of deficiencies. A pilot study is required to further ground this metabolic approach, and to finally evaluate its inclusion in the guidelines for clinical management of FMS.
Work Rehabilitation and Medical Retirement for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. A Review and Appraisal of Diagnostic Strategies
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome leads to severe functional impairment and work disability in a considerable number of patients. The majority of patients who manage to continue or return to work, work part-time instead of full time in a physically less demanding job. The prognosis in terms of returning to work is poor if patients have been on long-term sick leave for more than two to three years. Being older and more ill when falling ill are associated with a worse employment outcome. Cognitive behavioural therapy and graded exercise therapy do not restore the ability to work. Consequently, many patients will eventually be medically retired depending on the requirements of the retirement policy, the progress that has been made since they have fallen ill in combination with the severity of their impairments compared to the sort of work they do or are offered to do. However, there is one thing that occupational health physicians and other doctors can do to try and prevent chronic and severe incapacity in the absence of effective treatments. Patients who are given a period of enforced rest from the onset, have the best prognosis. Moreover, those who work or go back to work should not be forced to do more than they can to try and prevent relapses, long-term sick leave and medical retirement. View Full-Text
Analysis of the 2008 Cochrane review of cognitive behavioural therapy for chronic fatigue syndrome shows that seven patients with mild chronic fatigue syndrome need to be treated for one to report a small, short-lived subjective improvement of fatigue. This is not matched by an objective improvement of physical fitness or employment and illness benefit status. Most studies in the Cochrane review failed to report on safety or adverse reactions. Patient evidence suggests adverse outcomes in 20 per cent of cases. If a trial of a drug or surgical procedure uncovered a similar high rate, it would be unlikely to be accepted as safe. It is time to downgrade cognitive behavioural therapy to an adjunct support-level therapy, rather than a treatment for chronic fatigue syndrome.
The analysis of the 2017 Cochrane review reveals flaws, which means that contrary to its findings, there is no evidence that graded exercise therapy is effective. Because of the failure to report harms adequately in the trials covered by the review, it cannot be said that graded exercise therapy is safe. The analysis of the objective outcomes in the trials provides sufficient evidence to conclude that graded exercise therapy is an ineffective treatment for myalgic encephalomyelitis/chronic fatigue syndrome.
Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients
Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME) is a debilitating disorder that is accompanied by reduced cytotoxic activity in natural killer (NK) cells. NK cells are an essential innate immune cell, responsible for recognising and inducing apoptosis of tumour and virus infected cells. Calcium is an essential component in mediating this cellular function. Transient Receptor Potential Melastatin 3 (TRPM3) cation channels have an important regulatory role in mediating calcium influx to help maintain cellular homeostasis. Several single nucleotide polymorphisms have been reported in TRPM3genes from isolated peripheral blood mononuclear cells, NK and B cells in patients with CFS/ME and have been proposed to correlate with illness presentation. Moreover, a significant reduction in both TRPM3 surface expression and intracellular calcium mobilisation in NK cells has been found in CFS/ME patients compared with healthy controls. Despite the functional importance of TRPM3, little is known about the ion channel function in NK cells and the epiphenomenon of CFS/ME. The objective of the present study was to characterise the TRPM3 ion channel function in NK cells from CFS/ME patients in comparison with healthy controls using whole cell patch-clamp techniques.
Methods
NK cells were isolated from 12 age- and sex-matched healthy controls and CFS patients. Whole cell electrophysiology recording has been used to assess TRPM3 ion channel activity after modulation with pregnenolone sulfate and ononetin.
Results
We report a significant reduction in amplitude of TRPM3 current after pregnenolone sulfate stimulation in isolated NK cells from CFS/ME patients compared with healthy controls. In addition, we found pregnenolone sulfate-evoked ionic currents through TRPM3 channels were significantly modulated by ononetin in isolated NK cells from healthy controls compared with CFS/ME patients.
Conclusions
TRPM3 activity is impaired in CFS/ME patients suggesting changes in intracellular Ca2+ concentration, which may impact NK cellular functions. This investigation further helps to understand the intracellular-mediated roles in NK cells and confirm the potential role of TRPM3 ion channels in the aetiology and pathomechanism of CFS/ME.
Damning criticism of the flawed #PACEtrial in a new book by Prof Brian Hughes on the “rampant methodological crisis” in psychology.
'Rampant methodological crisis' - describes how psychologists invent their own study methods, change them part way if the data don't fit their preconceptions, misuse stats etc.
“The controversies surrounding the PACE trial can be seen as emblematic of the real-world problems caused by psychology’s many crises.”
From p. 140:
That the PACE Trial continues to be so doggedly defended, despite a litany of damaging critiques, shows us how psychologists can retain an unswerving allegiance to their own ideas.
By Tom Whipple, Science Editor,
August 21 2018, 12:01am, The Times
More than a hundred academics have joined ten MPs and scores of patient groups from around the world to sign an open letter calling for The Lancet to reanalyse a study into treatment for myalgic encephalomyelitis (ME).
The letter follows a debate in parliament in which one MP said that the study, which is used to set NHS guidelines, “will go down as one of the biggest medical scandals of the 21st century”. The authors of the research paper stood by their findings and said that the letter represented a campaign to discredit solid research and force the retraction of papers simply because patients disagreed with their findings.
The signatories, who include academics from Harvard, Stanford, UCL and the London School of Hygiene and Tropical Medicine, said that the 2011 Pace trial, which recommended therapy and exercise as a treatment for the condition, had “major flaws” and “unacceptable methodological lapses”.
The £5 million publicly funded trial was published in The Lancet and has informed advice on treating people with ME in the NHS and abroad, but is controversial among ME sufferers. Some claim that its advice perpetuates an idea that the disease, which causes debilitating disability, is all in the mind.
Review of the FatiGo trial (Vos-Vromans), one of the 13 pieces of evidence NICE will review. FatiGo, a trial with many problems including ignoring its own results.
The FatiGo trial concluded that multidisciplinary rehabilitation treatment is more effective for chronic fatigue syndrome/myalgic encephalomyelitis in the long term than cognitive behaviour therapy and that multidisciplinary rehabilitation treatment is more cost-effective for fatigue and cognitive behaviour therapy for quality of life. However, FatiGo suffered from a number of serious methodological flaws. Moreover, it ignored the results of the activity metre, its only objective outcome. This jeopardizes the validity of FatiGo. Its analysis shows that there was no statistically significant difference between multidisciplinary rehabilitation treatment and cognitive behaviour therapy and neither are (cost-)effective. FatiGo’s claims of efficacy of multidisciplinary rehabilitation treatment and cognitive behaviour therapy for chronic fatigue syndrome/myalgic encephalomyelitis are misleading and not justified by their results.
No problem making Endpoint changes during an unblinded trial if your mates who also ignore all the evidence that #MEcfs is a physical disease (PACE trial's Alastair Miller (infectious disease specialist and former Action for ME Medical advisor, the only "ME charity" that was part of the PACE trial and psychologist Rona Moss- Morris) are the trial steering committee and your PACE trial mates are part of the Data Monitoring and Ethics Committee.
GETSET Data Monitoring and Ethics Committee (DMEC):
Astrid Fletcher, Charlotte Feinman and Irwin Nazareth who has co-authored MEcfs articles with Esther Crawley and Peter D. White ...
PACE trial Data Monitoring and Ethics Committee (DMEC):
Professor Paul Dieppe (initial chair), Dr Charlotte Feinmann (liaison psychiatrist) and
Professor Astrid Fletcher (final Chair, epidemiologist).
In 2012 a group of doctors in the UK wrote a letter to the Independent on Sunday and all British newspapers to condemn the harassment and death threats by patients of Simon Wessely of which he had never provided any evidence; the foi commissioner last year ruled that the psychiatrists had grossly exaggerated things/made things up and that there were no death threats.
Amongst those signing that letter were:
the three principal investigators of the PACE trial (Peter White, Michael Sharpe and Trudie Chalder), Alastair Miller, Rona Moss-Morris, Charlotte Feinmann, Esther Crawley, and MEGA's chairman Stephen Holgate.
http://www.independent.co.uk/voices/letters/ios-letters-emails-online-postings-2-december-2012-8373777.html
By Mark Vink, (Family Physician) the author of the 2016 Review of the PACE trial for which he was nominated for the John Maddox Prize for Standing up for Science.
If CBT and GET had really been effective there would have been no need for an extensive number of changes to the recovery criteria made during an unblinded trial, making the definition much less accurate to the point that people who were still (severely) ill were classed as recovered.
The time has now come for the PACE trial authors to stop misrepresenting their own results; acknowledge the inefficacy and harmfulness of CBT and GET to prevent further unnecessary suffering inflicted on patients by physicians/therapists, which is the worst of all harms, yet totally preventable.
Daniel Missailidis
Silvia Maria Lattanzio
Francesca Imbesi
Mark Vink 
