miRNA profiling of circulating EVs in ME/CFS

Posted on 12/03/2018 by wames

miRNA profiling of circulating EVs in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) by Eloy Almenar-Pérez, Lubov Nathanson, Teresa Sánchez-Fito, Leonor Sarria, Germán Cerdá-Olmedo, Elisa Oltra  in Journal of Extracellular Vesicles, suppl. Supplement 1; Abingdon Vol. 7,  (2018): 139.

 

Research abstract:

Background:

ME/CFS (ICD-10; G93.3) is a complex multisystem disease of unknown origin with characteristic clinical features that include postexertional malaise, cognitive dysfunction, orthostatic intolerance, ongoing flu-like symptoms and unrefreshing sleep in conjunction with other. Its worldwide prevalence is 0.4%–1% with a female to male ratio of 6:1. Current treatments rely on the management of symptoms due to a lack of understanding of the underlying mechanisms of disease onset and progression. The aim of this work was to identify biomarkers of ME/CFS by analysing miRNA profiles of patient plasma EVs and comparing them to those of their PBMCs. This information should improve our knowledge of ME/CFS and allow the development of unbiased quantitative diagnostic methods.

Methods:

miRNA profiles of PBMCs or EVs isolated from plasma (Invitrogen cat.4484450) of  ME/CFS patients and population, sex, age and BMI-matched healthy participants (N = 15 per group) from the ME UK Biobank (London, UK) were determined using Nanostring technology (nCounter Human v3 miRNA Expression Assay Kit).

Gene ontology (GO) and the Kyoto encyclopedia of genes and genomes (KEGG) were used to determine disrupted cellular functions in ME/CFS. The study was approved by the DGSP-CSISP CEIC (ref. UCV201701), Spain. Signed informed consent was required for inclusion of samples.

Results:

miRNA profiles evidenced a global trend for miRNA downregulation in patients with respect to healthy controls (76% and 64% of the miRNAs presented inhibition, by at least 50%, in PBMCs and EVs respectively; while only one miRNA in PBMCs and 6% of them in EVs showed upregulation to this level). Qualitatively, miRNA profiles in PBMCs did not match those obtained from EVs indicating active packaging of miRNAs in EVs. The functions to be affected by the deregulated miRNAs support a model of immune, mitochondrial and neural defects for this disorder.

Summary/Conclusion:

This is the first report of paired PBMCs and EV miRNA profiles of ME/CFS patients by enzyme-free array technology. The results confirm previous proposals that this epigenetic mechanism is linked to the pathophysiology of ME/CFS. Validation studies with expanded cohorts are needed before particular miRNA profiles can be used as biomarkers of ME/CFS in a clinical setting.

Funding: The study was funded by the ME Association’s Ramsay Research Fund (RRF) (UK).

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Online pacing tutorial begins January 2019

Posted on 11/30/2018 by wames

Online Pacing Tutorial

US based ME/CFS & Fibromyalgia Self-help program hold quarterly online tutorials to teach the basics of pacing.

  • Open to to all English language speakers
  • 7 week course
  • Offered quarterly and conducted via email list server, the class is a structured discussion group
  • It is led by trained volunteer moderators, all of whom have ME/CFS and/or FM
  • Register now for classes that begin on Wed 21 Jan 2019. Registration closes on Jan 14.
  • Cost: $20.00 for course alone or $30 / $34 for course and book

The Three Parts of Pacing:

  1. Define Your Current Limits (Energy Envelope)
    The foundation for pacing is understanding your current limits. This includes limits on physical activity, and also mental activity, socializing, sense data, and stress.
  2. Adapt Using Pacing Strategies
    The second part of pacing is adjusting your life so you live within your limits. This is a gradual process, usually involving the use of multiple strategies.
  3. Expand Your Limits
    If you pace consistently, you may be able to expand your limits, doing more without increasing your symptoms.

The effects of pacing can be transformative, but progress is gradual. Learning to pace requires discipline, patience, and time, but you can see benefits immediately from even a small change such as those you’ll find in the tutorial.

NB   People with ME in Wales have found this course helpful, but please check that it is right for you. Ensure you have enough time and energy to make the most of it.

The ME/CFS and Fibromyalgia Self-Help Program is a non-profit organization offering a suite of low-cost and free online self-help courses, plus other resources for people affected by ME/CFS and fibromyalgia.

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Dr Anne McIntyre RIP

Posted on 11/27/2018 by wames

A long time advocate and sufferer of ME, Dr Anne McIntyre, died on Saturday 24th November 2018.  She had been living with rheumatoid arthritis for many years and developed pulmonary fibrosis as a complication of that.

Her book M.E. Chronic Fatigue Syndrome: a practical guide was written in the 1990s but is still considered by many to be one of the most helpful.

She will be remembered for her compassion and willingness to help, and for her work as advisor to the ME Association, and writing and speaking about ME.

 

Read tributes by Dr Charles Shepherd and her friend Jenny Wilson.

Watch Frontline documentary, presented by Dr McIntyre and featuring the Gilderdale family and Ean Proctor.

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Low sensitivity of abbreviated tilt table testing for diagnosing postural tachycardia syndrome in adults with ME/CFS

Posted on 11/26/2018 by wames

Low sensitivity of abbreviated tilt table testing for diagnosing postural tachycardia syndrome in adults with ME/CFS, by C (Linda) M van Campen, Peter C Rowe and Frans C Visser in Front. Pediatr., 16 November 2018

Introduction:

Orthostatic intolerance is common among individuals with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). In some ME/CFS case definitions, orthostatic intolerance is considered a core feature of the disorder.

Some studies have employed tilt table tests lasting 2-5 minutes to diagnose one common form of orthostatic intolerance, postural tachycardia syndrome (POTS). We examined the diagnostic yield of abbreviated durations of tilt testing in adults meeting criteria for ME/CFS, and identified the proportion with POTS misdiagnosed using testing of less than 10 minutes.

Methods:

Eligible participants were consecutive individuals satisfying study criteria for ME/CFS and POTS evaluated at the Stichting CardioZorg (SCZ, Hoofddorp, NL) between November 2012 and August 2018. Individuals being treated with medications commonly used to manage orthostatic intolerance were excluded. Head-up tilt table testing involved 15 minutes of supine posture then 20 minutes at 70 degrees upright. Only the data from the first 10-minutes upright were used.

POTS was defined as an increase in HR during a maximum of 10 minutes of upright tilt of at least 30 beats per minute (bpm), in the absence of either classical or delayed orthostatic hypotension. We measured the time until HR criteria for POTS were reached using survival curves, and compared survival curves between subgroups divided by age, sex, disease duration, and degree of hypocapnia during the test.

Results:

Of 627 individuals with ME/CFS evaluated during the study period, 155 met criteria for POTS. The median time to reaching HR criteria for POTS was 3 minutes. A two-minute tilt table test would miss 55% (95% CI, 48 – 63%) of those meeting POTS criteria over the course of 10 minutes upright. The median time to reaching HR criteria for POTS did not differ by sex, age, duration of ME/CFS, or hypocapnia during tilt.

Conclusions:

Abbreviated tilt table testing misses a substantial proportion of those ultimately diagnosed with POTS during a 10-minute tilt table test, and should be abandoned for the clinical diagnosis and in epidemiologic studies designed to estimate the prevalence of POTS among those with ME/CFS.

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Blood volume status in CFS/ME correlates with the presence or absence of orthostatic symptoms

Posted on 11/23/2018 by wames

Blood volume status in CFS/ME correlates with the presence or absence of orthostatic symptoms, by C (Linda) Van Campen,  Peter C Rowe and Frans C Visser in Front. Pediatr.  Oct 2018

Introduction:

Conflicting data have been published on the reduction of circulating blood volume in adults with Myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). The aim of the present study was to compare blood volumes based on the presence or absence of orthostatic symptoms.

Methods and results:

12 consecutive adults with ME/CFS participated in the study. All underwent dual isotope blood volume measurement and were evaluated for a clinical suspicion of orthostatic intolerance (OI). The mean age was 34 (10) years, and median duration of disease was 7.5 (6-10) years. The mean (SD) absolute blood volume was 59 (8) ml/kg, a value -11 (7) ml/kg below the reference blood volume.

Of the 12 patients, 4 had no OI and 8 had a clinical suspicion of OI. In 8 patients with OI, absolute blood volumes were significantly lower than for the 4 without OI (56 [2] vs 66 [5]; p<0.05) as were the differences between the measured and the reference blood volume (-14 [2]; vs -4 [3]; p<0.02).

Conclusions:

Adults with ME/CFS had a significantly lower blood volume if they had a clinical suspicion of OI compared to those without a clinical suspicion of OI, as well as a significantly lower blood volume compared to the expected value. The data suggest that accounting for symptoms of OI could enhance the detection of the subset with reduced blood volume.

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A poem about Me and M.E – One stupid dot

Posted on 11/22/2018 by wames

‘What’s up TV’ presents a 2 minute poem by Stacy Hart: Me and M.E, how ‘One Stupid Dot’ makes all the difference

Stacy’s blog: Mama Chill…Stacy Hart…Runnin On Empty

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The development of the DePaul symptom questionnaire: original, expanded, brief & pediatric versions

Posted on 11/22/2018 by wames

The development of the DePaul symptom questionnaire: Original, expanded, brief and pediatric versions, by Leonard A Jason, Madison Sunnquist in Frontiers in Pediatrics, 6 Nov 2018

One of the key requirements of a reliable case definition is the use of standardized procedures for assessing symptoms. This article chronicles the development of the DePaul Symptom Questionnaire (DSQ) to assess symptoms of the major chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (ME) case definitions.

The original questionnaire has been modified and expanded over time to more fully capture symptoms from various adult case definitions, and a brief as well as pediatric version have also been developed.

The DSQ has demonstrated strong psychometric properties in terms of test-retest reliability and sensitivity/specificity, as well as construct, predictive, and discriminant validity. The DSQ allows for a well-defined characterization of a patient’s illness and allows scientists and clinicians to improve diagnostic reliability when employing case
definitions of ME and CFS.

 

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CD24 expression & B cell maturation shows a novel link with energy metabolism: potential implications for patients with ME/CFS

Posted on 11/21/2018 by wames

CD24 expression and B cell maturation shows a novel link with energy metabolism: potential implications for patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome , by Fane K. Mensah, Christopher W Armstrong, Venkat Reddy, Amolak S Bansal, Saul Berkovitz, Maria Leandro and Geraldine Cambridge in Front. Immunol. 22 Oct 2018

Research abstract:

CD24 expression on pro-B cells plays a role in B cell selection and development in the bone marrow. We previously detected higher CD24 expression and frequency within IgD+ naïve and memory B cells in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) compared with age-matched healthy controls (HC). Here, we investigated the relationship between CD24 expression and B cell maturation.

In vitro stimulation of isolated B cells in response to conventional agonists were used to follow the dynamics of CD24 positivity during proliferation and differentiation (or maturation). The relationship between CD24 expression to cycles of proliferation and metabolism in purified B cells from HC was also investigated using phospho-flow (phosphorylation of AMPK-pAMPK), 1proton nuclear magnetic resonance and Mitotracker Far-red (Mitochondrial mass-MM).

In vitro, in the absence of stimulation, there was an increased percentage of CD24+ viable B cells in ME/CFS patients compared to HC (p< 0.05) following 5 days culture. Following stimulation with B cell agonists, percentage of CD24+B cells in both naïve and memory B cell populations decreased. p< 0.01). There was a negative relationship between percentage of CD24+B cells with MM (R2=0.76; p< 0.01), which was subsequently lost over sequential cycles of proliferation. There was a significant correlation between CD24 expression on B cells and the usage of glucose and secretion of lactate in vitro. Short term ligation of the B cell receptor with anti-IgM antibody significantly reduced the viability of CD24+ memory B cells compared to those cross-linked by anti-IgD or anti-IgG antibody. A clear difference was found between naïve and memory B cells with respect to CD24 expression and pAMPK, most notably a strong positive association in IgD+IgM+ memory B cells. In vitro findings confirmed dysregulation of CD24-expressing B cells from ME/CFS patients previously suggested by immunophenotype studies of B cells from peripheral blood.

CD24-negative B cells underwent productive proliferation whereas CD24+ B cells were either unresponsive or susceptible to cell death upon BCR-engagement alone. We suggest that CD24 expression may reflect variations in energy metabolism on different B cell subsets.

Cort Johnson discusses this research on the Simmaron Research blog: Immune Study Adds to Evidence Of Body-Wide Problems With Energy Production in Chronic Fatigue Syndrome (ME/CFS)

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Workwell’s two-day exercise tests & breaking the deconditioning dilemma in ME/CFS

Posted on 11/21/2018 by wames

Workwell’s two-day exercise tests and breaking the deconditioning dilemma in Chronic Fatigue Syndrome (ME/CFS) by Cort Johnson in Health rising blog, 19 Nov 2018

The first word in the first sentence of the paper says it all:

“Concise methodological directions for administration of serial cardiopulmonary exercise testing (CPET) are needed for testing of patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).”

Why concise? Because Workwell asserts that in the universe of diseases known to man Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is so different when it comes to exercise that it needs a place all it’s own. It needs it’s own concise methodology, and above all it needs to be understood differently.

This methodology paper, then, is an attempt by the exercise physiologists at Workwell (Staci Stevens, Mark Van Ness, Chris Snell, Jared Stevens) and Betsy Keller to spread the word that something very different, something perhaps even unique in the annals of medicine, is occurring in people with chronic fatigue syndrome when they exercise.

Someone, it seems, is listening. This dry, seemingly obscure methodology paper (“Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome“) has proven to be a surprise hit. In the two months since its publication it’s been viewed by over 7400 people spread across the globe…

It’s a remarkable fact that even people with disabling diseases can exercise to exhaustion two days in a row without effecting their ability to produce energy

Workwell has been giving two-day CPETs for years. I asked Staci if the drop in energy production seen in an exercise test given one day after a previous test was really unique in ME/CFS. Her answer demonstrated just how much we have to learn:

Clinically we have seen patients with more than 30 different fatiguing conditions including POTS and fibromyalgia. ME/CFS is unique but more research is needed to determine ME/CFS CPET subsets and if other conditions have abnormal test 2 responses.

Our clinical patients often have comorbid conditions, so this makes it more difficult to sort out. That said, several distinct subsets of abnormal responses are emerging. We have a case series on this very topic comparing fatiguing conditions with ME/CFS which will be published soon.

Read more about:

  • POTS & deconditioning
  • Workwell’s plans for larger exercise tests
  • A Guide to Giving a Two-Day Exercise Test in ME/CFS – The Methodology Section
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Associations between clinical symptoms, plasma norepinephrine & deregulated immune gene networks in subgroups of adolescents with CFS

Posted on 11/19/2018 by wames

Associations between clinical symptoms, plasma norepinephrine and deregulated immune gene networks in subgroups of adolescent with Chronic Fatigue Syndrome, by Chinh Bkrong Nguyen, Surendra Kumar, Manuela Zucknick, Vessela N Kristensen, Johannes Gjerstad, Hilde Nilsen, Vegard BruunWyller, in Brain Behav Immun. 2018 Nov 9. pii: S0889-1591(18)30796-7 [Epub ahead of print]

Highlights:

Research abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is one of the most important causes of disability among adolescents while limited knowledge exists on genetic determinants underlying disease pathophysiology.

METHODS: We analyzed deregulated immune-gene modules using Pathifier software on whole blood gene expression data (29 CFS patients, 18 controls). Deconvolution of immune cell subtypes based on gene expression profile was performed using CIBERSORT. Supervised consensus clustering on pathway deregulation score (PDS) was used to define CFS subgroups. Associations between PDS and immune, neuroendocrine/autonomic and clinical markers were examined. The impact of plasma norepinephrine level on clinical markers over time was assessed in a larger cohort (91 patients).

RESULTS: A group of 29 immune-gene sets was shown to differ patients from controls and detect subgroups within CFS. Group 1P (high PDS, low norepinephrine, low naïve CD4+ composition) had strong association with levels of serum C-reactive protein and Transforming Growth Factor-beta. Group 2P (low PDS, high norepinephrine, high naïve CD4+composition) had strong associations with neuroendocrine/autonomic markers. The corresponding plasma norepinephrine level delineated 91 patients into two subgroups with significant differences in fatigue score.

CONCLUSION: We identified 29 immune-gene sets linked to plasma norepinephrine level that could delineate CFS subgroups. Plasma norepinephrine stratification revealed that lower levels of norepinephrine were associated with higher fatigue. Our data suggests potential involvement of neuro-immune dysregulation and genetic stratification in CFS.

Read full article

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