The other MEGA ME/CFS project

Posted on 07/15/2016 by wames

Simmaron research blog post, by Cort Johnson, 29 June 2016: The Other MEGA Chronic Fatigue Syndrome (ME/CFS) Project: Dr. Hornig Talks

Three MEGA chronic fatigue syndrome (ME/CFS) projects (The OMF’s Severe ME/CFS Big Data project, NIH’s Clinical Center Study, The UK’s Grand Challenge) were recently discussed on Health Rising, but another “mega” project exists.

They all have some similarities. Like the others, the mega project underway at the Center for Infection and Immunity (CII)  is attempting to get at the molecular roots of chronic fatigue syndrome (ME/CFS). Like the others it’ll be searching through vast amounts of data in an attempt to uncover the unique biological signature(s).

Like the Open Medicine Foundation and NIH Clinical Center projects, some of the technology has been developed in-house. We’re blessed with the attention of some of the most innovative researchers in the world.

Let’s take advantage of a recent talk by Simmaron Research Foundation Scientific Board member Mady Hornig in Sweden and check out the CII’s big plans for ME/CFS. (A transcript of the talk is provided  on the striking, new Microbe Discovery website).

We learned recently that the internationally renowned Ian Lipkin is all in for chronic fatigue syndrome (ME/CFS); that his bucket list includes just two diseases: ours and autism.  Mady Hornig certainly didn’t skimp on her vision for ME/CFS at the talk either; she wants to create a Center of Excellence for ME/CFS at the CII, and hopes that the large array of studies the Center is engaged in will lay the foundation for that.

You can’t have research centers without funding, though. The NIH has been very responsive recently, and the big Clinical Center study is very exciting, but extramural funding is where it’s at and little money thus far has flowed to outside researchers. Last year Ian Lipkin and Mady Hornig in one of the weirdest grant awards ever received money for sampling but no money for analysis (?) –  and then had to drop in 500 K in to complete their sampling. It’s no wonder then that Mady Hornig (six months ago) referred to a “crisis” in funding. This, of course, is a crisis that’s been present for over 20 years.

Times are changing, though, and hopefully we’ll get some good news soon about the Trans NIH Working Group’s”strategy to reinvent ME/CFS at the NIH.

Even with this dearth of federal funding the CII, with the help of the Chronic Fatigue Initiative (funding metabolomics, proteomics, immune signatures, pathogen discovery projects), the Microbe Discovery Project, the (microbiome), the Stanford program (pathogens), the Simmaron Research Foundation (spinal fluid) and others, has put together a megaproject – a diverse, multidimensional attack focused on getting at the molecular underbelly of ME/CFS.

Check out the different stabs at ME/CFS the group is taking.

The Pathogen Slant  – in a very large study, the CII using PCR, Mass Tag PCR  (developed in Lipkin’s laboratory) and high throughput will scan for 1.7 million agents in, if I’m reading it right, 800 patients and controls. In his Spring 2015 and 2016 newsletters, Dr. Montoya said to expect some exciting results. They’re looking at viruses, bacteria, and for the first time ever in ME/CFS, fungi.

The Gut Plus Slant – (n=100) -The CII expects their microbiome analysis of the bacteria and fungi in gut will tell them a lot about immune functioning. It turns out that no less than 60% of our immune cells travel through and get altered by bacterial metabolites in the gut before they make it to the blood. They’re also looking at the throat area to see what this common collection point for pathogens might tell them. The CII has finished their first analyses of their initial gut study: the results were apparently good enough for the team to expand their study and begin taking multiple samples from the same patient over time.

It’s this kind of rigorous, dogged, longitudinal approach to ME/CFS – which no one by the way as ever done before – that they hope will put them first in line for a Center of Excellence. I don’t think anyone, ever, has watched the immune and microbiome systems over the length of time (12-18 months) the CII is. It would be very hard, indeed, to discount any pattern that consistently showed up over that period of time.

Plus, they’re building quite a biobank of samples at the same time. The CII will surely be at the top of the NIH’s list of potential ME/CFS research consortiums.

The Autoimmune Slant – Autoantibodies could conceivably be behind everything that happens in ME/CFS. The CII will be looking for autoantibodies to human cells and  pathogens including viruses, bacteria and fungi. This will allow them to dig up evidence of past infections that may have triggered ME/CFS. Their search will also include those adrenergic autoantibodies recently found in POTS patients that dysregulate their heart rates.

The RNA Seq / miRNA – Gene expression Slant – Gene expression tells  us which genes are doing what. This study will determine what’s happening with the immune genes in ME/CFS. Right now we might guess they’ll see increased immune gene expression early in the disease and reduced gene expression.

Since studies have shown that unique patterns of gene expression or genetics predispose people to prolonged courses of illness after an infection, this study is ripe with promise.  (If I’m reading this right a paper should be out in the not too distant future.)

The CII could end up identifying:

  1. pathogens that kick off the illness
  2. a pattern of gene expression that makes ME/CFS patients particularly vulnerable to that pathogen and
  3. the autoimmune reaction that grew out of an inadequate immune response that failed to quickly dispatch the pathogen.

Itraq / MRM Metabolomics ( amino acids, kynurenine, serotonin) Slant – The CII is particularly interested in how metabolomics (the search for metabolites in the blood) may be able to tell them what’s happening in gut.

The L-tryptophan and the kynurenine pathway is a particular focus.  L-tryptophan should metabolize into serotonin, a feel good chemical involved in sleep, sex drive, vigilance and mood regulation. L-tryptophan, however, can also be captured by the kynurenine pathway which metabolizes it into some nasty products (bye-bye good feelings). The kynurenine pathway has popped up in an array of neurological and neuropsychiatric diseases.

Dr. Hornig noted their metabolomic analyses suggest the kynurenine pathway is alive and well in some ME/CFS patients. In a prior talk, she reported that their early data suggests that a subset of people with ME/CFS with low serotonin have increased immune activation ( IL-1 beta, TNF alpha, IL-12p40, and L-17F) as well.

Interestingly, interferon gamma (IFN-y) (see below) – an antiviral and proinflammatory activating cytokine, and TNF-a – a powerful pro-inflammatory cytokine, both of which may have become activated early in the disease, both push tryptophan metabolism into the kynurenine pathway.

Dr. Hornig said they were “very keen” to understand tryptophan’s role in ME/CFS.

Cytokine and Immune Arrays Slant  – They are or will be examining a wide array of cytokine levels over time to pluck out the most consistent contributors to ME/CFS.  Many people are interested in the role the autonomic nervous system plays in ME/CFS but the Lipkin/Hornig group may be the first to examine the role the immune system plays in causing  the ANS  issues and/or problems with orthostatic intolerance.

Allergy related cytokines (IL-4, IL-13, IL-17A, IL-10, Eotaxin) that can affect histamine production and alter blood pressure have popped up in their studies (and eotaxin has popped in other studies). Histamine, of course, can have devastating effects of blood pressure and circulation.  Dr. Hornig believes some of the “systemic fatigue” in chronic fatigue syndrome could originate here.

The Spinal Fluid Slant – The Simmaron/CII study was not only the first study ever to document similar immune changes in the blood and spinal fluid, but it also introduced two new subsets; Dr. Peterson’s typical / atypical patietnts.  Dr. Lipkin was so high on expanding the spinal fluid study that he flew out to Lake Tahoe for the first time in 20 years to rally support for it.

An expanded Simmaron/CII spinal fluid study with more participants and more testing is underway. Should testing reveal similar findings in the spinal fluid and the blood again, a powerful message would be sent that ME/CFS is a immune disease.

Treatment

People with shorter duration illnesses could possibly benefit from  antibodies to IL-17A or interferon gamma that could  reduce their hyperactive response to these cytokines. Many commercial antibodies, in fact, are now available. If Hornig/Lipkin can validate upregulated IL-17A or interferon gamma is present those treatments could become available to people with ME/CFS.

For the longer duration patients Dr. Hornig suggested that increasing the immune response by using Ampligen or [ an IL-1 receptor antagonist could be helpful.

Networking

The immune system doesn’t just poop out in the longer duration patients – it kind of goes bananas. An immune networking comparison in short vs longer duration patients suggested  a very focused and active immune network existed in short duration patients. In the longer duration patients, though, a much more complex immune network featuring many down-regulated immune pathways was present. It’s the stark a portrayal of these two subsets that I’ve seen.

Biomarker? – Despite the fact that interferon gamma levels were not particularly high they were incredibly predictive of short duration patients. That suggested, as Jarred Younger’s and Gordon Broderick’s work has suggested, that context is the key. It’s possible that increased IFN-y in the context of ME/CFS has unexpectedly strong effects.

Remember This – A big surprise in the longer duration patients spinal fluid was the almost complete disappearance of IL-6, a cytokine needed for memory storage and retrieval.  The IL-1 receptor- antagonist (IL-1ra) was very low as well. That was an intriguing finding given that (a) the network analysis suggested that IL-1ra was a key down-regulating element in ME/CFS and (b) drugs such as Anakinra could boost it back up – and presumably stop the central nervous system down-regulation.

Conclusion

The Center for Infection and Immunity, led by Dr. Lipkin and Dr. Hornig, is engaged – largely thanks to the Chronic Fatigue Initiative as well as the Simmaron Research Foundation – in the third mega study of ME/CFS under way. Among the unique elements of this project are it’s continuing spinal fluid component, it’s strong focus on the gut and the kynurenine pathway, and it’s long term longitudinal study that could prove pivotal in validating ME/CFS as a disease.

The CII’s strong blood immune and spinal fluid studies last year probably helped the NIH agree to reinvigorate ME/CFS research. Hopefully, that’s just beginning of the role the Center will play in deciphering ME/CFS. Boasting one of the most extensive research efforts on ME/CFS, it surely it’s a strong candidate to be one of the ME/CFS research consortiums we hope will get funding.

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Down-regulation of renin-aldosterone and antidiuretic hormone systems in ME/CFS

Posted on 07/15/2016 by wames

Research abstract:

BACKGROUND:

Central nervous system dysfunction associated with myalgic encephalomyelitis (ME) has been postulated as the cause of chronic fatigue syndrome (CFS). A small heart or reduced left ventricular volume with reduced cardiac output has been reported to be common in patients with ME. The main circulatory blood volume regulators may be down-regulated.

METHODS:

Plasma levels of the neurohumoral factors that regulate circulatory blood volume were determined in 18 patients with ME and 15 healthy subjects (Controls).

RESULTS:

The echocardiographic examination revealed that the mean values for the left ventricular end-diastolic diameters, stroke volume index, and cardiac index as well as the mean blood pressure were all significantly smaller in the ME group than in the Controls. The mean plasma renin activity (1.6±1.0ng/ml/h vs. 2.5±1.5ng/ml/h, p=0.06) was considerably lower in the ME group than in the Controls. Both the mean plasma aldosterone (104±37pg/ml vs. 157±67pg/ml, p=0.004) and antidiuretic hormone (ADH) (2.2±1.0pg/ml vs. 3.3±1.5pg/ml, p=0.02) concentrations were significantly lower in the ME group than in the Controls.

Desmopressin (120μg), a synthetic version of arginine vasopressin, was orally administered for five successive days to 10 patients with ME. In five patients (50%), the symptoms of orthostatic intolerance during a 10min active standing test were ameliorated in association with a significant increase in urinary osmotic pressure and decrease in heart rate. Furthermore, in five patients (50%), the performance status scores for the activities of daily living were improved.

CONCLUSIONS:

Both the renin-aldosterone and ADH systems were down-regulated despite the existence of reduction in cardiac preload and output in patients with ME. Desmopressin improved symptoms in half of the patients.

Down-regulation of renin-aldosterone and antidiuretic hormone systems in patients with myalgic encephalomyelitis/chronic fatigue syndrome by K Miwa in J Cardiol. 2016 Jul 8. pii [Epub ahead of print]

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Widespread pain and altered renal function in ME/CFS

Posted on 07/14/2016 by wames

Research abstract:

Widespread pain is noted in many patients with Chronic Fatigue Syndrome (MECFS), Fibromyalgia (FM) and Temporomandibular disorders (TMD). These conditions usually start as a localized condition and spread to a widespread pain condition with increasing illness duration. The aim of this paper was to assess the changes in biochemistry associated with pin expression and altered renal function.

Forty-seven MECFS patients and age/sex matched controls had: a clinical examination, completed questionnaires, standard serum biochemistry, glucose tolerance tests and serum and urine metabolomes in an observational study.

Increases in pain distribution were associated with reductions in serum essential amino acids, urea, serum sodium and increases in serum glucose and the 24-hour urine volume however the biochemistry was different for each pain area.

Regression modelling revealed potential acetylation and methylation defects in the pain subjects. These findings confirm and extend our earlier findings. These changes appear consistent with repeated minor inflammatory mediated alterations in kidney function resulting in essential amino acid deprivation and inhibition of protein synthesis and genetic translation within tissues.

Widespread pain and altered renal function in ME/CFS patients, by Neil R Mcgregor, Christopher W Armstrong, Paul Raymond Gooley in Researchgate, July 2016

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Alternatives to exercise from ‘Trust me I’m a doctor’

Posted on 07/14/2016 by wames

BBC TV programme Trust me I’m a doctor: summer special, looks at a number of ways to improve your health, lose belly fat, and cope with the sun and heat.

3 alternatives to exercise are explored on the programme:

  • to have a hot bath or sauna to lower your blood sugar and burn calories;
  • to have your muscles stretched by someone else to lower your blood sugar levels and burn calories;
  • mental training, or motor imagery to increase the strength of your muscles (audio guides available online)

The 55 min programme is available Sunday 17 July 2016 BBC 2, 7pm  OR online until Thurs 11 August 2016

Moseley hotpool

BBC news: Can you get the benefits of exercise by having a hot bath?

Daily Mail: How you can get fit just by THINKING about exercise! Scientists say imagining yourself working out could actually make your muscles stronger

 

 

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Do the answers to ME/CFS lie within our gut?

Posted on 07/13/2016 by wames

Institute of Food Research Blog post, by Ben Halford, 8 July: Do the answers to ME/CFS lie within our gut?

Researchers on the Norwich Research Park have published a review of evidence for a role of the gut microbiota and virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Commonly presenting with hugely diverse and debilitating symptoms including post-exertional tiredness, unrefreshing sleep, concentration problems and widespread pain, ME/CFS is very difficult to diagnose and treat. The disease affects around 250,000 people in the UK and with an average age of 33, patients are often affected at a highly demanding time in life. Direct and indirect economic costs are estimated in the USA to be $20 billion annually. The severity of symptoms varies. Around 25% of sufferers will be classed as disabled; often bed bound at some point in their lives with periods of relapse and remission common and only 6% returning to full health.

The detailed review, published in The Journal of Clinical Medicine, examines mounting evidence pointing towards an infectious and autoimmune basis for ME/CFS, with emphasis placed on the impact of the intestinal microbiota and virome, the bacterial and viral communities resident within our gut. The review was written by medical students Navena Navaneetharaja and Verity Griffiths, with Professor Simon Carding and Professor Tom Wileman from the University of East Anglia Norwich Medical School and Institute of Food Research, all based at the Norwich Research Park.

The gut, given its continued exposure to microbes, is an important location for autoimmune activity which could cause chronic disease if exposure becomes uncontrolled. Studies using sterile, germ-free mice models for inflammatory bowel disease, autoimmune arthritis and type 1 diabetes showed that the animals have reduced severity/incidence of these conditions, possibly indicative of the microbiota as a trigger. No similar models have been developed for ME/CFS, but the review cites several independent studies as evidence, linking the abnormal movement of gut bacteria across the intestinal epithelial barrier to increased systemic inflammatory disease activity – so-called “leaky gut syndrome,” highlighting the importance of how the microbiota could become exposed to the host immune system.

The co-existence of ME/CFS and gastrointestinal symptoms is well documented with one study reporting that 92% of ME/CFS patients have co-existent irritable bowel syndrome. Significantly higher levels of Enterococcus and Streptococcus and lower levels of Bifidobacteria bacterial species has been reported in ME/CFS patients with 77% of them having some form of bacterial overgrowth. But it is too early to say if specific ME/CFS microbiota signatures exist. Data have so far lacked consistency but changes in intestinal balance (dysbiosis) could play a key role in ME/CFS development.

The Norwich Research Park has a concentration of interdisciplinary researchers studying the microbiota, including the authors of this review. The human microbiota is often described by its bacterial populations, but it is much more complex and includes many other microorganisms, in particular viruses. With both viruses and the microbiota being implicated in ME/CFS, the review advocates a pronounced move of attention from the bacterial to the viral population of the intestine, particularly in relation to bacteriophages, viruses that infect bacteria. Whilst virus detection and identification is currently difficult, the virome is considered more stable and personal than our resident bacterial communities potentially pointing towards a specific virome profile for ME/CFS patients.

If the detailed research efforts can be accelerated and conducted in a co-ordinated fashion, it will support the development of therapeutics to address and alleviate the diverse range of incapacitating symptoms of ME/CFS, and will then ultimately provide much hope in moving towards prevention of a disease ignored for too long.

You can read more about this review in an article by Naveena Navaneetharaja on the Gut Health and Food Safety Programme blog

Reference:

Navaneetharaja N., Griffiths V., Wileman T., Carding S.R. (2016). A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), J. Clin. Med. 5, 55; doi:10.3390/jcm5060055

 

 

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Gut Bacteria Are Different in People With CFS

Posted on 07/13/2016 by wames

Well blog post:, by Nicholas Bakalar, 7 July 2016: Gut Bacteria Are Different in People With Chronic Fatigue Syndrome

A new study has identified a bacterial blueprint for chronic fatigue syndrome, offering further evidence that it is a physical disease with biological causes and not a psychological condition.

Chronic fatigue syndrome is a condition that causes extreme and lasting fatigue, preventing people from taking part in even the most routine daily activities. There are no tests to confirm the diagnosis, which has prompted speculation that it is a psychological condition rather than a physical illness.

In a study published in Microbiome, researchers recruited 48 people with C.F.S. and 39 healthy controls. Then they analyzed the quantity and variety of bacteria species in their stool. They also searched for markers of inflammation in their blood.

The stool samples of those with C.F.S. had significantly lower diversity of species compared with the healthy people — a finding typical of inflammatory bowel disease as well.

The scientists also discovered that people with C.F.S. had higher blood levels of lipopolysaccharides, inflammatory molecules that may indicate that bacteria have moved from the gut into the bloodstream, where they can produce various symptoms of disease.

Using these criteria, the researchers were able to accurately identify more than 83 percent of C.F.S. cases based on the diversity of their gut bacteria and lipopolysaccharides in their blood.

Finding a biomarker for C.F.S. has been an ongoing goal for researchers who hope to one day develop a diagnostic test for the condition. Still, the senior author of the study, Maureen R. Hanson, a professor of molecular biology at Cornell, said the bacteria blueprint in the new study is not yet a method of definitively diagnosing C.F.S. The importance of the finding, she said, is that it may offer new clues as to why people have these symptoms.

“There’s a biological difference between people with C.F.S. and healthy people,” she said. “The long-lasting idea that it’s a psychological illness should be abandoned.”

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Mast cell dysfunction in ME/CFS

Posted on 07/11/2016 by wames

Research abstract:

BACKGROUND: Mast cells (MCs) mediate inflammation through neuropeptides and cytokines, along with histamine and reactive oxygen species (ROS).

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is an illness characterized by an unexplained disabling fatigue with multiple physiological impairments as well as dysregulated cytokine profiles.

OBJECTIVE: To determine mast cell phenotypes in isolated human PBMCs, in healthy controls and in CFS/ME patients. Second, determine receptor expression of RAGE and its ligand high mobility group box 1 protein (HMGB1).

METHOD: Moderately severe CFS/ME patients (n=12, mean age 39.25±SD3.52 years), severe CFS/ME patients (n=6, mean age 43.00±SD4.02 years) and healthy controls (n=13, mean age 42.69±SD3.87 years) were included in this study. CFS/ME patients were classified according to the 2011 International Consensus Criteria.

LSRFortessa X-20 Flow cytometry was used for the identification of phenotypic peripheral mast cell population in PBMCs using an exclusion marker Lin2 cocktail (anti-CD3, anti-CD14, anti-CD19, anti-CD20 and anti-CD56) and inclusion markers (CD117, CD34, FCεRI, chymase, HLA-DR and CD154) following comparative investigation. HMGB1 and soluble RAGE expression in plasma was measured by sandwich ELISA assay.

RESULTS: There was a significant increase in CD117+CD34+FCεRI-chymase- mast cell populations in moderate and severe CFS/ME patients compared with healthy controls. There was a significant increase in CD40 ligand and MHC-II receptors on differentiated mast cell populations in the severe CFS/ME compared with healthy controls and moderate CFS/ME.

There were no significant differences between groups for HMGB1 and sRAGE.

CONCLUSIONS: This preliminary study investigates mast cell phenotypes from PBMCs in healthy controls. We report significant increase of naïve MCs in moderate and severe CFS/ME patients compared with healthy controls. Moreover, a significant increase in CD40 ligand and MHC-II receptors on differentiated mast cells in severe CFS/ME patients.

Peripheral MCs may be present in CFS/ME pathology however, further investigation to determine their role is required.

Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in chronic fatigue syndrome/myalgic encephalomyelitis patients, by Nguyen T, Johnston S, Chacko A, Gibson D, Cepon J, Smith P, Staines D, Marshall-Gradisnik S in Asian Pac J Allergy Immunol. 2016 Jun 30. [Epub ahead of print]

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Dr David Systrom’s exercise intolerance research

Posted on 07/08/2016 by wames

Health rising blog post, by Cort Johnson: The Exercise intolerance in ME/CFS, Fibromyalgia and POTS Explained?

Dr. Systrom’s huge study on people with unexplained exercise intolerance suggests that the current explanation (deconditioning, lack of effort) couldn’t be more wrong. In fact, Systrom’s study suggests that when these peoples hearts were asked to pump more blood during exercise they couldn’t.

He concluded that the problem was every bit as functionally debilitating as heart failure and other major diseases. He also concluded that the problem was not in the heart. Is he explaining what’s going on in ME/CFS and FM?

Introduction:

It’s always  encouraging to see established researchers from outside the chronic fatigue syndrome (ME/CFS) and fibromyalgia fields converging on them. David Systrom, a pulmonologist at Brigham and Women’s hospital in Boston, has been interested in idiopathic or unexplained exercise intolerance for at least a decade.

A significant number of people who cannot exercise have been a medical mystery to cardiologists and pulmonologists

He and Oldham recently published their magnus opus on exercise intolerance; a study employing over six hundred patients that stretches back nine years.

Unexplained exertional dyspnea caused by low ventricular filling pressures: results from clinical invasive cardiopulmonary exercise testing. William M. Oldham,1,2,3 Gregory D. Lewis,3,4 Alexander R. Opotowsky,2,3,5 Aaron B. Waxman,1,2,3 David M. Systrom1,2,3. Pulm Circ 2016;6(1):55-62. DOI: 10.1086/685054.

In it they proposed that a significant subset of patients with exercise intolerance and heart abnormalities have simply slipped through the cracks.  No diagnosis has been able to explain their low energy production (VO2 max) during exercise; they don’t have heart failure or arrythmia or cystic fibrosis or known mitochondrial problems. Aside from telling them that they’re deconditioned or depressed the medical profession hasn’t known what to do with these patients.

How a field that gets over $2 billion in funding year in and year out could let any significant group “slip through” the cracks is unclear. Systrom’s use of invasive cardiopulmonary testing techniques apparently has given him a unique insight into these patients.

“In this study, we tested the hypothesis that failure of these mechanisms to increase cardiac preload during exercise….may be the primary limitation….in an undiagnosed population of patients with unexplained exercise intolerance.”

Some of them, perhaps many of them, have ME/CFS/FM or POTS (or would be diagnosed with it if anyone tried) and those that don’t must have something close.  (At least three people with ME/CFS/FM have ended up in Systrom’s office, and probably many more were in the study.)

Systrom, though, is ignoring the ME/CFS/FM for the moment – and probably rightly so.  He has bigger fish to fry; his goal right now is to enroll his colleagues in the idea that they haven’t been correctly diagnosing a significant subset of their patients.

If my reading of medical history (I highly recommend “The Biography of Cancer” and “The Death of Cancer”) is representative, that conclusion is probably not going to go over well.

Systrom found that hearts of the exercise intolerant patients did not expand when they exercised.  This inability to fill with more blood during exercise was why they exhibited low energy production (VO2 max). (We just saw a similar pattern in ME/CFS in “Chronic Fatigue Syndrome: A Small Heart Disease” and A Mestinon Miracle.)

Read more

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MAGENTA: GET for teenagers research trial protocol

Posted on 07/08/2016 by wames

Research protocol abstract:

Introduction:

Paediatric chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is a relatively common and disabling condition, yet there is a limited evidence base for treatment. There is good evidence that graded exercise therapy is moderately effective in adults with CFS/ME, but there is little evidence for the effectiveness, cost-effectiveness, acceptability or best method of delivery for paediatric CFS/ME.

This study aims to investigate the acceptability and feasibility of carrying out a multicentre randomised controlled trial investigating the effectiveness of graded exercise therapy compared with activity management for children/teenagers who are mildly or moderately affected with CFS/ME.

Methods and analysis 100 paediatric patients (8–17 years) with CFS/ME will be recruited from 3 specialist UK National Health Service (NHS) CFS/ME services (Bath, Cambridge and Newcastle). Patients will be randomised (1:1) to receive either graded exercise therapy or activity management. Feasibility analysis will include the number of young people eligible, approached and consented to the trial; attrition rate and treatment adherence; questionnaire and accelerometer completion rates. Integrated qualitative methods will ascertain perceptions of feasibility and acceptability of recruitment, randomisation and the interventions. All adverse events will be monitored to assess the safety of the trial.

Ethics and dissemination: The trial has received ethical approval from the National Research Ethics Service (South West—Frenchay 15/SW/0124).

Trial registration number ISRCTN23962803; Pre-results.

Strengths and limitations of this study

  • This feasibility study is the first trial to investigate graded exercise therapy in children with chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) in the outpatient setting.
  • Integrated qualitative methodology is being used to optimise recruitment and retention, and to investigate the feasibility and acceptability of the study processes and interventions.
  • This is a multicentre study which will test the feasibility of running this trial in different National Health Service (NHS) settings.
  • The participants and clinicians will not be blinded to allocation.
  • Participant outcomes are self-reported

Managed Activity Graded Exercise iN Teenagers and pre-Adolescents (MAGENTA) feasibility randomised controlled trial: study protocol, by Amberly Brigden, Lucy Beasant, William Hollingworth, Chris Metcalfe, Daisy Gaunt, Nicola Mills, Russell Jago, Esther Crawley in BMJ Open Volume 6, Issue 7 2016 [Published 4 July 2016]

University of Bristol MAGENTA website with information about the trial, questionnaires & information sheets.

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How mestinon helped one ME/CFS patient exercise

Posted on 07/07/2016 by wames

Health Rising blog post, by Cort Johnson, 17 June 2016: A mestinon miracle: vagus nerve stimulating drug helps long time ME/CFS patient exercise.

She’d had chronic fatigue syndrome (ME/CFS) for twenty-eight years and has left no stone unturned in her attempts to get well. She’s traveled widely and seen some of the best ME/CFS doctors in the world. Despite being connected to the hilt in the ME/CFS, her results have been all too familiar; her health has improved a bit but she, a former fitness buff, has never been able to exercise.

She’d had a really tough year. Multiple surgeries including a gall bladder removal, multiple emergency room visits and a mysterious drug reaction had laid her as low as she had ever been.

Many people might have given up after that (and several decades of mostly fruitless searching) but last year there she was in a pulmonary specialist’s office with a catheter in her arm working away on an exercise test.

There she was, almost 30 years later, doing an exercise test in an attempt to figure what had gone wrong.

Her goal – to determine if the latest hot topic in ME/CFS – mitochondrial issues – were it for her. It turned out that they weren’t – her mitochondria appeared to be working fine.  Nor, despite the sarcoidosis she had, was her lung capacity diminished – she still had the lungs of an athlete.

Her autonomic nervous system, however, was  decidedly off. Her heart was beating way too fast and her blood was pooling in her legs instead of getting pushed back up to her heart, leaving her heart without much blood to pump. Her doctor, David Systrom at Brigham’s Women’s Hospital in Boston,  turned to her and suggested Mestinon (pyridostigmine bromide). It’s helped, he said, with fatigue in patients like you have.

Mestinon turned out to be something of a miracle for her.  She took too much at first – had some rather drastic side-effects but then ratcheted it down and then back up again.

Now she’s at the upper limit prescribed for people with myasthenia gravis (180 mgs/day).  She hasn’t been able to exercise without paying for it for almost three decades but it was clear within a couple of weeks that something was different. She described suddenly feeling like “going for a run” – a feeling she hadn’t had in decades. She was tired afterwards but the dreaded PEM never materialized.

Then she went cross-country skiing – one of the most energy intensive exercises there is.  She’s now running 3 plus miles a couple of days a week and working out in the gym. She has one side effect that’s apparently caused by the medication; after exercise sometimes she feels lightheaded.

Other symptoms improved. She does take sleeping pills but now they seem to be working better and she was able to cut down her sleep by an hour or two a night. She’s able to work full days. Much of her alcohol intolerance has disappeared. Her very high resting heart rate has returned to normal.  She’s not healthy but she’s improved enormously and she can exercise (!).

Imagine her shock when she learned that the drug that has done so much for her has been around for decades. It’s even prescribed for the orthostatic intolerance she has, but until Dr Systrom no one had ever mentioned it.

Read more about mestinon, Dr David Systrom and his research into exercise intolerance

 

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