Midodrine is effective for orthostatic hypotension

Posted on 08/31/2016 by wames

Research abstract:

OBJECTIVE

Midodrine hydrochloride is a short-acting pressor agent that raises blood pressure in the upright position in patients with orthostatic hypotension. The US Food and Drug Administration’s Subpart H approval, under which midodrine was initially approved, requires post-marketing studies to confirm midodrine’s clinical benefit in this indication. The purpose of this study was to evaluate the clinical benefit of midodrine with regard to symptom response.

METHODS

This was a double-blind, placebo-controlled, randomized, crossover, multicenter study (NCT01518946). Following screening, patients aged ≥18 years with severe symptomatic orthostatic hypotension and on a stable dose of midodrine for at least 3 months were randomized to treatment with either their previous midodrine dose or placebo on day 1 and the respective alternate treatment on day 2. The primary endpoint measured time to syncopal symptoms or near-syncope using a 45-min tilt-table test at 1 h post-dose.

RESULTS

Thirty-three patients were screened for inclusion: 19 received at least one dose of midodrine and had at least one post-dose measurement of the primary endpoint. The least-squares mean time to syncopal symptoms or near-syncope after tilt-table initiation (mean ± standard error) was 1626.6 ± 186.8 s for midodrine and 1105.6 ± 186.8 s for placebo (difference, 521.0 s; 95 % confidence interval 124.2–971.7 s; p = 0.0131). There were 15 adverse events in 10 patients; all of these were mild or moderate in severity, with none considered by the investigators to be related to midodrine.

INTERPRETATION

Midodrine is a well-tolerated and clinically effective treatment for symptomatic orthostatic hypotension.

Clinical benefit of midodrine hydrochloride in symptomatic orthostatic hypotension: a phase 4, double-blind, placebo-controlled, randomized, tilt-table study, by William Smith, Hong Wan, David Much, Antoine G. Robinson, and Patrick Martin in Clinical Autonomic Research, 2 July 2016

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Creativity and illness: Marion’s story on Radio 4

Posted on 08/31/2016 by wames

Women’s Hour on BBC Radio Four: “Creativity and illness: Marion’s Story”

Marion Michell has lived with ME and chronic fatigue for the last 17 years. She talks about  how she became an artist through rediscovering crochet.

Listen to Marion [Duration: 07:12″ (27:03-34:15)]

MMichellartling32forblog

Read her blog Supinesublime

 

 

 

 

 

 

 

Download podcast:

http://bit.ly/2bNfS6v  i.e.

 

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CFS could be the body trying to hibernate

Posted on 08/31/2016 by wames

The Times comments on Naviaux et al’s chemical signature research, by Tom Whipple, 30 August 2016: Chronic fatigue syndrome could be the body trying to hibernate

An estimated 250,000 people have CFS in Britain. The disease, which is difficult to diagnose, causes people to suffer from persistent exhaustion

Chronic fatigue syndrome may be caused by the body mistakenly going into a semi-hibernation state, a study has suggested.

An estimated 250,000 people have CFS, also known as ME, in Britain. The mysterious disease, which is difficult to diagnose, causes people to suffer from persistent exhaustion and can strike with no obvious cause. Theories about the cause have ranged from a bacterial or viral infection to psychiatric issues, and there are few effective treatments.

A previous major study suggesting the best treatments involved cognitive behaviour therapy or exercise angered those suffering from ME, with many saying that it trivialised their disease and ignored possible biological causes.

Now US scientists have found a chemical signature of the disease in the blood of sufferers. They claim that it is similar to a state found in nematode worms called dauer. In this state, the metabolism adjusts to a difficult environment by slowing down — enabling existence, but not much more.

Writing in the journal Proceedings of the National Academy of Sciences, the researchers said that dauer “permits survival and persistence under conditions of environmental stress, but at the cost of severely curtailed function and quality of life”. For many ME sufferers that is an apt description of their condition.

All animals have ways of responding to changes in environmental conditions that threaten survival

For their study, scientists screened the blood plasma of 85 people for metabolites. These are by-products of the chemical reactions in cells, including the breakdown of molecules to release energy. More than half of those screened had been told they had ME.

The aim of the study was to come up with a simple way to diagnose ME. At present, there is no blood test, so doctors have to judge if a patient’s lifestyle and behaviour fit the criteria.

However, as well as finding 20 markers that were indicative of the disease, Robert Naviaux, from the University of California, San Diego, found that these matched markers that would be expected in invertebrates in the dauer state.

This suggested that the condition could be a misfiring response to the environment, with the body mistakenly entering a state designed for survival in harsh conditions. Under this theory, just as allergies are overactive immune responses, ME could be an overactive response of the metabolic system.

“All animals have ways of responding to changes in environmental conditions that threaten survival,” Professor Naviaux said. “Historical changes in the seasonal availability of calories, microbial pathogens, water stress and other environmental stresses have ensured that we all have inherited hundreds to thousands of genes that our ancestors used to survive all of these conditions.”

Other scientists welcomed the research, but cautioned that it was too early to say what was going on. Andrew McIntosh, from the University of Edinburgh, said: “It is difficult to know whether the changes reported are a cause or an effect of CFS.”

Disease worsened by stigma
A complex disease biologically, ME is equally fraught politically (Tom Whipple writes). For many sufferers this latest study is more than just an insight into a disease — it adds weight to their battle against another piece of research that was published in 2011.

The Pace trial, run by UK researchers, remains one of the most comprehensive investigations into treatment for ME. It concluded that cognitive behavioural therapy and exercise could treat it.

Some sufferers took this as implying that their condition was all in the mind. They questioned the methodology and amid bitter arguments have sought to gain access to the full data. Academics involved in the trial said they had received abuse just for doing their jobs.

Now, after a legal battle, Alem Matthees, who has ME, has succeeded in forcing Queen Mary, University of London to release data from the trial. He said: “There is a growing chorus of academics . . . speaking out about the methodological problems with the Pace trial, yet for many years patients were left to speak out alone.”

Those with ME often feel they are being judged, that people think they are lazy or “faking it”. In that context, yesterday’s study will be seen as a victory.

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Lancet invites letter re PACE, then decides not to publish

Posted on 08/30/2016 by wames

Virology blog post, by Vincent Racaniello, 29 August 2016: Once Again, Lancet Stumbles on PACE

Last February, Virology Blog posted an open letter to The Lancet and its editor, Dr. Richard Horton, describing the indefensible flaws of the PACE trial of treatments for ME/CFS, the disease otherwise known as chronic fatigue syndrome (link to letter). Forty-two well-regarded scientists, academics and clinicians put their names to the letter, which declared flatly that the flaws in PACE “have no place in published research.” The letter called for a completely independent re-analysis of the PACE trial data, since the authors have refused to publish the results they outlined in their original protocol. The letter was also sent directly to Dr. Horton.

The open letter was based on the extensive investigative report written by David Tuller, the academic coordinator of UC Berkeley’s joint program in journalism and public health, which Virology Blog posted last October (link to report). This report outlines such egregious failings as outcome thresholds that overlapped with entry criteria, mid-trial promotion of the therapies under investigation, failure to provide the original results as outlined in the protocol, failure to adhere to a specific promise in the protocol to inform participants about the investigators’ conflicts of interest, and other serious lapses.

Virology Blog first posted the open letter in November, with six signatories (link to letter). At that time, Dr. Horton’s office responded that he would reply after returning from “traveling.” Three months later, we still had not heard back from Dr. Horton–perhaps he was still “traveling”–so we decided to republish it with many more people signed on.

The day the second open letter was posted, Dr Horton e-mailed me and solicited a letter from the group. (He did not explain where he had been “traveling” for the previous three months.) Here’s what he wrote: “Many thanks for your email. In the interests of transparency, I would like to invite you to submit a letter for publication–please keep your letter to around 500 words. We will then invite the authors of the study to reply to your very serious allegations.”

Dr. Horton’s e-mail clearly indicated that the letter would be published, with the PACE authors’ response to the charges raised; there was no equivocation or possibility of misinterpretation. In good faith, we submitted a letter for publication the following month, with 43 signatories this time, through The Lancet’s online editorial system (see the end of this article for a list of those who signed the letter). After several months with no response, we learned only recently by checking the online editorial system that The Lancet had flatly rejected the letter, with no explanation. No one contacted me to explain the decision or why we were asked to spend time creating a letter that The Lancet clearly had no intention of publishing.

I wrote back to Dr. Horton, pointing out that his behavior was highly unprofessional and requesting an explanation for the rejection. I also asked him if he was in the habit of soliciting letters from busy scientists and researchers that his journal had no actual interest in publishing. I further asked if the journal planned to reconsider this rejection, in light of the recent First-Tier Tribunal decision, which demolished the PACE authors’ bogus reasons for refusing to provide data for independent analysis.

Dr. Horton did not himself apologize or even deign to respond. Instead, Audrey Ceschia, the Lancet’s correspondence editor, replied, explaining that the Lancet editorial staff decided, after discussing the matter with the PACE authors, that the letter did not add anything substantially new to the discussion. She assured us that if we submitted another letter focused on the First-Tier Tribunal decision, it would be “seriously” considered. I’m not sure why she or Dr. Horton think that any such assurance from The Lancet is credible at this point.

The reasons given for the rejection are clearly specious. The letter for publication reflected the matters addressed in the open letter that prompted Dr. Horton’s invitation in the first place, and closely adhered to his directive  to outline our “serious allegations”. If outlining these allegations was not considered publication-worthy by The Lancet, it is incomprehensible to us why Dr. Horton solicited the letter in the first place. Perhaps it was just an effort to hold off further criticism for a period of months while we awaited publication of the letter, unaware of the journal’s intention to reject it. It is certainly surprising that The Lancet appears to have given the PACE authors some power to determine what letters appear in the journal itself.

Dr. Tuller’s investigation, based on the groundbreaking analyses conducted by many savvy patients and advocates since The Lancet published the first PACE results in 2011, has effectively demolished the credibility of the findings. So has a follow-up analysis by Dr. Rebecca Goldin, a math professor at George Mason University and director of Stats.org, a think tank co-sponsored by the American Statistical Association. In short, the PACE study is a sham, with meaningless results. In this case, the emperor truly has no clothes. Dr. Horton and his editorial team at The Lancet are stark naked.

Yet the PACE study remains in the literature. Its recommendation of treatments that are potentially harmful to patients–specifically, graded exercise therapy and cognitive behavior therapy, both designed specifically to increase patients’ activity levels–remains highly influential.

Of particular concern, the PACE findings have laid the groundwork for the MAGENTA study, a so-called “PACE for kids” that will be testing graded exercise therapy in children and adolescents. A feasibility study, sponsored by Royal United Hospitals Bath NHS Foundation Trust, is currently recruiting participants. It is, of course, completely unacceptable that any study should justify itself based on the uninterpretable findings of the PACE trial. The MAGENTA trial should be halted until the PACE authors have done what the First-Tier Tribunal ordered them to do–release their raw data and allow others to analyze it according to the outcomes specified in the PACE trial protocol.

Today, because of the urgency of the issue, we are posting on PubMed Commons the letter that The Lancet rejected. That way readers can judge for themselves whether it adds anything to the current debate.

Please note that the opinions in this blog post are mine only, not those of any of the other signers of the Lancet letter

Vincent R. Racaniello, PhD
Professor of Microbiology and Immunology
Columbia University
New York, New York

Ronald W. Davis, PhD
Professor of Biochemistry and Genetics
Stanford University
Stanford, California

Jonathan C.W. Edwards, MD
Emeritus Professor of Medicine
University College London
London, England, United Kingdom

Leonard A. Jason, PhD
Professor of Psychology
DePaul University
Chicago, Illinois

Bruce Levin, PhD
Professor of Biostatistics
Columbia University
New York, New York

Arthur L. Reingold, MD
Professor of Epidemiology
University of California, Berkeley
Berkeley, California

******

Dharam V. Ablashi, DVM, MS, Dip Bact
Scientific Director – HHV-6 Foundation
Former Senior Investigator
National Cancer Institute, NIH
Bethesda, Maryland

James N. Baraniuk, MD
Professor, Department of Medicine
Georgetown University
Washington, D.C.

Lisa F. Barcellos, PhD, MPH
Professor of Epidemiology
School of Public Health
California Institute for Quantitative Biosciences
University of California
Berkeley, California

Lucinda Bateman MD PC
MECFS and Fibromyalgia clinician
Salt Lake City, Utah

Alison C. Bested MD FRCPC
Clinical Associate Professor of Hematology
University of British Columbia
Vancouver, British Columbia, Canada

John Chia, MD
Clinician/Researcher
EV Med Research
Lomita, California

Lily Chu, MD, MSHS
Independent Researcher
San Francisco, California

Derek Enlander, MD, MRCS, LRCP
Attending Physician
Mount Sinai Medical Center, New York
ME CFS Center, Mount Sinai School of Medicine
New York, New York

Mary Ann Fletcher, PhD
Schemel Professor of Neuroimmune Medicine
College of Osteopathic Medicine
Nova Southeastern University
Professor Emeritus, University of Miami School of Medicine
Fort Lauderdale, Florida

Kenneth Friedman, PhD
Associate Professor of Pharmacology and Physiology (retired)
New Jersey Medical School
University of Medicine and Dentistry of NJ
Newark, New Jersey

Robert F. Garry, PhD
Professor of Microbiology and Immunology
Tulane University School of Medicine
New Orleans, Louisiana

Rebecca Goldin, PhD
Professor of Mathematics
George Mason University
Fairfax, Virginia

David L. Kaufman, MD,
Medical Director
Open Medicine Institute
Mountain View, California

Susan Levine, MD
Clinician, Private Practice
Visiting Fellow, Cornell University
New York, New York

Alan R. Light, PhD
Professor, Department of Anesthesiology
Department of Neurobiology and Anatomy
University of Utah
Salt Lake City, Utah

Patrick E. McKnight, PhD
Professor of Psychology
George Mason University
Fairfax, Virginia

Zaher Nahle, PhD, MPA
Vice President for Research and Scientific Programs
Solve ME/CFS Initiative
Los Angeles, California

James M. Oleske, MD, MPH
Francois-Xavier Bagnoud Professor of Pediatrics
Senator of RBHS Research Centers, Bureaus, and Institutes
Director, Division of Pediatrics Allergy, Immunology & Infectious Diseases
Department of Pediatrics
Rutgers – New Jersey Medical School
Newark, New Jersey

Richard N. Podell, M.D., MPH
Clinical Professor
Rutgers Robert Wood Johnson Medical School
New Brunswick, New Jersey

William Satariano, PhD
Professor of Epidemiology and Community Health
University of California, Berkeley
Berkeley, California

Paul T Seed MSc CStat CSci
Senior Lecturer in Medical Statistics
King’s College London, Division of Women’s Health
St Thomas’ Hospital
London, England, United Kingdom

Charles Shepherd, MB BS
Honorary Medical Adviser to the ME Association
London, England, United Kingdom

Christopher R. Snell, PhD
Scientific Director
WorkWell Foundation
Ripon, California

Nigel Speight, MA, MC, BChir, FRCP, FRCPCH, DCH
Pediatrician
Durham, England, United Kingdom

Philip B. Stark, PhD
Professor of Statistics
University of California, Berkeley
Berkeley, California

Eleanor Stein, MD FRCP(C)
Assistant Clinical Professor
University of Calgary
Calgary, Alberta, Canada

John Swartzberg, MD
Clinical Professor Emeritus
School of Public Health
University of California, Berkeley
Berkeley, California

Ronald G. Tompkins, MD, ScD
Summer M Redstone Professor of Surgery
Harvard University
Boston, Massachusetts

Rosemary Underhill, MB BS.
Physician, Independent Researcher
Palm Coast, Florida

Dr Rosamund Vallings MNZM, MB BS
General Practitioner
Auckland, New Zealand

Michael VanElzakker, PhD
Research Fellow, Psychiatric Neuroscience Division
Harvard Medical School and Massachusetts General Hospital
Boston, Massachusetts

Mark Vink, MD
Family Physician
Soerabaja Research Center
Amsterdam, The Netherlands

Prof Dr FC Visser
Cardiologist
Stichting CardioZorg
Hoofddorp, The Netherlands

William Weir, FRCP
Infectious Disease Consultant
London, England, United Kingdom

John Whiting, MD
Specialist Physician
Private Practice
Brisbane, Australia

Marcie Zinn, PhD
Research Consultant in Experimental Neuropsychology, qEEG/LORETA, Medical/Psychological Statistics
NeuroCognitive Research Institute, Chicago
Center for Community Research
DePaul University
Chicago, Illinois

Mark Zinn, MM
Research consultant in experimental electrophysiology
Center for Community Research
DePaul University
Chicago, Illinoi

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Researchers identify characteristic chemical signature for CFS

Posted on 08/30/2016 by wames

UC San Diego Press release, by Scott LaFee, 29 August 2016: Researchers Identify Characteristic Chemical Signature for Chronic Fatigue Syndrome

Discovery, along with revealed underlying biology, could lead to faster, more accurate diagnoses and more effective, personalized therapies

Chronic fatigue syndrome (CFS) is a mysterious and maddening condition, with no cure or known cause. But researchers at the University of California San Diego School of Medicine, using a variety of techniques to identify and assess targeted metabolites in blood plasma, have identified a characteristic chemical signature for the debilitating ailment and an unexpected underlying biology: It is similar to the state of dauer, and other hypometabolic syndromes like caloric restriction, diapause and hibernation.

Dauer is the German word for persistence or long-lived. It is a type of stasis in the development in some invertebrates that is prompted by harsh environmental conditions. The findings are published online in the August 29 issue of PNAS.

“CFS is a very challenging disease,”

said first author Robert K. Naviaux, MD, PhD, professor of medicine, pediatrics and pathology and director of the Mitochondrial and Metabolic Disease Center at UC San Diego School of Medicine.

“It affects multiple systems of the body. Symptoms vary and are common to many other diseases. There is no diagnostic laboratory test. Patients may spend tens of thousands of dollars and years trying to get a correct diagnosis.”

As many as 2.5 million Americans are believed to have CFS. It most often afflicts women in their 30s to 50s, though both genders and all ages can be affected. The primary symptom is severe fatigue lasting at least six months, with corollary symptoms ranging from muscle pain and headaches to sleep and memory problems.

Naviaux and colleagues studied 84 subjects: 45 men and women who met the diagnostic criteria for CFS and 39 matched controls. The researchers targeted 612 metabolites (substances produced by the processes of metabolism) from 63 biochemical pathways in blood plasma. They found that individuals with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites measured were decreased, consistent with hypometabolic syndrome or reduced metabolism. The diagnostic accuracy rate exceeded 90 percent.

“Despite the heterogeneity of CFS, the diversity of factors that lead to this condition, our findings show that the cellular metabolic response is the same in patients,” said Naviaux. “And interestingly, it’s chemically similar to the dauer state you see in some organisms, which kicks in when environmental stresses trigger a slow-down in metabolism to permit survival under conditions that might otherwise cause cell death. In CFS, this slow-down comes at the cost of long-term pain and disability.”

Naviaux said the findings show that CFS possesses an objectively identifiable chemical signature in both men and women and that targeted metabolomics, which provide direct small molecule information, can provide actionable treatment information. Only 25 percent of the metabolite disturbances found in each person were needed for the diagnosis of CFS. Roughly 75 percent of abnormalities were unique to each individual, which Naviaux said is useful in guiding personalized treatment.

“This work opens a fresh path to both understanding the biology of CFS and, more importantly to patients, a robust, rational way to develop new therapeutics for a disease sorely in need of them.”

The study authors noted additional research using larger groups of participants from diverse geographical areas is needed to validate both the universality and specificity of the findings.

Co-authors include: Jane C. Naviaux, Kefeng Li, A. Taylor Bright, William A. Alaynick, and Lin Wang, all at UC San Diego; and Asha Baxter, Neil Nathan, Wayne Anderson, and Eric Gordon, Gordon Medical Associates.

Funding for this research came, in part, from the UC San Diego Christini Fund, The Wright Family Foundation, The Lennox Foundation, the It Takes Guts Foundation, the UC San Diego Mitochondrial Disease Research Fund and gifts from Tom Eames and Tonye Marie Castenada.

Metabolic features of chronic fatigue syndrome, by Robert K. Naviaux, Jane C. Naviaux, Kefeng Lia, A. Taylor Bright, William A. Alaynick, Lin Wang, Asha Baxter, Neil Nathan, Wayne Anderson, and Eric Gordon in PNAS [Published online before print August 29, 2016]

For more information about CFS and mitochondrial research, visit naviauxlab.ucsd.edu

See also:

Daily mail article, 29 Auust 2016: ‘Chronic fatigue IS a real condition’: People with the debilitating illness have ‘telltale signs in their blood’

Times article, 30 August 2016: Chronic fatigue syndrome could be the body trying to hibernate

Open Medicine Foundation blog: ME/CFS Ground-breaking Metabolomics results, Ronald W Davis

Science alert: Chronic fatigue syndrome appears to leave a ‘chemical signature’ in
the blood

Pacific standard: How Chronic Fatigue Syndrome affects your metabolism

Health rising: The Core Problem in Chronic Fatigue Syndrome Identified? Naviaux’s Metabolomics Study Breaks Fresh Ground by Cort Johnson

ME Action:  Naviaux’s metabolism paper is about as big as you think

Washington Post: Chronic fatigue syndrome may be a human version of ‘hibernation’

 

 

 

 

 

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Protein kinase gene dysfunction in severe CFS/ME

Posted on 08/30/2016 by wames

Research abstract:

Background:

The etiology and pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are unknown. However, natural killer (NK) cell dysfunction, in particular reduced NK cytotoxic activity, is a consistent finding in CFS/ME patients. Previous research has reported significant changes in intracellular mitogen-activated protein kinase pathways from isolated NK cells. The purpose of this present investigation was to examine whether protein kinase genes have a role in abnormal NK cell intracellular signaling in CFS/ME.

Method:

Messenger RNA (mRNA) expression of 528 protein kinase genes in isolated NK cells was analyzed (nCounter GX Human Kinase Kit v2 (XT); NanoString Technologies) from moderate (n = 11; age, 54.9 ± 10.3 years) and severe (n = 12; age, 47.5 ± 8.0 years) CFS/ME patients (classified by the 2011 International Consensus Criteria) and nonfatigued controls (n = 11; age, 50.0 ± 12.3 years).

Results:

The expression of 92 protein kinase genes was significantly different in the severe CFS/ME group compared with nonfatigued controls. Among these, 37 genes were significantly upregulated and 55 genes were significantly downregulated in severe CFS/ME patients compared with nonfatigued controls.

Conclusions:

In severe CFS/ME patients, dysfunction in protein kinase genes may contribute to impairments in NK cell intracellular signaling and effector function. Similar changes in protein kinase genes may be present in other cells, potentially contributing to the pathomechanism of this illness.

Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients, by Anu Chacko, Donald R. Staines, Samantha C. Johnston and Sonya M Marshall-Gradisnik in Gene Regulation and Systems Biology 2016:10 85-93, 28 Aug 2016

 

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MRI of hearts of women with CFS found lower left ventricular function

Posted on 08/30/2016 by wames

Research abstract:

Objective:
In chronic fatigue syndrome (CFS), only a few imaging and histopathological studies have previously assessed either cardiac dimensions/function or myocardial tissue, suggesting smaller left ventricular (LV) dimensions, LV wall motion abnormalities and occasionally viral persistence that may lead to cardiomyopathy. The present study with cardiac magnetic resonance (CMR) imaging is the first to use a contrast-enhanced approach to assess cardiac involvement, including tissue characterisation of the LV wall.

Methods:
CMR measurements of 12 female CFS patients were compared with data of 36 age-matched, healthy female controls. With cine imaging, LV volumes, ejection fraction (EF), mass, and wall motion abnormalities were assessed. T2-weighted images were analysed for increased signal intensity, reflecting oedema (i. e. inflammation). In addition, the presence of contrast enhancement, reflecting fibrosis (i. e. myocardial damage), was analysed.

Results:
When comparing CFS patients and healthy controls, LVEF (57.9 p/m 4.3 % vs. 63.7 p/m 3.7 %; p<0.01), end-diastolic diameter (44 p/m 3.7 mm vs. 49 p/m 3.7 mm; p<0.01), as well as body surface area corrected LV end-diastolic volume (77.5 p/m 6.2 ml/m^2 vs. 86.0 p/m 9.3 ml/m^2; p<0.01), stroke volume (44.9 p/m 4.5 ml/m^2 vs. 54.9 p/m 6.3 ml/m^2; p<0.001), and mass (39.8 p/m 6.5 g/m^2 vs. 49.6 p/m 7.1 g/m^2; p=0.02) were significantly lower in patients. Wall motion abnormalities were observed in four patients and contrast enhancement (fibrosis) in three; none of the controls showed wall motion abnormalities or contrast enhancement. None of the patients or controls showed increased signal intensity on the T2-weighted images.

Conclusion:
In patients with CFS, CMR demonstrated lower LV dimensions and a mildly reduced LV function. The presence of myocardial fibrosis in some CFS patients suggests that CMR assessment of cardiac involvement is warranted as part of the scientific exploration, which may imply serial non-invasive examinations.

Chronic fatigue syndrome in women assessed with combined cardiac magnetic resonance imaging, by M.A.G.M. Olimulder, M.A. Galjee, L.J. Wagenaar, J. van Es, J. van der Palen, F.C. Visser, R.C.W. Vermeulen, C. von Birgelen in Netherlands Heart Journal [Preprint]
August 25, 2016

 

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Post-exertional malaise: an exploratory factor analysis

Posted on 08/29/2016 by wames

Research abstract:

Post-exertional malaise is a cardinal symptom of myalgic encephalomyelitis and chronic fatigue syndrome. There are two differing focuses when defining post-exertional malaise: a generalized, full-body fatigue and a muscle-specific fatigue.

This study aimed to discern whether post-exertional malaise is a unified construct or whether it is composed of two smaller constructs, muscle fatigue and generalized fatigue. An exploratory factor analysis was conducted on several symptoms that assess post-exertional malaise. The results suggest that post-exertional malaise is composed of two empirically different experiences, one for generalized fatigue and one for muscle-specific fatigue.

Deconstructing post-exertional malaise: An exploratory factor analysis, by Stephanie L McManimen, Madison L Sunnquist, Leonard A Jason in J Health Psychol August 24, 2016

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Ampligen – the first drug approved in the world for ME/CFS

Posted on 08/26/2016 by wames

Health rising blog post, by Cort Johnson, 25 August, 2016: Ampligen Takes Big Step Forward – Becomes First Drug Approved Anywhere For Chronic Fatigue Syndrome

Ampligen became the first drug approved for chronic fatigue syndrome (ME/CFS) anywhere in the world this week when ANMAT, the Argentine FDA, approved the drug for use in people with severe ME/CFS.

Why should we get excited about Ampligen’s approval in Argentina? Because Argentina has a modern medical system which includes having a rigorous drug approval process. Hopefully this will be a harbinger of things to come for Ampligen.

Argentina was the first Latin American country Hemispherx Biopharma (HB) – the maker of the drug – tried to get Ampligen approval in. The process, which took four years, began when HB teamed up with GP Pharm, an Argentine pharmaceutical company. GP Pharm used the same studies to shepherd the approval through ANMAT, the Argentine form of the FDA, that HB used in its FDA application for Ampligen two years ago.

Ampligen was approved for use in people with “severe ME/CFS” – a designation that was based on the type of ME/CFS patients that took part in the company’s original U.S. studies. A person with severe ME/CFS in Argentina needs to meet the new IOM and the (old) Holmes criteria, and have a Karnovsky score between 40 and 60 in order to get access to the drug.

40: Disabled; requires special care and assistance.
50: Requires considerable assistance and frequent medical care.
60: Requires occasional assistance, but is able to care for most of his personal needs.

Hemispherx believes that at least 100,000 and perhaps as many as 500,000 patients in the 42 million person country will meet the criteria.

Equel’s has been making the rounds of media outlets to discuss Ampligen. A financial analyst with Crystal Research agreed in an interview at Small Cap Nation – a financial media outlet focused on small companies – that the potential for Ampligen in the ME/CFS market alone was huge. With Ampligen the sole drug even being considered at this point for ME/CFS it would have the market to itself. He called the Argentine approval “very significant” and put the potential valuation of the drug in the multi-billion dollar range.

Watch interview

He also agreed the Argentine approval will make getting approval elsewhere easier.

The FDA Question

I talked with Nancy McGrory at Hemispherx about the recent approval. She believes the approval could help HB in other countries with similar regulatory drug processes. The fact that Ampligen passed muster in a country with a modern medical system with a rigorous drug approval process will likely, McGrory thought, prompt other countries to take a much closer look at the drug.

Ten years ago, she noted, most pharmaceutical drug companies concentrated on getting drug approval at the FDA first in the belief that making it through the FDA’s notoriously tough regulatory process would give other countries confidence that the drug was safe and effective. The FDA – which is focused first on protecting the public health – has proved so risk averse lately, though, that some drug companies are choosing to get drug approval outside the U.S. first.

That brought up the question, though, what’s going with FDA approval for Ampligen? When I asked McGrory about the reception Ampligen was getting at the FDA these days, she sounded hopeful. She said she believed that the work of patients, advocates and ME/CFS experts to educate the FDA about ME/CFS had paid off. The FDA Workshop and other meetings, she believed, really got the message across about how serious disease is, and that produced a sea-change in the agencies attitude towards ME/CFS. The FDA she thought, would like very much to approve a drug for this illness.

Thomas Equels, HB’s new President has made Ampligen approval the companies top priority and has stated that he will to do whatever is necessary to get it done. McGrory said HB officials have meet with the FDA and the NIH several times, and will soon meet to finalize the protocol for what will hopefully be the final phase III study on ME/CFS.

The FDA wants, and is going to get a several hundred person trial. Equel’s job now is to find partners to fund it. The companies new stance – that it’s committed to reach out and either license its technology or find a major pharmaceutical company or investor to assist it – is a distinct change of pace at HB.

In another hopeful note, Hemispherx reported it’s at long last identified a subset of high responders to Ampligen and will present a paper to that effect at the IACFS/ME conference in October. Finding high responders to Ampligen would, of course, greatly help HB be successful in a phase III trial.

Read what Equels said about what a potential investor should know about Ampligen

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Milk protein intolerance in ME/CFS

Posted on 08/26/2016 by wames

ME Research UK article, 23 Aug 2016: Milk protein intolerance

intolerances
Around 20% of people in developed societies have adverse reactions to particular foods, and some have outright food intolerances, defined as undesirable non-allergic reactions that do not involve a direct immune response. The most common food ‘sensitivities’ in the modern world are to gluten, lactose, fructose, milk and eggs, but there are a plethora of other candidates (see Figure).

Food intolerances also have a significant role in ME/CFS. Sensitivity to foodstuffs is one of the possible “immune, gastro-intestinal & genitourinary impairments” used for diagnosis (see the 2011 ICC definition), and many individual patients say that they benefit from avoiding certain foods.

Gluten is a good example, and we know from emails and phone calls to ME Research UK that excluding gluten from the diet improves some patients’ symptoms. These symptoms not only include gut discomfort (abdominal pain, bloating etc.) as might be expected but more systemic manifestations such as brain fog, headache, joint and muscle pain. Now, a new report in the August 2016 issue of Acta Pediatrica (read more) suggests that milk protein may also be contributing to symptoms, at least in some ME/CFS patients.

The very active group led by Prof Peter Rowe at Johns Hopkins University School of Medicine in Baltimore has been conducting a two-year cohort study of physical findings and outcomes in young people with ME/CFS. One of the beauties of a programme of research is that unexpected observations can be followed up, and the group had noticed that a number of their patients had symptoms and signs consistent with a delayed reaction to milk protein.

To test whether milk intolerance might be a factor in the maintenance of illness, they designed a sub-study to examine overall quality of life (including fatigue, sleep and activity limitations caused by physical health problems) before and after a 6-month period of dietary milk protein restriction. Intolerance to milk protein is diagnosed on clinical grounds alone because no validated laboratory tests exist as yet, so the team performed an initial dietary trial.

Of 55 young ME/CFS patients,  17 (31%) were found to be milk-protein intolerant. In the testing phase of the study, a clinically important improvement in the frequency and severity of symptoms was reported by some participants once milk protein was eliminated from their diet. These patients were then put on a milk-free diet for 6 months, and their quality of life was compared at the start and end of the study with that of patients who could tolerate milk protein.

At the start of the study, health-related quality of life was significantly worse in patients who were milk protein intolerant than in those who were not. However, six months after the milk-free diet, quality of life had improved to a greater degree in the patients with milk protein intolerance, and there was no longer a difference in quality of life between the two groups.

Also, milk-intolerant patients on the milk-free diet had improvements in upper gastrointestinal and systemic symptoms, and these improvements occurred within two weeks of starting the diet. Of course, as this was not a randomised trial, it’s not possible to say that these effects were due to the milk-free diet alone. The evidence is certainly suggestive, however, and it may be that a milk-free diet could have a significant positive effect in some ME/CFS patients.

For the authors, the importance of the results is that almost a third of adolescents and young adults with ME/CFS “had evidence of treatable milk protein intolerance”, a higher proportion than expected given the evidence that the prevalence of ‘true’ reactions to food may be quite small in the general population (read more). Crucially, most of the study patients who benefitted from a milk-free diet  had previously been unaware of the contribution of milk to their symptoms, probably because of the time delay between consumption and symptoms (unlike in true food allergy where symptoms develop far more rapidly).

The authors point out that for patients with ME/CFS the situation can be clarified by a two-week trial of a milk-free diet. While stopping or reducing milk consumption is not the ‘answer’ to ME/CFS, it’s worth being aware that the symptoms of ME/CFS may be exacerbated in some people by milk, a common foodstuff. If patients’ experience of avoiding gluten is anything to go by (read more), the effects of a milk-free diet for a short period could be both surprising and welcome.

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