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Meet the Newly Formed London Med Ed Workgroup

15/10/2016

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The London Med Ed Workgroup is a new initiative formed during the 11th Invest in ME International ME Conference 2016 (IIMEC11), held in London on June 3, 2016.
Solve ME/CFS Initiative’s vice president for research and scientific programs, Dr. Zaher Nahle, was tasked by meeting organizers to assemble a starter team of Med Ed experts from conference participants to examine national and international medical educational efforts in ME/CFS and explore areas for potential collaboration.
The goals of the London Med Ed Workgroup are to 1) create effective vehicles for improving current medical information on ME/CFS, 2) improve the dissemination and exchange of medical information, and 3) develop educational materials building on existing tools and relevant literature.
On June 4, 2016, the team held its first meeting in London, followed by a teleconference in July. In addition to Dr. Nahle, the team thus far is comprised of several prominent patient advocates and ME/CFS experts including Mary Dimmock, Dr. Rosamund Vallings, Dr. James Baraniuk, and Dr. Vicky Whittemore. Regular updates will be provided on the work of this team as well as its ongoing efforts and expansion.
“This collaborative work is yet another way in which we are trying to create momentum on all fronts of ME/CFS,” said Dr. Nahle. “When it comes to a complex, poorly understood disease like this, it is critical that every medical health professional, all medical school curricula, and every governmental agency site is up to date and equipped with the right information and tool kits; this is feasible in this day and age.”
Notably, Dr. Nahle is also part of the CDC Technical Development Workgroup (TDW) that provides input on the accuracy and effectiveness of the CDC website and the dissemination of correct information to healthcare providers as well as the general public. There are many aspects of the current CDC website that provide insufficient or incorrect information to the public; we are actively engaged in working to correct this serious deficiency.
 
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Input for New Research Strategies for ME/CFS - NIH Request For Information (RFI): Ron Davis

15/10/2016

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We are grateful for the opportunity to provide input to the Trans-National Institutes of Health (NIH) ME/CFS Working Group as they develop strategies to guide NIH's research efforts and priority setting for research on ME/CFS. Our mission at the Stanford Chronic Fatigue Syndrome Research Center is to discover causes, a molecular diagnosis, and treatment options for ME/CFS. Through our research efforts, collaborations with the ME/CFS research and clinical community, and extensive engagement with patients, we have defined several elements of importance for future ME/CFS research programs.
 
A key consideration in ME/CFS research efforts is the complex and multisystemic nature of this disease, and we are happy to see the involvement of several NIH institutes in developing this plan. Because the causative factors driving the disease remain unknown, and because work from our team and others has indicated effects on neurology, metabolism, immunity, and more, it will be crucial that calls for proposals allow for open, unbiased, multifaceted, and systematic research. Broadening the scope of ME/CFS research will create opportunities for engaging researchers in other disciplines. Similarly, investigating numerous organ systems and biological pathways perturbed in ME/CFS may well reveal informative parallels to other diseases – for example, we and others have observed symptomatic, transcriptomic, and metabolic overlap between ME/CFS and neurodegenerative disorders like Parkinson's Disease. It is important not to limit research to single organs like the brain, and to integrate results from many different organs and molecular processes so that they can be understood at the systems level. Big data approaches and high-throughput, large-scale molecular profiling should therefore be prioritized. Such efforts hold promise to identify key genes or pathways underlying ME/CFS. Similarly, large-scale in vitro drug screening efforts would help point to a variety of molecules and molecular processes as therapeutic targets. 
 
Understanding the molecular etiology of ME/CFS is another important opportunity. A long-standing belief in the field is that an infectious agent causes the disease, and that the pathogenicity of the as-yet-undiscovered organism is responsible for the severity of the illness. An equally plausible explanation is that a stressor such as trauma, infection, or genotoxic stress may trigger a series of events that lead to a hypometabolic state. This model is observed in children with congenital mitochondrial disorders, where the phenotype does not present itself until after a serious viral infection. This shift in thinking opens up the possibility that ME/CFS has strong genetic and environmental associations, which may also explain the extensive heterogeneity in its presentation, progression, and recovery across patients. The search for novel infectious agents should continue, but research efforts should also focus on understanding individual host susceptibility and response to infection. For example, it may not be a particular infectious agent that results in the disease, but rather a particular host state as a function of numerous biological and external factors that governs an individual’s susceptibility. This perspective mirrors the NIGMS-funded Glue Grant on Inflammation and Host Response to Injury, which used an integrated omics approach to define variable responses to infection and trauma. Characterizing host responses to infection and understanding the mechanisms of the long-term sequelae may reveal insights into ME/CFS that are relevant to numerous other diseases of infectious origin, such as Chronic Lyme Disease and Post-Ebola Syndrome (Mattia et al., 2016). Moreover, such precision medicine approaches would build a more comprehensive understanding of ME/CFS and offer richer opportunities for therapeutic intervention.
 
Another major challenge is our lack of understanding of the prevalence and landscape of ME/CFS, which is largely due to the difficulty in diagnosing the disease. The search for precise molecular biomarkers is a great opportunity afforded by this research program, which would be accelerated through multi-omics approaches in large patient cohorts. Current estimates of the prevalence of ME/CFS vary widely (800,000 to 2.5 million cases in the US) due to varying diagnostic and data collection methods. There is an opportunity here to improve these estimates based on modernized methods and community-defined standards, including criteria specified in the 2015 Institute of Medicine Report, and by considering questionnaire-based responses like the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort in the United Kingdom (Collin et al., 2016). 
 
Because of these complex scientific challenges, ME/CFS research presents an excellent opportunity for developing and piloting novel methods and technologies in discovering biomarkers, elucidating disease mechanisms, and revealing therapeutic possiblities. The methods we need to understand this complex disease may very well not exist yet. Engineering and technology development efforts towards highly sensitive, quantitative molecular profiling and/or measuring novel cellular properties, as well as novel computational analyses that integrate multiple datatypes to define disease mechanisms, should be encouraged. Again, it is highly likely that such efforts will prove useful in the study of other diseases, be they infectious, genetic, or complex in origin.
 
Beyond scientific considerations, we would like to note several programmatic considerations that we believe are key for rapid progress. Long-term studies of patients are absolutely essential. Such a mechanism has proven effective in the NIGMS Glue Grants described above. Moreover, maintaining an open structure in RFAs will allow scientists to develop and refine their hypotheses as research progresses, as appropriate for the unknown/uncertain nature of the field. As highlighted in several places above, the opportunities for collaborative efforts within and beyond the ME/CFS research community to understand and treat this disease are numerous. There are numerous experts spread across the world, each taking their own approaches based on their own expertise. We believe future funding programs should not only encourage, but establish frameworks for highly collaborative data sharing and strategizing that bring together researchers and clinicians. All data should be made publicly available as early as possible (even before publication), in both raw and accessible formats. This will not only facilitate collaboration (for example by encouraging biocomputing experts to engage with the data) and integrative analyses, but also empower patients to understand more about their disease and what progress is being made. As we have all seen, the ME/CFS patient community is extremely active, engaged, and eager for actionable results.
 We thank you once again for the opportunity to provide input on this matter, and look forward to the new strategies for ME/CFS research efforts put forth by this working group.
 Yours sincerely, 
Ronald W. Davis, Ph.D.  Professor of Biochemistry and Genetics, Stanford University
Director, Stanford Chronic Fatigue Syndrome Research Center and Stanford Genome Technology Center
Director, Scientific Advisory Board, Open Medicine Foundation
 
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Teens With POTS: How Long Does It Last?

15/10/2016

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Medscape paediatrics
​William T. Basco, Jr, MD, MS…. August 31, 2016  

Postural Orthostatic Tachycardia Syndrome
Postural orthostatic tachycardia syndrome (POTS) occurs in approximately 1% of adolescents. Teens often develop the condition after infectious illnesses (eg, mononucleosis) or athletic injuries.
POTS is characterized by chronic symptoms, including neurologic symptoms (eg, nausea, vision change, or dizziness), and an increase in heart rate of at least 40 beats/min when standing, without an alternative diagnosis for these symptoms. Overhydration, increasing salt intake, medications, exercise, and biofeedback can ameliorate symptoms.[1] The natural history of POTS in adults shows that the symptoms improve over time, but few data exist on adolescents.[2]
POTS in Teens
A recent study[3] assessed outcomes in a cohort of adolescents (aged 13-18 years; mean, 16.5 years) who were diagnosed with POTS at a single clinic from 2003 to 2010. In 2013, the teens were surveyed and asked to report on their symptom trajectory as they aged into young adulthood.
The survey was sent to 502 patients, and responses were received from 172 (response rate, 34%). A majority (84%) of the respondents were girls, and the average age at the time of the survey was 21.8 years. The average period between being evaluated for POTS and completing the survey was 5.4 years.
Of interest, 81% of respondents had attained some college or technical training compared with 41% of the US population in the same age range. Among respondents older than 23 years, 49% were college graduates—a proportion greater than that among the general US population.
At the time of POTS diagnosis, 72% of the respondents reported being prescribed a beta-blocker, and 27% of respondents were still taking these drugs. The second most common drug used to treat POTS was a selective serotonin reuptake inhibitor, prescribed for 28% of patients. When asked which treatment they believed had helped most, 48% of respondents chose excessive hydration, 45% chose physical conditioning, and 41% chose a high-salt diet. Fewer than 30% of the respondents reported that a drug was the most helpful treatment.
At the time of the survey, 71% of respondents reported being in excellent, very good, or good health, and 86% responded that their symptoms were either resolved, improved, or just intermittent. Symptoms had completely resolved in 19% of respondents, and 51.2% reported that their symptoms persisted but were milder. Whereas 15.7% of respondents reported a relapsing/remitting course of POTS, only 8.7% reported that their symptoms persisted with unchanged severity. Unfortunately, 3.5% reported persistent and more severe symptoms. Young men were more likely than young women to report complete remission (36% vs 16%).
Mean self-reported physical functioning and health assessment were lower than population means. In fact, physical health scores had the greatest correlation with overall health scores. The lowest health self-assessment scores were seen among those who reported pain, nausea, and exercise intolerance in conjunction with POTS symptoms. Among all respondents, despite improvement overall, 73% reported that they still experienced some degree of physical limitation during vigorous activity, 38% reported some effect on work or other activities, and 50% said that they accomplished less than they would like to accomplish.
These findings demonstrate that a large majority of adolescents with POTS improve over time and that persistence of physical symptoms correlates heavily with perceived health.
Viewpoint
In the introduction to their study,[3] Bhatia and colleagues review published data demonstrating that a multifaceted approach is often the best way to improve symptoms in patients with POTS. My anecdotal experience correlates with their finding that many patients present after an illness or injury, and prolonged inactivity often exacerbates both the real symptoms and the patient's psychological responses to them.
The take-home message from this study is to remember to offer these families hope, as confirmed by follow-up data on POTS in teens. The biggest concern for these patients is that they will never feel any better, given that they are often experiencing prolonged symptoms by the time they come to medical attention. I plan to use these findings to reinforce with families the need to take a multipronged approach. Searching for additional diagnoses is not always helpful, and rarely does one silver bullet relieve all symptoms.
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Hanson's Metabolomics ME/CFS Study Validates Naviaux's Core Finding

15/10/2016

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A Great Addition to the ME/CFS Field

Dr. Maureen Hanson has been all over the place in chronic fatigue syndrome (ME/CFS) lately.
Hailing from Duke and Harvard and now at Cornell she has quite a pedigree. With a family member with chronic fatigue syndrome (ME/CFS), she also has a personal stake in this disease, and has penned several editorials supporting ME/CFS research. Her "Be Aware and Beware" Huffington Post blog and her Congressional Hill post "When Hoofbeats are Zebras" showed that she's not afraid to leave the laboratory and get out and advocate. At every opportunity she makes it very clear that ME/CFS is a real disorder. Her last gut study went viral and was picked up by over 50 media outlets.

She recently spoke at the Invest in ME Conference, and at the Simmaron Patient event, and is on the scientific board of the Simmaron Research Foundation.

As and added bonus she appears to be very good at getting NIH grants. She first popped up in ME/CFS with a grant to study XMRV in 2011. Since 2011 she's gotten three R21 grants on ME/CFS, and is a collaborator on a big RO1 immune functioning grant with Fabian Campagne at Cornell. She's also being funded by the Hitchens Foundation's Chronic Fatigue Initiative. She seems to have a talent for taking on interesting studies. She's definitely someone to keep an eye on.

Metabolomics

Now she's moving into metabolomics. In the Solve ME/CFS webinar this week Hanson revealed that a small metabolomics study she pieced together using donations had replicated Naviaux's core finding - that ME/CFS is hypometabolic disorder.

Her study was smaller than Naviaux's: compare the 80 or so patients/controls and 612 metabolites measured in his study to the 32 patients/controls and 361 metabolites in the Hanson pilot study. All the participants n her study were also female and all came from an ME/CFS expert, Dr. Susan Levine, who has been collaborating heavily with Dr. Hanson.

Naviaux noted that the field is moving so quickly that it lacks standardization and this study showed it. The Hanson team used a different kind of mass spectrometer, and handled the samples differently. In fact, the way Hanson was talking, it sounded like everything was done differently in the Hanson study.

Nevertheless, Hanson's core findings were strikingly similar to Naviaux's. She found an almost across the board reduction in metabolite levels; fully eighty-eight percent of the metabolites in the ME/CFS patients were reduced (compared to 84% in Naviaux's study.)

Some similar pathways (phospholipids, purines, proline, fatty acid metabolism) showed up and others did not. The dramatic sphingolipid reductions Naviaux found, for instance, did not show up in the Hanson study, and Hanson found several pathways that did not show up in the Naviaux study.

Hanson suggested that the completely different methods used as well as the different geographic region the patients hailed from could explain the differences found. Whatever the differences found, the core finding of a distinct hypometabolism in chronic fatigue syndrome (ME/CFS) clearly excited Hanson and she stated:
"The similarities are very promising for metabolomics to give some very useful information about ME/CFS"
Click to expand...
Hanson's metabolomic money is gone, but she's applying for an NIH grant. Scoring a big ROI grant - say $3,000,000 over several years - would, of course, be a major step forward for metabolomic research in ME/CFS.

How to Fit Many Symptoms into One Core Pathology ...

With the Chronic Fatigue Initiative's help, Hanson has also been studying mitochondrial genetics. Naviaux has stated that people with ME/CFCS do not have a genetic mitochondrial disease, and Hanson's results backed that assertion up; in fact, none of the almost 200 patients tested had anything suggesting an inherited mitochondrial condition. She did, however, find evidence - as Ron Davis has suggested - that genetic polymorphisms could be producing different symptoms in different ME/CFS patients.

Maureen Hanson's Solve ME/CFS Initiative Webinar

One altered mitochondrial DNA gene, for instance, appeared to be associated with gut symptoms; another was correlated with chemical sensitivity - a problem that gets almost no research attention - but can be terribly impactful. (Dr. Naviaux believes, interestingly enough, that low energy states lend themselves to hypersensitivity reactions. )Hanson's study suggested genetic differences in the mitochondria could result in widely varying symptoms in ME/CFS. She noted though, that much, much larger studies are needed to validate her findings.

Hanson is not by any means done with the mitochondria; she is also examining the mitochondrial functioning of NK, T and B cells. The poor functioning of NK cells is one of the most consistently found immune abnormalities in ME/CFS, but problems with T-cell functioning have also been found, and reports of poorly functioning B-cells have shown up as well.

Could the immune problems in ME/CFS be caused by a hypo-metabolic or under-energized immune system? Hanson will use an Agilent device to determine if problems with glyoclysis - the energy pathway that releases ATP and ATP through the conversion of glucose - are sending immune cells into a somnolent state.

Hanson then went on talk about her recent gut findings which included a reduction (another reduction) in diversity and abundance of microbial species in ME/CFS. She also suggested that the reduction in microbial diversity seen in an ill twin might be associated with that twins reduced aerobic capacity.

A New Chronic Fatigue Syndrome (ME/CFS) Center

In some very good news Hanson announced that the Dean at Cornell has allowed Dr. Hanson to create a new ME/CFS research center called the "Center for Enervating NeuroImmune Disease" (CEND). (Enervating means feeling weak and lacking in energy). The Center will collaborate with Betsy Keller at Ithaca College. It contains three researchers, involves eight labs which have or are applying for an ME/CFS grant, and is working with no less than five physicians - and Hanson hopes it will grow significantly.

The fact that Hanson felt it was time to create a formal center for ME/CFS at Cornell, plus her ability to hit the ground running with a strong staff is very encouraging particularly at Cornell - which has a top ranked Medical School. The new Center will surely be a strong candidate for the projected NIH research consortium.

Maureen Hanson is clearly the kind of researcher we've been looking for and hope to get more of. She's very committed, she can get grants, she's daring enough to start an ME/CFS research center and she clearly works well with others.

Some ME/CFS Metabolomic / Metabolic Studies Coming Up

The Naviaux study really caught our attention but a surprising number of other groups are doing metabolomics/metabolic/mitochondrial studies. McGregor in Australia, for instance, has been studying metabolism/metabolomics in ME/CFS for years. Here are some metabolomic / mitochondrial studies underway.
o    Hanson's small ME/CFS metabolic study (under review now).
o    The Naviaux/Ron Davis OMF funded expansion of Naviaux's recent study
o    Naviaux's studycomparing the metabolome of ME/CFS patients and other diseases
o    Hanson's NK, T and B cell energy production study
o    The Lipkin/Hornig study tying metabolomics results in the blood to their gut findings.
o    The Bateman Horne Center/Watanabe Japanese metabolomics study. In what is clearly a Suzanne Vernon study, the Watanabe study, a Michael Hougton Canadian Cytokine Study, and Alan Light's Autoantibody study will all use the same 100 patients samples - thus allowing them potentially to merge their findings.....
o    Nath's metabolic chamber study in the Intramural study
o    Several studies from Armstrong and McGregor in Australia
o    The SolveME/CFS in house mitochondrial study (more on that later.)
The Bateman-Horne Study
Depression - Sometimes a Metabolic Disorder?

ME/CFS might not be the only disease which may get turned around by metabolomics. Let's take a quick look at a metabolomic study that could turn the medical profession's conception of depression - a disease that's often been confused with ME/CFS by doctors - upside down.

The potential breakthrough started, as many breakthroughs do, with one patient. As reported in the Pittsburg Post-Gazette, frustrated doctors who had run out of options with a treatment resistant young man with suicidal depression, turned to a biochemical geneticist for help.
The geneticist suggested doing a metabolic analysis of the young mans cerebral spinal fluid. That analysis turned the his life around. After finding that he had deficient levels of a protein called tetrahydrobiopterin, or BH4, they began treating him with a substance called sapropterin. He was able to recover, return to school and is now working in his chosen field.

After getting the same results in five other treatment resistant depressed patients, the group began a larger study looking at hundreds of metabolites in the spinal fluid of 33 patients. About two thirds of them displayed significant metabolic abnormalities; of those more than half (12/21) had the same cerebral folate deficiency found in the young man. All showed improvements including reductions in suicidal thoughts on a high dose regimen of folinic acid.

For some young people on the protocol the improvements have been dramatic. The parents of one 13 year stated that within a month of taking the folinic acid, “we felt like we had our Ben back."

This isn't to say that all the patients had that kind of result, but it does indicate the power of this technology to uncover new insights that can lead to dramatic improvements even in seemingly intractable diseases like treatment resistant depression (and who knows...perhaps ME/CFS.)

What would, one wonders, a metabolomic analysis of ME/CFS patients cerebral spinal fluid find?
 
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Metabolic features of chronic fatigue syndrome

15/10/2016

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The Economist
Chronic-fatigue syndrome
A new test may diagnose a mysterious illness, and also help to explain it
Sep 3rd 2016 | From the print edition
·          
CHRONIC-FATIGUE SYNDROME, or CFS, which afflicts over 1m people in America and 250,000 in Britain, is certainly chronic and surely fatiguing. But is it truly a syndrome, a set of symptoms reliably associated together and thought to have a single underlying cause—in other words, a definable disease?
CFS’s symptoms—debilitating exhaustion often accompanied by pain, muscle weakness, sleep problems, “brain fog” and depression—overlap with those of other conditions. These include fibromyalgia (itself the subject of existential doubt), clinical depression, insomnia and other sleep disorders, anaemia and diabetes. These overlaps lead some to be sceptical about CFS’s syndromic nature. They also mean many people with CFS spend years on an expensive “diagnostic odyssey” to try to find out what is going on.
Scepticism about CFS’s true nature is reinforced by the number of causes proposed for it. Viruses, bacteria, fungi and other types of parasite have all had the finger pointed at them. So have various chemicals and physical trauma. Evidence that CFS truly does deserve all three elements of its name has accumulated over the years but a definitive diagnostic test has remained elusive. Until, perhaps, now. For in this week’s Proceedings of the National Academy of Sciences Robert Naviaux of the University of California, San Diego, and his colleagues published evidence that the metabolisms of those diagnosed with CFS are all changing in the same way. Their data suggest it is this cellular response to CFS-triggering traumas, and not the way the response is set in motion, which should define the illness. They also show that this response produces a chemical signal that might be used for diagnosis.

Dr Naviaux and his team collected and analysed blood samples from 45 people who had been diagnosed with CFS, and also from 39 controls who were free of any CFS-related symptom. They then trawled through those samples looking at the levels of 612 specific chemicals, known as metabolites, which are produced during the day-to-day operations of living cells.
These metabolite profiles, they found, differed clearly and systematically between the patients and the controls. Some 20 metabolic pathways were affected, with most patients having about 40 specific abnormalities. The biggest differences were in levels of sphingolipids, which are involved in intercellular communication, though other molecules played a role as well. These differences should give clues as to what is happening at a cellular level during CFS. More immediately, a handful of the abnormalities—eight in men and 13 in women—were enough, collectively, to diagnose with greater than 90% accuracy who had the disease.
That is a good start. If this discovery is to lead to a reliable test for CFS, though, Dr Naviaux’s experiment will have to be repeated to compare those diagnosed as having CFS with those who are not so diagnosed yet display some of its symptoms. The answer should soon become apparent, for he is already applying his method to people who have depression, autism, traumatic brain injury and post-traumatic-stress disorder.
One crucial question that needs an answer if CFS is to be understood better is: what cellular changes are these metabolic abnormalities bringing about? Here, Dr Naviaux has already made an intriguing and slightly disturbing discovery. Similar metabolite profiles to those seen in CFS are characteristic of a state known as “dauer” that occurs in one of biology’s most-studied animals, a soil-dwelling threadworm called C. elegans (pictured). In dauer, which is reminiscent of hibernation in larger creatures, the worm puts its development on hold and enters a state of suspended animation in response to threats such as reduced food, water or oxygen levels. It can survive this way for months, though the lifespan of an active worm is mere weeks.
It may be a coincidence, but six of the diagnostic metabolites whose levels are low in CFS are also low in dauer. If it is not a coincidence, though, that suggests a biochemical overlap between the two conditions. If this were true, it could be of great value both in understanding CFS’s underlying biology and (because C. elegans is so well examined and easy to study) in experimenting with potential treatments.
From the print edition: Science and technology
 

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