Dr Zahler Nahle’s outline of ME/CFS research needs

Posted on 07/18/2016 by wames

Solve ME/CFS Initiative blog post: Dr. Zaher Nahle’s Response to the NIH RFI

Solve ME/CFS Initiative submitted a unique and pointed response to the recent NIH request for information (RFI), NOT-NS-16-024, regarding new research strategies for ME/CFS.

On May 24, 2016, the National Institutes for Health (NIH) released the first ever Request for Information (RFI) regarding ME/CFS. The RFI specifically requested submissions to address new research strategies for ME/CFS. From one research organization to another, Solve ME/CFS Initiative (SMCI) used this opportunity to articulate what our vision for an ideal research opportunity from the NIH would look like.

On June 24, 2016, SMCI submitted to the NIH a sample funding opportunity announcement (FOA) addressing the key elements we feel have been absent or underfunded in ME/CFS research. This hypothetical FOA was authored by SMCI’s vice president for research and scientific programs, Dr. Zaher Nahle, and presented utilizing the formatting and language of the NIH itself. The reasoning behind replicating the NIH’s own model was to highlight the dire need for research funding and encourage discussion of the NIH’s responsibility to further ME/CFS studies.

Dr. Nahle’s submission includes discussion on the following topics:

  • Interdisciplinary research and biomarkers
  • Bioenergetics
  • Neuroendocrine systems
  • Immunity and inflammation
  • Epidemiology and diagnosis
  • Physiological interactions
  • Treatment and quality of life
  • Methodological considerations
  • Funding support and timelines

To read SMCI’s full RFI submission, please click here.

[Please note that this is NOT an announcement of (or any part of) an actual FOA. This document was prepared and submitted by Dr. Zaher Nahle, vice president for research and scientific programs at SMCI, using existing material from the NIH website combined with original content and opinions. This document is intended for informational use only and is a fictional FOA.]

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Gut microbes identify 83% of ME/CFS patients

Posted on 07/18/2016 by wames

MEAction blog post by Jaime S, 13 July 2016: New research: gut microbes identify 83% of patients 

Signs of bacterial infection and inflammation

Recently, a team of researchers led by Ludovic Giloteaux of Cornell University measured the levels of several biomarkers in 49 ME/CFS patients and 39 controls, including LPS to measure bacteria in the bloodstream and CD14 and C-reactive protein to measure inflammation.  Researchers also measured the levels of intestinal fatty acid binding protein (I-FABP) to show GI damage.

ME/CFS patients showed significantly higher levels of lipopolysaccharides (LPS) in their blood, which means that they had more gram-negative bacteria than controls. These elevated levels of bacteria then caused the liver to produce LPS-binding protein, which was also elevated above levels found in controls. sCD14 is one of the ways that the body senses invading bacteria.  Levels of this inflammatory marker are high in those experiencing severe bacterial infections.  CD14 levels were also high in ME/CFS patients.

Microbial diversity

Giloteaux found that “ME/CFS samples had a significant overall lower microbial diversity, [which] differed at the phylum and family levels”: ME/CFS patients had especially low levels of Firmicutes in comparison to controls, and higher levels of Proteobacteria.

Proteobacteria include a wide range of pathogens, such as Escherichia, Salmonella, Helicobacter, and Yersinia.  Firmicutes are the largest group of bacteria in the human gut, and include Clostridium, Bacilli, and Ruminococcaceae.  ME/CFS patients were low in Ruminococcaeaea in particular, which has been associated with poor gut health, and low in Bifidobacterium, which is often used as a probiotic.

By using both inflammatory markers and the microbiome ‘blueprint’ of the disease, researchers found they could identify 83% of patients.

Microbiome as biomarker

The coupling of increased inflammatory markers plus dysbiosis led the researchers to conclude that damage to the gut is leading to microbial translocation, or the movement of bacteria from the inside of the gut to the bloodstream.  This in turn could lead to more inflammation and greater immune dysregulation.  While Giloteaux and his team did not claim to have found ‘the answer’ to ME/CFS, they may have identified a series of biomarkers: by using both the inflammatory markers and the microbiome ‘blueprint’, the researchers found they could identify 83% of patients.

More evidence

This is far from the first study to identify microbial dysregulation in ME or CFS patients — it’s not even the first to identify dysregulation in Firmicutes populations in particular.

In 2015, S.K. Shukla and colleagues examined blood and stool samples taken after patients and controls had exerted themselves. They found that both blood and stool sample microbiomes differed in ME/CFS patients (defined using the Fukuda criteria) in the abundance of “several major bacterial phyla”, including Bacilli in blood 48 hours post-exercise and Clostridium XIVa and IV (Firmicutes) in blood samples collected 15 minutes after exercise.  Moreover, the relative abundance of Firmicutes to Bacilli was skewed high in ME/CFS patients.

Other studies have verified dysregulation in the intestinal microbiota in ME/CFS. For example, a study of Norwegian ME patients demonstrated an increase of Firmicutes in patients over controls, including a fifty-fold decrease in Holdemania, and a 20-fold increase in Lactonifactor.

A piece of the puzzle

The gut microbiome plays a crucial role in human health, as 70% of the immune cells of the body live in the gut.  Healthy digestion supplies nutrients, produces beneficial or toxic metabolites and waste products, and destroys – or does not destroy – ingested pathogens.  The gut microbiome can also play a vital role in endocrinology by helping to generate and/or stimulate release of dopamine, norepinephrine, serotonin, nitric oxide, and the inhibitory transmitter aminobutyric acid — the gut bacteria may even directly affect the vagus nerve.

All this means that the gut microbiome could be a central key to unlocking the pathology of ME and CFS.

In the era of the metagenome, efforts to understand chronic disease have forced a shift from reliance on a ‘‘one microbe, one disease’’ model to a focus on how entire populations of microbes can become dysregulated. It is more likely that the structure of entire communities of microbes shift in individuals as they become ill, rather than that one pathogen is to blame.

For a more in-depth review of evidence of microbiome involvement in ME/CFS, see Navaneetharaja et al’s A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)? in the Journal of Clinical Medicine and check out MEpedia’s page on the microbiome.

[Edit!] If you’re interested in the microbiome’s effect on human health, a new text is coming out in October with a whole chapter devoted to gut dysbiosis and its relation to CNS disturbances. While this author can’t attest to the quality, it does look interesting! The Human Microbiota and Chronic Disease: Dysbiosis as a Cause of Human Pathology by Brian Henderson, Luigi Nibali.

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Six year study of abnormal brain changes in ME/CFS

Posted on 07/18/2016 by wames

ME Australia blog post, by  Sasha Nimmo, 12 July 2016: Six year study of abnormal brain changes in chronic fatigue syndrome patients

An Australian six year study evaluating progressive brain changes associated with chronic fatigue syndrome (Fukuda and Canadian Consensus Criteria definitions) shows patients’ brains deteriorate at an abnormal rate.

The study used optimized voxel based morphometry (VBM), a commonly-used automated tool for studying patterns of brain change in neurological diseases. It shows chronic fatigue syndrome (Fukuda & CCC) is a chronic illness with abnormal connections among brain regions and white matter deficits which continue to deteriorate.

The study, Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study, was published in the Journal of Magnetic Imaging in April 2016.

The authors are from Griffith University’s National Centre for Neuroimmunology and Emerging Diseases and South Australia’s Lyell McEwin Hospital and Royal Adelaide Hospital. Many of this paper’s authors also published a paper about brain connectivity problems causing signalling problems in March 2016.

The six year study looked at the brains of 15 patients and 10 controls and found white matter decreased over time in the CFS patients. It also says hypoxia, which is a deficiency in the amount of oxygen reaching the tissues, could be causing neurodegeneration.

“The rate-of-change of regional white matter volumes in CFS patients was significantly different from that in controls in the left posterior part of the inferior fronto-occipital fasciculus (IFOF) and/or arcuate fasciculus. In this location, white matter volume relative to global white matter volume decreased with time in the CFS group while in controls it was unchanged.

This study detected continuing shrinkage of white matter in the left IFOF in patients with CFS, but not in controls. This result was consolidated by the pooled inter group comparisons revealing decreased regional white matter volumes in adjacent regions and decreased GM and blood volumes in contralateral regions and by regression analysis showing significant correlations of white matter and grey matter volumes and T2w intensities with CFS symptom scores in those regions.”

The IFOF connects networks of cognitive control, attention, language processing and working memory.

The study may explain symptoms such as impaired concentration, working memory loss, inability to focus vision and poor motor coordination.

This seems to agree with the findings of Boissoneault et al 2005 in the their paper  Abnormal resting state functional connectivity in patients with chronic fatigue syndrome: an arterial spin-labeling fMRI study, which said “results demonstrate altered functional connectivity of several regions associated with cognitive, affective, memory, and higher cognitive function in ME/CFS (Fukuda criteria) patients. Connectivity to memory related brain areas (parahippocampal gyrus) was correlated with clinical fatigue ratings, providing supporting evidence that brain network abnormalities may contribute to ME/CFS pathogenesis”.

BRAIN CROSS SECTIONS

“Chronic functional hypoxia due to dysfunction of the neurovascular unit could also cause neurodegeneration.[34] Of interest, a recent study found seventeen single nucleotide polymorphisms (SNPs) were significantly associated with CFS.[35] Nine of these SNPs were associated with muscarinic acetylcholine receptors and eight with nicotinic ACh receptors (nAChRs). ACh, a neuromodulator in the brain, changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs. Control of synaptic Ca2+ concentration following nAChR stimulation is a major pathway for ACh to influence neuronal networks.[36] Furthermore, nAChRs are also present in the cerebral vascular endothelium and smooth muscles.[37] Thus, aberrant AChR function may impair cerebrovascular autoregulation and cause chronic functional hypoxia.

This study warrants further investigations to understand the pathomechanism of white matter deficits in the IFOF in CFS.”

The study was funded by the Judith Jane Mason Foundation.
Summary piece. The full paper came out in April.

 

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Canadian perspective on gut research

Posted on 07/15/2016 by wames

The star article, by Lauren Pelley, 4 July 2016: New research unlocking mysteries behind chronic fatigue syndrome,

Study showing biological markers of long-misunderstood condition “one more piece of the puzzle,” researchers say.

’80 per cent of patients still go undiagnosed’

Scott Simpson remembers the exact day his whole world changed.

It was August 9, 2012, and the then 47-year-old medal-winning triathlete woke up with a feeling unlike anything he’d experienced before. It was a deep, inexplicable fatigue and sickness affecting every part of his body, including his thinking and speaking abilities.

The next day, and the day after, Simpson recalls feeling a bit better – enough to compete in another triathlon. But that put him into a much deeper hole.

It felt like the typical exhaustion of competing in a triathlon, coupled with the crippling feelings of influenza and a bad hangover, the west-end Toronto resident says. And it didn’t go away. Simpson had been through a medical crisis before after finding out he was HIV positive more than a decade prior, but this bout of illness was a total mystery, with no link to his HIV status, according to his doctors.

After six weeks of strange symptoms – and no formal diagnosis – Simpson began his own online research.

One condition jumped out: Myalgic encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), a complex condition characterized by a cluster of symptoms that often overlap with other illnesses. The range of debilitating issues includes pain, unrefreshing sleep, and fatigue that grows worse after exertion, according to medical literature.

“I hit so many of them, especially the cardinal symptom, the post-exertional malaise,” Simpson says, adding he still hasn’t received a formal diagnosis for the frustrating condition that’s left him, four years later, with constant lingering symptoms of pain and fatigue.

ME/CFS has long been a controversial and misunderstood illness, and one that’s often met with stigma both by the general public and the medical community, with no widely-accepted treatment, single diagnostic test, or known cause.

It may affect around 408,000 Canadians, according to self-reported data from Statistics Canada’s 2014 Canadian Community Health Survey, and experts say a large percentage of sufferers aren’t properly diagnosed.

But new research is providing legitimacy to ME/CFS, while shedding light on what’s actually happening inside the bodies of people with the condition.

In a study published June 23 in the journal Microbiome, a team from Cornell University reports finding biological markers of the disease in gut bacteria and inflammatory microbial agents in the blood.

The researchers were also able to correctly diagnose ME/CFS in nearly 83 per cent of subjects just by analyzing stool samples and blood work.

Researcher Maureen Hanson, a professor in Cornell’s department of molecular biology and genetics, says the findings show people with ME/CFS have abnormalities in their gut, much like patients with inflammatory conditions including Crohn’s disease.

The study involved 88 participants – a mix of control subjects and patients with ME/CFS, who were identified by a specialist in New York.

Dr. Harvey Moldofsky, a professor emeritus in the University of Toronto’s department of psychiatry, who spent more than four decades studying the causes and treatments of the illnesses now known as fibromyalgia and ME/CFS and was not involved in the research, says the study has several methodological concerns.

“(The researchers) acknowledge that they really need to study a larger population. OK, fair enough. But there is the question as to who the other people are that they’re going to study,” he says. “What do you mean by normal? How do these people differ in their diet? How do these people differ in terms of their exercise?”

Since the symptoms of ME/CFS often overlap with other conditions, such as fibromyalgia and chronic headaches, Moldofsky says further research also needs to explore these other patient populations sharing similar symptoms.

Still, he says, “this is a beginning,” and it’s one Hanson and her team hopes to build on. Other researchers are conducting similar studies, she says, which could replicate the Cornell results down the road, and her own team plans to keep exploring what’s happening in the gut microbiome of people with ME/CFS.

“There’s lots of biological evidence now indicating this is a biological disease,” she adds. “Our information is one more piece of the puzzle.”

In 2014, a study from Stanford University found abnormalities in the white matter of patients with ME/CFS, while research published the following year by Columbia University researchers showed distinct differences in the immune systems of people with the disease, compared to healthy controls.

Piece by piece, this growing body of research is providing more evidence that ME/CFS is “absolutely a real, physiological illness,” says Dr. Alison Bested, a hematological pathologist who has spent 25 years helping patients with the disease.

“But the whole area of ME/CFS is not being taught in the medical curriculum or the post-grad curriculum,” she adds. “The average doctor in our community is not knowledgeable about ME/CFS, and there’s still a lot of stigmatism – that it’s a belief system, that it’s all in your head.”

Around 80 per cent of patients still go undiagnosed, she says. “It’s shocking to me.”

Simpson, now 50, feels betrayed by the medical system. He said when he was diagnosed with HIV at 33 years of age the treatment he received from physicians was “nothing but positive.” (He is currently on antiretroviral medications and physicians still haven’t linked his ongoing pain and fatigue symptoms to having HIV, he says.)

In contrast, his search for answers to his potential ME/CFS symptoms led to nothing but stigma, such as one internal medicine doctor telling him it was just a “mood disorder.” He’s now advocating for people with the condition as part of a grassroots group called Millions Missing for ME Canada, focused on pushing for more research funding.

“This is basically a crisis situation,” Simpson says. “We are health-care system victims.”

Still, Bested says the medical community has made “tremendous strides” at the research level, which now needs to translate into clinical tools to help patients – including those, like Simpson, who’ve been told the debilitating condition is just make-believe.

“We know it’s a physiological illness,” Bested says.

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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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