Epigenetic modifications & glucocorticoid sensitivity in ME/CFS

Posted on 02/28/2017 by wames

Research abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

(ME/CFS) is a debilitating idiopathic disease characterized by unexplained fatigue that fails to resolve with sufficient rest.

Diagnosis is based on a list of symptoms and exclusion of other fatigue-related health conditions. Despite a heterogeneous patient population, immune and hypothalamic-pituitary-adrenal (HPA) axis function differences, such as enhanced negative feedback to glucocorticoids, are recurring findings in ME/CFS studies. Epigenetic modifications, such as CpG methylation, are known to regulate long-term phenotypic differences and previous work by our group found DNA methylome differences in ME/CFS, however the relationship between DNA methylome modifications, clinical and functional characteristics associated with ME/CFS has not been examined.

Methods: We examined the DNA methylome in peripheral blood mononuclear cells (PBMCs) of a larger cohort of female ME/CFS patients using the Illumina HumanMethylation450 BeadChip Array. In parallel to the DNA methylome analysis, we investigated in vitro glucocorticoid sensitivity differences by stimulating PBMCs with phytohaemagglutinin and suppressed growth with dexamethasone.

We explored DNA methylation differences using bisulfite pyrosequencing and statistical permutation. Linear regression was implemented to discover epigenomic regions associated with self-reported quality of life and network analysis of gene ontology terms to biologically contextualize results.

Results: We detected 12,608 differentially methylated sites between ME/CFS patients and healthy controls predominantly localized to cellular metabolism genes, some of which were also related to self-reported quality of life health scores. Among ME/CFS patients, glucocorticoid sensitivity was associated with differential methylation at 13 loci.

Conclusions: Our results indicate DNA methylation modifications in cellular metabolism in ME/CFS despite a heterogeneous patient population, implicating these processes in immune and HPA axis dysfunction in ME/CFS. Modifications to epigenetic loci associated with differences in glucocorticoid sensitivity may be important as biomarkers for future clinical testing. Overall, these findings align with recent ME/CFS work that point towards impairment in cellular energy production in this patient population.

Epigenetic modifications and glucocorticoid sensitivity in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) by Wilfred C. de Vega, Santiago Herrera, Suzanne D. Vernon and Patrick O. McGowan in BMC Medical Genomics 2017 10:11 [Published: 23 February 2017]

University of Toronto news, by Don Campbell,  4 April 2017: University of Toronto study offers hope to sufferers of chronic fatigue syndrome

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People with ME in South Africa share their stories

Posted on 02/27/2017 by wames

Carte Blanche blog post, 19 February 2017: Living With Chronic Fatigue Syndrome

The effects of ME/CFS are very real and can change a patient’s life in a dramatic way. Three South African women share their stories on living with this condition: Retha, Rika and Nathalie  Read more

Nathalie & Retha

Nathalie Williams says:

Please share this video to help raise awareness of Myalgic Encephalomyelitis (ME), also referred to as Chronic Fatigue Syndrome (CFS).

To share this video on other platforms, here’s the link: https://www.facebook.com/NathalieHWilliams/videos/10156004031092619/

or watch it on the ME Association website:

A 10-film on M.E. was shown on Carte Blanche, South Africa’s longest-running TV investigation show, on 20 February 2017. It has won plaudits round the world for its straight talking about this illness, and choice of interview subjects – particularly Dr Ron Davis and David Tuller. Nathalie Williams is featured in the film  Watch video

ME/CFS Foundation South Africa

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Neuro inflammatory etiopathology of ME/CFS

Posted on 02/27/2017 by wames

Article abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic illness of unknown etiology, classified as a neurological disorder by the World Health Organization (WHO).

The symptomatology of the condition appears to emanate from a variety of sources of chronic neurological disturbance and associated distortions, and chronicity, in noxious sensory signaling and neuroimmune activation.

This article incorporates a summary review and discussion of biomedical research considered relevant to this essential conception perspective. It is intended to provide stakeholders with a concise, integrated outline disease model in order to help demystify this major public health problem.

The primary etiopathological factors presented are:

  • (A) Postural/biomechanical pain signaling, affecting adverse neuroexcitation, in the context of compression, constriction, strain, or damage of vertebral-regional bone and neuromuscular tissues;
  • (B) Immune mediated inflammatory sequelae, in the context of prolonged immunotropic neurotrophic infection—with lymphotropic/gliotropic/glio-toxic varieties implicated in particular;
  • (C) A combination of factors A and B. Sustained glial activation under such conditions is associated with oxidative and nitrosative stress, neuroinflammation, and neural sensitivity.

These processes collectively enhance the potential for multi-systemic disarray involving endocrine pathway aberration, immune and mitochondrial dysfunction, and neurodegeneration, and tend toward still more intractable synergistic neuro-glial dysfunction (gliopathy), autoimmunity, and central neuronal sensitization.

The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), by Independent Health Researcher and Consultant, Julian AG Glassford, from Shrewsbury in Front. Physiol., 17 February 2017

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The UK ME/CFS Biobank for biomedical research on ME/CFS & MS

Posted on 02/27/2017 by wames

Overview of a UK bioresource:

The UK ME/CFS Biobank was launched in August 2011 following extensive consultation with professionals and patient representatives. The bioresource aims to enhance research on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), related to pathophysiology, biomarkers and therapeutic approaches.

The cohort includes 18–60 year olds, encompassing 284 clinically-confirmed ME/CFS cases, 60 neurologist-diagnosed multiple sclerosis (MS) cases, and 135 healthy individuals.

The Biobank contains blood samples, aliquoted into serum, plasma, peripheral blood mononuclear cells (PBMC), red blood cells/granulocyte pellet, whole blood, and RNA (totalling 29,863 aliquots). Extensive dataset (700 clinical and socio-demographic variables/participant) enables comprehensive phenotyping. Potential reuse is conditional to ethical approval.

More info:
The UK ME/CFS Biobank for biomedical research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Multiple Sclerosis, by Eliana M Lacerda , Erinna W Bowman, Jacqueline M Cliff, Caroline C Kingdon, Elizabeth C King, Ji-Sook Lee, Taane G Clark, Hazel M Dockrell, Eleanor M Riley, Hayley Curran, Luis Nacul in Open Journal of Bioresources 4(1), p.4 [Published on 20 Feb 2017]

 

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Vitamin D could boost the immune system

Posted on 02/24/2017 by wames

Recent news reports of research claiming vitamin D supplements can boost the immune system as well as the health of bones, has raised questions for how people with ME can obtain enough of this vital nutrient.

Get vitamin D from:

  • sunshine, but not through glass or sun creams
  • oily fish e.g. fresh salmon, tuna, mackerel – tinned tuna and some tinned salmon doesn’t contain much, if any
  • fortified foods – some bread, spreads and cereals have vitamin D added
  • egg yolks
  • beef liver
  • supplements

More info about the recent research:

BBC news report, by James Gallagher, 16 Feb 2017: Vitamin D pills ‘could stop colds or flu’

Vitamin D supplements could spare more than three million people from colds or flu in the UK each year, researchers claim. The sunshine vitamin is vital for healthy bones, but also has a role in the immune system.

The analysis, published in the British Medical Journal, argues food should be fortified with the vitamin.

But Public Health England (PHE) says the infections data is not conclusive, although it does recommend supplements. These, it says, should be taken for improved bone and muscle health.    Read more

Independent: Vitamin D supplements ‘the key to beating colds and flu’, study finds

ITV news: Vitamin D pills ‘key to beating colds and flu’ says study

Guardian: Vitamin D ‘proved to cut risk of colds and flu’

ME Association: Vitamin D supplements may help to prevent viral and bacterial infections

More info about Vitamin D and other supplements:

Independent: Five ways to boost your Vitamin D levels

Dr Lapp’s Recommendations on Supplements

Independent: Can you get a suntan and absorb vitamin D through a window?

 

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Citric Acid Cycle is deficient in people with ME/CFS

Posted on 02/24/2017 by wames

MEAction blog post, by Adrianne Tillman, 22 Feb 2017: Stanford team announces breakthrough in ME/CFS research

A research team at Stanford announced yesterday that it has made some breakthroughs in understanding the metabolic cycles that are not working properly in people with ME/CFS that might be at the heart of the disease.

Ronald W. Davis, PhD, made the announcement via YouTube. Davis directs the CFS Research Center team at the Stanford Genome Technology Center (SGTC).

You tube video: Problems with metabolic cycles (18 mins)

The team’s metabolomics tests on severely-ill patients revealed problems with the citric acid cycle. Participants’ blood work showed that some of the chemicals involved in the citric acid cycle are very low, making it difficult for the patient to generate the chemicals we use for energy. Several chemicals were found to be two standard deviations away from those of healthy controls, which is serious, according to Davis.

Recent research by Fluge and Mella has also suggested that pyruvate dehydrogenase, the enzyme that helps glycolysis transition into the citric acid cycle, may be blocked.

“We have not investigated that, but it is consistent with glycolysis being shut down,” Davis said. “We also think that pyruvate kinase might be shut down. Those are not inconsistent and it is possible there are blocks in both of them.”

The problem with NIH
Davis and his team applied for federal funding from the National Institute of Health (NIH) for the research that led to the data showing the dysfunctional citric acid cycle in people with ME/CFS. The NIH turned down both of his grants “because we were trying to do discovery, and they wanted us to only do hypothesis testing,” Davis said.

“I said to them: the scientific method is first observation, then hypothesis. And if you have virtually no observations you can’t generate a good hypothesis. I think one of the big problems we have is that we do not know enough at the molecular level to generate hypotheses.”

Technology to screen drugs without using patients
Davis also announced a device that the Stanford team has developed to test metabolic functions, which will enable them to do mass screenings of drugs without the time and cost restraints of using patients.

The device is about the size of a computer chip. It has a small channel in it to accommodate a tenth-of-a-drop of blood, all that is needed for this assay. It has 2500 electrodes in it, and each electrode is sampled 200 times a second. This generates a massive amount of data.

Davis explains how the device works:

“What we have noticed from this device is that if we put bacterial population into this, we will get a certain electrical impedance signal. If we then add an antibiotic that kills the bacteria, the electrical impedance will rapidly increase. If the bacteria are resistant to the antibiotic, we see no change.

“So, if we put healthy cells and their serum into the device, it is pretty stable and does not change. If we put in ME/CFS cells and their serum, it doesn’t change. However, if we put a demand on the cells, we require them to consume energy, and that demand is seen in this graph where there is a slight dip in the healthy controls – but they handle that demand quite well and don’t change after that – however the cells from the ME/CFS patient shows a rapid increase in impedance. And that has been shown for every patient we have looked at, and also every healthy control is the same.”

Most importantly, the device provides a way for Davis and his team to test drugs on ME/CFS cells and serum to see the effect.

Davis noted that the rapid rise in impedance is caused by the serum, not the cell, which means that there is something being released into the serum that may be causing or contributing to symptoms.

“If it is in the serum, we probably can find it,” Davis said. “And that is what we’re trying to do now, which is find the component or components – most likely plural – that is causing this effect… Now this a good hypothesis, and we are now testing it.”

Davis said that the next step is to use the device to test the effects of various drugs on the cells and serum of ME/CFS patients. For example, Davis’ team found that adding ATP to unhealthy ME/CFS cells and serum made the cells respond normally. The team also plans to test drugs that many ME/CFS patients have reported helpful using this device, such as Valcyte and Rituximab.

If the device turns out to be a good diagnostic test for ME/CFS, Davis said his team will disseminate information to doctors’ offices.

This device may be applicable to other diseases as well, including Lyme and Fibromyalgia.

The magnetic levitation device
Davis and his team have also developed a magnetic levitation device which separates cells based on their magnetic properties. The device is small and can fit onto an iPhone.  This device can be used to separate and examine cells with differing properties, which has broad applications, including examining specific cell types in ME/CFS patients.  The magnetic levitation device costs 5 cents per assay.

“We’re accumulating a list of things that we are trying with this device,” Davis said.

“One of our focuses is on developing engineered biosensors and devices. We also have a synthetic biology core that is used to develop new ways to do production of drugs and test drugs… So we have a heavy focus on how to reduce cost of tests and simplicity of those tests and portability,” Davis said.

The Open Medicine Foundation (OMF) is helping fund the work of Dr. Davis’ CFS Research Center team at SGTC. So far, their breakthroughs have been achieved by doing one experiment at a time, week-by-week. At this point, the team is ready to ramp up the project in order to carry out multiple parallel investigations to get answers as fast as possible. However, substantially more funding is needed for this to happen.

Opportunity to donate to Stanford’s research

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Dr Light’s video interview about his PEM research

Posted on 02/23/2017 by wames

Dr Podell’s blog, 9 January 2017: Powerful Proof that Symptoms of Chronic Fatigue Syndrome and Fibromyalgia are REAL and MAINLY PHYSICAL

Dr Rich Podell interviewed Dr. ALan Light, Ph. D by Skype in a three part video series.

His research is among the very most innovative and important in the fields of chronic fatigue syndrome and Fibromyalgia. He, along with Lucinda Bateman, M.D. and colleagues from the University of Utah School of Medicine, has successfully conducted one study out of a very few that identify an objective laboratory marker which closely correlates with the patients’ “subjective” complaint of prolonged fatigue after modest exertion. This proves that the patients’ subjective reports of post-exertional malaise (PEM) are honest, real and based on physical events.

More details on this study and its significance can be found in the three 10-minute videos and text.

Latest research:

Neural Consequences of Post-Exertion Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Dane B. Cook, Alan R. Light, Kathleen C. Light, Gordon Broderick, Morgan R. Shields, Ryan J. Dougherty, Jacob D. Meyer, Stephanie VanRiper, Aaron J. Stegner, Laura D. Ellingson, Suzanne D. Vernon, William S. Middleton in Brain, Behavior, and Immunity [published online: 17 February 2017]

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Australian researchers discover abnormalities in immune cell receptors in ME/CFS

Posted on 02/23/2017 by wames

Huffington Post Australia, by Luke Cooper, 22 Feb 2017: Queensland Scientists Make Chronic Fatigue Syndrome Research Breakthrough

The condition has been linked to abnormal immune system cells.

Queensland scientists have linked Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME), to a dysfunctional immune system — proving for the first time that the condition does stem from the body rather than the mind.

Researchers from Griffith University’s National Centre for Neuroimmunology and Emerging Diseases (NCNED) told the Huffington Post Australia the breakthrough came through findings that showed abnormalities in immune cell receptors.

NCNED Co-Director, Professor Don Staines, said:

“We have discovered and reported for the first time abnormalities of a certain receptor in immune cells of the body and hence it’s likely to be in every cell in the body.

“What this is, is a defect in the receptor, which is a change in the gene transcription of these receptors, meaning they no longer function the way they should. What the receptors should do is to be able to transfer calcium from outside the cell to the inside.”

According to Staines, the discovery of abnormal calcium immune system cells affects CFS sufferers in three main areas of the body where CFS-related pain usually occurs — the brain and spinal cord, the pancreas and the stomach.

CFS is a debilitating, flu-like medical condition characterised not only by long-term fatigue but a whole host of other symptoms that limit a person’s ability to carry out daily life.

There is no cure or effective treatment for chronic fatigue and a lack of understanding of the disease within the medical community has led to many sufferers being misdiagnosed.

“This is huge because for the first time we have documented the pathology in this illness. Up until now people have not really understood the illness,” Staines said.

“This illness is very much under-diagnosed. We think about 1-2% of the population have this illness but it could be higher than that. This is a much more debilitating illness than people have realised.”

Queensland Science Minister Leeanne Enoch said the findings are an important breakthrough in understanding CFS and helping those who suffer from it, in a statement released on Tuesday.

“This discovery is great news for all people living with [CFS] and the related [ME], as it confirms what people with these conditions have long known – that it is a ‘real’ illness – not a psychological issue,” she said.

“The Griffith University breakthrough now means we have a target for therapeutic intervention, which is welcome news to the 250,000 Australians believed to be affected by CFS and ME.”

Staines told HuffPost Australia researchers have now turned their sights towards creating a test that could identify dysfunctional cells in sufferers and developing future laboratory drug trials that could limit the cost of the condition on families.

“People can go for years of getting different tests and these are very substantial costs to the Australian economy, and also there are big costs for families who have to stay home or be a carer,” he said.

“Now there’s a lot of scope to develop, design and use different drugs. We can use different samples of drugs in what we call in-vitro, and then we can test them based on predictions that they would be a benefit in this condition.”

The costs of CFS and ME diagnosis, treatment and management in Australia is estimated to be around $700 million annually, according to the Queensland Government’s statement.

The findings come after NCNED received $1.6 million in research funding from the Queensland Government and a $4 million grant from the Stafford Fox Medical Research Foundation.

Staines believes this breakthrough is now a step forward for sufferers.

“We now know that this is a pronounced dysfunction of a very critical receptor and the critical role that this has, which causes severe problems to cells in the body.” he said.

“We don’t know that we can necessarily cure the illness but we can help people lead a normal life.”

More info:

Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels, by T Nguyen, S. Johnston, L. Clarke, P. Smith, D. Staines, and S. Marshall‐Gradisnik in Clin Exp Immunol. 2017 Feb; 187(2): 284–293.
[Published online 2016 Nov 23]

Science alert, by Fiona McDonald, 22 Feb 2017: One of the Biggest Myths About Chronic Fatigue Syndrome Just Got Debunked

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Neural consequences of PEM in ME/CFS

Posted on 02/22/2017 by wames

Research abstract:

Highlights:

  • Acute exercise affects symptoms, cognitive performance and brain function in ME/CFS.
  • Symptom provocation by exercise is a useful model to study post-exertion malaise.
  • Objective neurophysiological evidence of the phenomenon of post-exertion malaise.

Post exertion malaise is one of the most debilitating aspects of Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, yet the neurobiological consequences are largely unexplored.

The objective of the study was to determine the neural consequences of acute exercise using functional brain imaging. Fifteen female Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients and 15 healthy female controls completed 30 minutes of submaximal exercise (70% of peak heart rate) on a cycle ergometer.

Symptom assessments (e.g. fatigue, pain, mood) and brain imaging data were collected one week prior to and 24 hours following exercise.

Functional brain images were obtained during performance of: 1) a fatiguing cognitive task – the Paced Auditory Serial Addition Task, 2) a non-fatiguing cognitive task – simple number recognition, and 3) a non-fatiguing motor task – finger tapping.

Symptom and exercise data were analyzed using independent samples t-tests. Cognitive performance data were analyzed using mixed-model analysis of variance with repeated measures. Brain responses to fatiguing and non-fatiguing tasks were analyzed using linear mixed effects with cluster-wise (101-voxels) alpha of 0.05.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients reported large symptom changes compared to controls (effect size ≥0.8, p<0.05).

Patients and controls had similar physiological responses to exercise (p>0.05). However, patients exercised at significantly lower Watts and reported greater exertion and leg muscle pain (p<0.05).

For cognitive performance, a significant Group by Time interaction (p<0.05), demonstrated pre- to post-exercise improvements for controls and worsening for patients. Brain responses to finger tapping did not differ between groups at either time point.

During number recognition, controls exhibited greater brain activity (p<0.05) in the posterior cingulate cortex, but only for the pre-exercise scan. For the Paced Serial Auditory Addition Task, there was a significant Group by Time interaction (p<0.05) with patients exhibiting increased brain activity from pre- to post-exercise compared to controls bilaterally for inferior and superior parietal and cingulate cortices. Changes in brain activity were significantly related to symptoms for patients (p<0.05).

Acute exercise exacerbated symptoms, impaired cognitive performance and affected brain function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. These converging results, linking symptom exacerbation with brain function, provide objective evidence of the detrimental neurophysiological effects of post-exertion malaise.

Neural Consequences of Post-Exertion Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, by Dane B. Cook, Alan R. Light, Kathleen C. Light, Gordon Broderick, Morgan R. Shields, Ryan J. Dougherty, Jacob D. Meyer, Stephanie VanRiper, Aaron J. Stegner, Laura D. Ellingson, Suzanne D. Vernon, William S. Middleton in Brain, Behavior, and Immunity [published online: 17 February 2017]

Solve ME/CFS Initiative blog post, 14 April 2017: SMCI Funded study published, “Neural consequences of post-exertion malaise”

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No such thing as retirement for older carers

Posted on 02/20/2017 by wames

Carers Trust article, 7 Feb 2017: No such thing as retirement for older carers, says new Carers Trust report

Older carers say they are now doing the hardest job they have ever done, with no option to ring in sick if they are not well. Just when older carers thought it was time to put up their feet and retire, many of the older generation are finding that there is no such thing as retirement.

Instead of retiring, they have become or will remain lifelong unpaid carers for their sick or disabled partner or adult children.

The Carers Trust have launched “Retirement on Hold”, a new report which highlights some of the challenges the older population are facing.

The report gives a snapshot of the battles some older people are now fighting, including caring for someone else when they have their own age-related illnesses.

Many carers aren’t prepared for caring and are struggling to find their way around the social care system, and some say by the time they’ve received vital information it is too late. They say the burden of caring has resulted in them being exhausted, frustrated and becoming sick themselves.

 

 

 

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