Reduced glycolytic reserve in isolated natural killer cells from ME/CFS patients

Reduced glycolytic reserve in isolated natural killer cells from Myalgic encephalomyelitis/ chronic fatigue syndrome patients: A preliminary investigation, by Thao Nguyen, D Staines, S Johnston, S Marshall-Gradisnik in Asian Pac J Allergy Immunol. 2018 Jul 8. [Epub ahead of print]

Abstract:

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is medically unexplained post-exertional fatigue associated with significant reduction in natural killer cell (NK) cytotoxicity activity. Cytotoxic activity relies on glycolytic flux and mitochondrial respiration to fulfill energetic cellular demands. While mitochondrial dysfunction has been reported in ME/CFS patients, no previous investigation has examined the bioenergetic profile of isolated NK cells from ME/CFS patients.

OBJECTIVE: This study was to determine the metabolic function in resting NK cells from ME/CFS patients.

METHOD: Six ME/CFS patients (aged 50.33±4.95) were age and sex-matched with non-fatigued healthy controls (aged 50.00±5.04). Mitochondrial stress tests measured parameters of mitochondrial function in the NK cells including basal respiration, ATP production, proton leak, maximal respiration, spare respiratory capacity and bioenergetic health index. Glycolytic stress tests measured parameters of glycolytic function such as glycolytic reserve, glycolysis and glycolytic capacity in isolated NK cells from ME/CFS patients and healthy controls using an extracellular flux analyzer, Seahorse XFp.

RESULT: There was a significant reduction of glycolytic reserve in resting NK cells from ME/CFS patients (0.6±0.07 mpH/ min) compared with healthy control (2.25±1.3 mpH/min). Mitochondrial respiration in resting NK cells did not approach statistical significance between ME/CFS patients and healthy controls.

CONCLUSION: These findings suggest resting NK cells from ME/CFS patients have reduced ability to increase glycolytic flux to respond to high energetic demands for ATP production. Hence, the reduced glycolytic reserves we have identified in isolated resting isolated NK cells should be further investigated to assist in understanding ME/CFS pathogenesis.

Study finds reduced ability to respond to energy demands in ME patients’ immune systems

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Suicidal ideation in non-depressed individuals: the effects of a chronic, misunderstood illness

Suicidal ideation in non-depressed individuals: the effects of a chronic, misunderstood illness, by AR Devendorf, SL McManimen, LA Jason in Health Psychol. 2018 Jul 1:1359105318785450  [Epub ahead of print]

Abstract:

Chronic illness is a risk factor for suicide but is often explained with depression. Research has shown an increased suicide rate in patients with myalgic encephalomyelitis and chronic fatigue syndrome, but specific risk factors have been unexplored. We qualitatively analyzed responses from 29 patients who endorsed suicidal ideation but did not meet depression criteria.

Two themes were developed:

(1) feeling trapped and

(2) loss of self, loss of others, stigma and conflict.

Myalgic encephalomyelitis and chronic fatigue syndrome caused patients severe disability, restructured their lives, and inflicted serious pain. Participants emphasized that they were not depressed, but felt trapped by the lack of treatments available.

Read full article

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Nutritional modulation of the intestinal microbiota

Review abstract:

Nutritional modulation of the intestinal microbiota: future opportunities for the prevention and treatment of neuroimmune and neuroinflammatory disease, by Vincent C Lombardi, Kenny L De Meirleir, Krishnamurthy Subramanian, Sam M Nourani, Ruben K Dagda, Shannon L Delaney, András Palotás in The Journal of Nutritional Biochemistry, Volume 61, November 2018, Pages 1-16

The gut-brain-axis refers to the bidirectional communication between the enteric nervous system and the central nervous system. Mounting evidence supports the premise that the intestinal microbiota plays a pivotal role in its function and has led to the more common and perhaps more accurate term gut-microbiota-brain axis.

Numerous studies have identified associations between an altered microbiome and neuroimmune and neuroinflammatory diseases. In most cases, it is unknown if these associations are cause or effect; notwithstanding, maintaining or restoring homeostasis of the microbiota may represent future opportunities when treating or preventing these diseases.

In recent years, several studies have identified the diet as a primary contributing factor in shaping the composition of the gut microbiota, and in turn, the mucosal and systemic immune systems. In this review, we will discuss the potential opportunities and challenges with respect to modifying and shaping the microbiota through diet and nutrition in order to treat or prevent neuroimmune and neuroinflammatory disease.

Read full article

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New CFS test is 84% accurate

Medical News Today blog post, by Ana Sandoiu, 11 July 2018: New chronic fatigue syndrome test is 84 percent accurate

Myalgic encephalomyelitis/chronic fatigue syndrome does not currently have a diagnostic test. But this may soon change, as researchers have developed a test that can predict it with an unprecedented level of accuracy.

Currently, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is estimated to affect more than 1 million people in the United States, and up to 24 million people worldwide. This often debilitating condition is characterized by feelings of extreme exhaustion, muscle and joint pain, and insomnia, as well as difficulty concentrating or remembering things.

The causes of ME/CFS remain unknown, and in the absence of a proper diagnostic test for it, healthcare professionals have to exclude other disorders and examine a patient’s history before they can tell whether a person has ME/CFS or not.

However, this may soon change, as a team of researchers led by those at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health in New York City, NY, have engineered a highly accurate test for the disorder. The researchers detail their findings in a new study recently published in the journal Scientific
Reports. Dr. Dorottya Nagy-Szakal, a CII researcher, is the first author of the paper.

Engineering an ME/CFS diagnostic test

Dr. Nagy-Szakal and team examined the blood samples of 50 people with ME/CFS and compared them with those of 50 age-matched healthy controls. Using a special technique that identifies molecules by measuring their mass, the scientists found 562 metabolites that the ME/CFS patients had in common.

Metabolites are byproducts of the body’s metabolism – that is, its ability to process sugars, fats, and proteins. In the recent research, the scientists excluded metabolites resulting from antidepressants or other drugs.

Laboratory tests carried out by Dr. Nagy-Szakal and team revealed that certain metabolites were altered in a way that suggested that the patients’ mitochondria – which are the tiny organelles inside the cell responsible for turning nutrients into energy – were not functioning properly. The results are coherent with previous studies led by other researchers, as well as with research carried out by Dr. Nagy-Szakal and colleagues last year.

In 2017, the team found a distinct pattern of metabolites in people who had both irritable bowel syndrome (IBS) and ME/CFS. Other studies have reported that 35-90 percent of those with ME/CFS also have IBS. And in the new study, half of the ME/CFS patients also had IBS.

Test yields 84 percent accuracy

Dr. Nagy-Szakal and her colleagues combined biomarkers from both their  2017 study and their new study. The result was a predictive model with a 0.836 score, which translates into an accuracy rate of 84 percent.

‘This is a strong predictive model that suggests we’re getting close to the point where we’ll have lab tests that will allow us to say with a high level of certainty who has this disorder,’ explains Dr. Nagy-Szakal.

Corresponding author Dr. W. Ian Lipkin, director of CII and the National Institutes of Health (NIH) Center for Solutions for ME/CFS, also weighs in on the findings, saying,

‘We’re closing in on understanding how this disease works. We’re getting close to the point where we can develop animal models that will allow us to test various hypotheses, as well as potential therapies. For instance, some patients might benefit from probiotics to retune their gastrointestinal microflora or drugs that activate certain neurotransmitter systems.’

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Insights into ME/CFS phenotypes through comprehensive metabolomics

Research abstract:

Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics, by Dorottya Nagy-Szakal, Dinesh K. Barupal, Bohyun Lee,
Xiaoyu Che, Brent L. Williams, Ellie J. R. Kahn, Joy E. Ukaigwe, Lucinda Bateman, Nancy G. Klimas, Anthony L. Komaroff, Susan Levine, Jose G. Montoya, Daniel L. Peterson, Bruce Levin, Mady Hornig, Oliver Fiehn, W. Ian Lipkin in Scientific Reports  8: 10056 (2018)

The pathogenesis of ME/CFS, a disease characterized by fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, irritable bowel syndrome (IBS), and lymphadenopathy, is poorly understood.

We report biomarker discovery and topological analysis of plasma metabolomic, fecal bacterial metagenomic, and clinical data from 50 ME/CFS patients and 50 healthy controls. We confirm reports of altered plasma levels of choline, carnitine and complex lipid metabolites and demonstrate that patients with ME/CFS and IBS have increased plasma levels of ceramide.

Integration of fecal metagenomic and plasma metabolomic data resulted in a stronger predictive model of ME/CFS (cross-validated AUC = 0.836) than either metagenomic (cross-validated AUC = 0.745) or metabolomic (cross-validated AUC = 0.820) analysis alone.

Our findings may provide insights into the pathogenesis of ME/CFS and its subtypes and suggest pathways for the development of diagnostic and therapeutic strategies.

News medical, 10 July: Study identifies constellation of metabolites linked to ME/CFS

Science daily: Insights from metabolites get us closer to a test for chronic fatigue syndrome 

Review by Paul Whiteley PhD

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‘A Girl Behind Dark Glasses’ book by Jessica Taylor-Bearman

‘A Girl Behind Dark Glasses’ book by Jessica Taylor-Bearman

Book Description:

From a darkened world, bound by four walls, a young woman called Jessica tells the tale of her battle against the M.E Monster. The severest form of a neuro immune disease called Myalgic Encephalomyelitis went to war with her at just 15 years old. From beneath her dark glasses, Jessica glimpses a world far different from the one she remembers as a teenage school girl. This true story follows her path as she ends up living in hospital for years with tubes keeping her alive.

This harrowing story follows the highs and lows of the disease and being hospitalised, captured through her voice activated technology diary called `Bug’ that enables her to fulfil her dream of one day becoming an author.

It provides a raw, real-time honesty to the story that would be impossible to capture in hindsight.

Jo Moss’s review on her blog ‘The Mighty’: My Review of ‘A Girl Behind Dark Glasses’ as a Fellow ME Patient

I have just finished reading “A Girl Behind Dark Glasses: and I was so impressed I decided to write a review. “A Girl Behind Dark Glasses” is written by Jessica Taylor-Bearman and it’s an account of her life and struggles with a severe form of myalgic encephalomyelitis (ME).

“I was an inventor, a researcher, a model, and I travelled the world through my imagination. At that time, it was my only saving grace. I existed in a place I called Limbo Land, hovering between the conscious and the unconscious. I could hear my family talking to me, see images of them, yet I couldn’t reply or make sense of what they talked about.” – Jessica Taylor-Bearman

Order online from Jessica or from Amazon

Jessica’s website: Jaytay

Jessica’s book is available from Amazon   £4.99 for Kindle, £9.99 paper

 

Female First article, by Jessica Taylor-Bearman, 3 July 2018: 10 Things About Living With M.E. That You Want People To Know

Jessica Taylor-Bearman writes a piece for us upon the release of her new book A Girl Behind Dark Glasses.

I have been suffering with a chronic neuro immune disease for over twelve years called M.E. It stands for Myalgic Encephalomyelitis and remains very misunderstood in all aspects. You may have heard of it called by a multitude of different names including Chronic Fatigue Syndrome and sadly still, Yuppie Flu.

To find out more about the key things Jessica wants people to know read the full article

  1. There are so many things we do not know about M.E. but most importantly one thing we do know is that contrary to popular belief, M.E. is not ‘all in the mind’.
  2. It is not a rare condition.
  3. I live in constant pain
  4. It’s really hard being this sick for so many years without receiving any medication that will fix the problem.
  5. I lost all my independence when I was 15 years old.
  6. I spend most of my time living in a world of one room
  7. M.E. puts a huge strain on any family setup because everyone’s life has to revolve around the disease.
  8. I divide my day up into family time, rest time, and helping run my charity (Share a Star) from my bed.
  9. When you are chronically unwell, you really start to have to appreciate the little things in life.
  10. I’m bedridden activist
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Intracranial compliance is associated with symptoms of orthostatic intolerance in CFS

Research abstract:

Intracranial compliance is associated with symptoms of orthostatic intolerance in chronic fatigue syndrome, by Andreas Finkelmeyer, Jiabao He, Laura Maclachlan, Andrew M Blamire, Julia L Newton in PLoS One. 2018 Jul 3;13(7):e0200068

Symptoms of orthostatic intolerance (OI) are common in Chronic Fatigue Syndrome (CFS) and similar disorders. These symptoms may relate to individual differences in intracranial compliance and cerebral blood perfusion. The present study used phase-contrast, quantitative flow magnetic resonance imaging (MRI) to determine intracranial compliance based on arterial inflow, venous outflow and cerebrospinal fluid flow along the spinal canal into and out of the cranial cavity.

Flow-sensitive Alternating Inversion Recovery (FAIR) Arterial Spin Labelling was used to measure cerebral blood perfusion at rest. Forty patients with CFS and 10 age and gender matched controls were scanned.

Severity of symptoms of OI was determined from self-report using the Autonomic Symptom Profile. CFS patients reported significantly higher levels of OI (p < .001). Within the patient group, higher severity of OI symptoms were associated with lower intracranial compliance (r = -.346, p = .033) and higher resting perfusion (r = .337, p = .038). In both groups intracranial compliance was negatively correlated with cerebral perfusion.

There were no significant differences between the groups in intracranial compliance or perfusion. In patients with CFS, low intracranial compliance and high resting cerebral perfusion appear to be associated with an increased severity of symptoms of OI. This may signify alterations in the ability of the cerebral vasculature to cope with changes to systemic blood pressure due to orthostatic stress, but this may not be specific to CFS.

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Meta-analysis investigating post-exertional malaise between patients & controls

Review abstract:

Meta-analysis investigating post-exertional malaise between patients and controls by Abigail Brown and Leonard Jason in J Health Psychol. 2018 Jul [First published 5 July 2018]

Post-exertional malaise is either required or included in many previously proposed case definitions of myalgic encephalomyelitis/chronic fatigue syndrome. A meta-analysis of odds ratios (ORs; association between patient status and post-exertional malaise status) and a number of potential moderators (i.e. study-level characteristics) of effect size were conducted.

Post-exertional malaise was found to be 10.4 times more likely to be associated with a myalgic encephalomyelitis/chronic fatigue syndrome diagnosis than with control status. Significant moderators of effect size included patient recruitment strategy and control selection.

These findings suggest that post-exertional malaise should be considered a cardinal symptom of myalgic encephalomyelitis/chronic fatigue syndrome.

[The article lists possible definitions of PEM, including:

  • post-exertional neuroimmune exhaustion (Carruthers et al., 2011);
  • “an inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability … and a tendency for other associated symptoms to worsen” (Carruthers et al., 2003);
  • “prolonged exacerbation of a patient’s baseline symptoms after physical/cognitive/orthostatic stress; [it] may be delayed relative to the trigger.” (IOM, 2015)]

Read full article

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Dr Ron Davis’s big immune study is looking at HLA genes – here’s why

ME/CFS Research review blog post, by Simon McGrath, 28 June 2018: Dr Ron Davis’s big immune study is looking at HLA genes – here’s why

Dr Ron Davis has won a large NIH (US National Institutes of Health) grant for an immunology project with a strong focus on HLA genes. Which may have led some to wonder, ‘What are they?’

HLA (human leukocyte antigen) molecules play a critical role in the immune system, particularly by activating T cells. There is a huge amount of variation in the HLA genes that different people have, and Davis’s theory is that certain types of HLA genes could increase the risk of ME/CFS.

The following explanation of HLA molecules is taken from a piece I wrote a few years ago.

The short version

HLA molecules fire up T cells

T cells play a key role in the immune system. Like antibodies, the receptors of T cells respond to very specific antigens (foreign proteins), much like a lock matching just one key.

However, while antibodies will recognise and bind to part of a whole protein, such as the protein coat of a virus, T cell receptors only recognise tiny fragments of proteins. And T cell receptors can’t respond to antigens unless they are presented in just the right way.

That’s where HLA molecules come in. At a very basic level, HLA molecules act like waiters, serving up the antigen on a plate. More precisely, HLA molecules – which sit on the cell surface – have a groove that cradles the small antigen, and the T cell receptor binds to the antigen and HLA molecule together.

If the T cell receptor recognises the antigen proffered by the HLA molecule (strictly speaking, several different molecules combine to make an HLA complex) then the T cell will snap into action. But without HLA molecules, T cells wouldn’t be able to take action against threats to the body.

HLA in ME/CFS and other diseases

We have six different types of HLA molecule that present to T cells, and there are many different versions of each of the six types. Ron Davis at Stanford believes that the version of HLA genes you have may influence the risk of getting ME/CFS, and certainly HLA gene variants have been linked to numerous diseases.

One particular version of an HLA gene increases the risk of narcolepsy by 130 times. A version of another HLA gene conveys some protection against HIV developing into AIDS – though the same gene variant increases the risk of the autoimmune disease ankylosing spondylitis. In fact, HLA genes are linked to a number of autoimmune diseases…

A killer T cell in action against a cell infected by a virus. An HLA class I molecule offers up a viral antigen, and a T cell with a matching receptor binds to the HLA molecule and the antigen together. The T cell responds by killing the infected cell.

Back to the Ron Davis study: HLA and disease

There are three types of class I HLA molecules (HLA-A, HLA-B and HLA-C) – and three important types of class II HLA molecules (HLA-DP, HLA-DQ and HLA-DR). That makes six types, but there are huge numbers of different versions of each type.

Different versions of HLA are associated with increased risk (or even decreased risk) for certain diseases, particularly autoimmune diseases.

In 2014 Ron Davis reported that initial HLA profiling of 400 individuals indicated that patients had different versions of the genes that encode the HLA protein from healthy people – but that they needed to profile more people to confirm this finding. A new study that has just been announced should establish if particular versions of HLA molecules increase the risk of getting ME/CFS.

The project starts this month and is expected to complete by 2023. More information about the study at Health Rising.

Read Simon McGrath’s full article

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Status of research, treatment & perception of Myalgic Encephalomyelitis 2018

Invest in ME Research UK blog post, June 2018: Status of Research, Treatment and Perception of Myalgic Encephalomyelitis 2018

Accountability and Action

“None of the recommendations from the CMO Working Group report have been fulfilled
– a testament to the failure of governments, UK Chief Medical Officers, NHS and Department of Health
– and the Medical Research Council and those from the MRC charged with changing things for the better.

In all of the ways that ME has been handled over the past decades one inexorable fact remains – people with ME have continued to suffer and have continued to be let down.

Little more needs to be stated in order for parliament to take action.”

The charity reviewed the status of research, treatment and perception of ME in light of possible debates which might occur in UK.

We do not know if the parliamentary debate on 21st June 2018 is part of a pre-determined set of actions that leads to an agenda that has already been prepared in meetings over the past months.

Whatever the background this status document has been produced to suggest actions that need to be taken based on the lack of any real intent to make progress in the past.

Background

This is part of the status of research, treatment and perception of ME – in 2018.

The continual failure of those who have been responsible for the policies for ME – policies that should have improved the lives of patients and their families – must bring some accountability.

This continual merry-go-round which sees patients fooled by excuses and dead-end initiatives every few years must stop.

What Needs To Be Done

A number of actions which would enable a new beginning to be made

  • A Public Inquiry into ME
  • Implement the CMO Report Recommendations
  • Removal of Existing NICE Guidelines for ME
  • Annual Report to Parliament
  • Transparency of Meetings Concerning ME
  • Removal of Those Responsible for Current Situation from Positions of influence
  • Investment in ME Research

Things cannot go on as they have done before. Real change needs to occur – and not with the false change that is witnessed every few years with disingenuous attempts made by organisations and individuals who act as gatekeepers for meaningful change; – and not with continued apathy from establishment officials.

Going Forward

A five-year, ring-fenced budget of £20 million per year for biomedical research into ME should be allocated.

Funding for the Centre of Excellence for ME that the charity has been facilitating the development of for the last eight years.

The status document from the charity is here

 

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