PACE trial data assessment: in ME/CFS CBT and GET are ineffective

Posted on 01/17/2017 by wames

Research abstract:

The PACE trial concluded that Cognitive Behavioral Therapy (CBT) and Graded Exercise Therapy (GET) are moderately effective in managing Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and yielded a 22% recovery rate.

Nonetheless, the recently released individual participant data shows that 13.3% of patients had already recovered, on one or both primary outcomes, upon entering the trial. Moreover, no one classified as recovered achieved the physical functioning, together with the fatigue scores, of the healthy sedentary controls from another trial by the PACE trial‘s lead principal investigator or achieved Kennedy‘s definition of recovery, whereby symptoms are eliminated and patients return to premorbid levels of functioning, due to CBT or GET (alone).

Therefore, CBT and GET do not lead to actual recovery. After CBT and GET therapy, 59% and 61% of participants, respectively were labeled as improvers in the original paper, which was lowered by the PACE trial authors to 20% and 21% in the newly released papers in which they used the original protocol; nevertheless, only 3.7% and 6.3% were objective improvers in the objective 6-minute walk test as defined by the same improvement of 50% or more, as used by the trial itself, to classify someone as an improver.

If the effect of Specialist Medical Care had been removed from the analysis, then 0% and 1.3% of patients improved objectively with CBT and GET, respectively. Highlighting the fact that unblinded trials like the PACE trial, should not rely on subjective primary outcomes, but use either objective primary outcomes alone, or combined with subjective primary outcomes, as a methodological safeguard against the erroneous inference of efficacy in its absence.

The objective individual participant data shows that in up to 82.2% and 79.8% of ME patients their health might have been negatively affected by CBT and GET, respectively. The independent PACE trial review had shown that this proportion was between 46% and 96%, and found to be between 63% and 74% by surveys involving more than 3000 patients by the Norwegian, British, and the Dutch ME Associations.

These data confirm the conclusions of a number of studies that patient health was negatively affected by CBT and GET, including one that found that in 82% of patients with severe ME their symptoms were made worse by GET. Analysis of the individual participant PACE trial data has shown that CBT and GET are ineffective and (potentially) harmful, which invalidates the assumption and opinion-based biopsychosocial model.

Consequently, we should stop using CBT and GET as (compulsory) treatments for ME/ CFS to prevent further unnecessary suffering inflicted on patients by physicians, which is the worst of all harms, yet totally preventable.

Assessment of Individual PACE Trial Data: in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Cognitive Behavioral and Graded Exercise Therapy are Ineffective, Do Not Lead to Actual Recovery and Negative Outcomes may be Higher than Reported, by Mark Vink in Journal of Neurology and Neurobiology 3:1, 2017 [Published online 10 Jan 2017]

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Inquest into death of person with severe ME in North Wales

Posted on 01/16/2017 by wames

Daily Post article, by Gareth Hughes, 12 January 2017:  Coroner questions bed-blocking at Maelor Hospital after woman accidentally killed herself in A&E

A coroner is to ask what steps are being taken to tackle the problem of  bed-blocking at the Maelor Hospital, Wrexham. John Gittins, the coroner for North Wales East and Central, issued a Regulation 28 notice after hearing the situation was probably worse today than two years ago.

Julie Smith, assistant director for nursing with the Betsi Cadwaladr University Health Board, told an inquest that demand for beds constantly exceeded supply despite various efforts to solve the problem. ‘It is an absolutely massive challenge but we are doing our best to manage the pressure,’ she said.

Mrs Smith was giving evidence at an inquest into the death of mother-of-four Sarah Ann Tyler, who accidentally killed herself in the hospital’s emergency department where she had been on a trolley for about eight hours, having been admitted after taking an
overdose of paracetamol.

Miss Tyler, of Ffordd y Gaer, Bradley, was found unconscious with a ligature made of an ECG cable around her neck in the early hours of February 9, 2015.

The hearing was told that she had been suffering from depression and severe ME (myalgic encephalomyelitis) which had left her bed-bound. In a statement read at the inquest her partner David Millward, who was father to her four children, said she was virtually unable to move and was upset at being unable to care for her children. He said she was convinced that the chronic fatigue, not a mental health issue, was her main problem and she felt she was not receiving the specialist treatment for her condition.

In August, 2014, her son found her with a bungee cord around her neck and on February 9 Mr Millward found her with a phone charger cord around her neck, so called the out-of-hours doctor. In the doctor’s presence she took an overdose of paracetamol and Cocodamol and so she was admitted to the emergency department, where she refused to engage with staff. While lying on the trolley she disconnected her intra-venous drip
several times, claiming it had fallen out.

Senior House Officer Dr Thomas Minton told the inquest: ‘I explained what the risks were but she was not giving me anything back.’ Staff nurse Kate Roberts said that Miss Tyler was under half-hourly observation because of the tablets she had taken and was last seen at about 12.20am. About 15 minutes later she was found hanging and despite attempts to resuscitate her she died the following day.

Mrs Smith, who was involved in the serious incident review following the tragedy, said various steps had been taken as a result. These included psychiatric nurses being involved in assessment at a much earlier stage when a patient who has selfharmed arrives in the emergency department.

‘Two years ago nurses used their own professional judgment,’ she said.

Asked by the coroner whether such an incident was less likely to occur now, Mrs Smith replied: ‘Yes, I believe we have reduced the risk, though the improvements are on-going.’ Mr Gittins said his initial fears regarding observation of patients had been allayed but he remained concerned about the severe problem of finding beds for patients, even though he did not believe it played a part in Miss Tyler’s death.

‘Patient throughput continues to be a problem and perhaps even greater now than it was two years ago. I believe it does create a risk,’ he added. He recorded a conclusion of accidental death on Miss Tyler, a cleaner, as he was not persuaded that she wanted to kill herself as she had taken the action in a place where she could expect to be found.

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Narratives of parents living with a child affected by CFS/ME

Posted on 01/16/2017 by wames

Research abstract:

Background and Aims:
Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) remains a poorly understood condition, shrouded by debate, stigma, and uncertainty. Unsurprisingly, the little available research suggests that caring for a Child or Young Person (CYP) affected by the condition can be extremely challenging.

While the majority of available literature is quantitative in nature, there is some qualitative research examining the impact of having a CYP with CFS/ME on parents. However, there currently appear to be no studies examining the narratives of parents living with a CYP with CFS/ME. Therefore, this research aimed to hear how parents narrate their experiences of living with a CYP affected by CFS/ME, paying attention to how they construct their identity, and the contested condition.

Methodology:
This research drew on a qualitative approach that explored the narratives of the participants. A purposive sample of five parents of CYP affected by CFS/ME (5 mothers) was recruited for a single semi-structured interview. The interviews were audio-recorded, transcribed, and analysed using a narrative approach to explore what participants said and how they narrated their accounts. This was then situated within the social and cultural contexts that shaped them.

Analysis and Findings:
Multiple readings of the narratives allowed me to develop a summary of each individual’s narrative account. These were presented, after which similarities and differences across narratives were considered. Analysis identified six areas of collective focus: ‘stories of onset and diagnosis’, ‘stories of battle’, ‘stories of finding the person/people who can help’, stories of impact’, ‘stories of seeking social support’, and ‘stories of coping and adjustment’.

Participants’ narratives were heavily influenced by dominant societal discourses surrounding CFS/ME and motherhood, and could be seen as a response to these narratives.

Consequently, participants offered particular constructions of the condition, themselves, their CYP, and others that they had come into contact with. These findings are discussed with reference to their potential bearing for clinical practice, strengths and limitations of  the methodology, and directions for future research.

Narratives of parents living with a child affected by Chronic Fatigue Syndrome/Myalgic Encephalomyelitis, by  Rosalind Payne. Phd thesis University of Hertfordshire, June 2016 [Published 5 January 2016] Abstract

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The Brain Initiative: FM & ME/CFS perspective

Posted on 01/13/2017 by wames

Health rising blog post, by Cort Johnson, 8 Jan 2017: The Brain Initiative: a Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS) perspective

In the third of three blogs looking at the research efforts of tomorrow and their potential impact on fibromyalgia and chronic fatigue syndrome (ME/CFS) Health Rising looks at the biggest effort of all: the Brain Initiative.

The Brain Initiative

We’ve always suspected that technology is going to provide the answers for diseases like fibromyalgia (FM) and chronic fatigue syndrome (ME/CFS), and nowhere are technological advances more important or necessary than in the brain. With its 100 billion neurons and 100 trillion connections encased in its difficult to penetrate bone helmet it’s easily the hardest organ to get at and understand – and possibly the most important.

Almost all of the symptoms associated with FM and ME/CFS such as the fatigue, pain, cognitive issues, sleep and stimuli problems could conceivably have their origin in the brain. While brain scans regularly find abnormalities in FM, for instance, they’re not precise enough to tell us which neurons, astrocytes or glial cells are causing the problems in these diseases. Similarly, while magnetic stimulation and other brain stimulation techniques can be helpful they’re still crude techniques that lack the ability to target specific brain cells.

On April 2, 2013, the White House proposed a 10-year project—the BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies) – to unlock the mysteries of the brain. This Manhattan style project brought together a roster of experts to “catalyze an interdisciplinary effort of unprecedented scope. After a year of work the group reported a series of goals:

  • To classify all the cells in the brain in order to learn how to tweak what
    To produce a full “connectome” of all the millions of connective circuits in the brain
  • Understanding the electrical and chemical activity each type of neuron in the brain engages in
  • Finding new ways to effect brain activity

New tools need to be developed to succeed at each of these goals. The data gathered will be so immense as to require that new statistical methods be produced to adequately analyze it.

The Brain Initiative started funding projects in 2014. Here are some of its recently funded projects:

FIXING THE BRAIN

Changing Brain Activity – a “magnetothermal toolbox” that will locate and activate specific neurons in the brain – thereby paving the way for more precise ways of stimulating or de-stimulating the brain.

Transcranial Magnetic Stimulation to the Rescue?

  • miniaturized rTMS elements that will alter brain activity more precisely and at deeper levels of the brain
  • combine TMS with MRIs in order to simultaneously stimulate multiple brain regions

Focused…Really Focused Ultrasounds

  • Newer functional ultrasounds that use acoustic signals to measure blood vessel volume, however, put older techniques to shame. They’re about 10x more precise.
  • low intensity ultrasound to regulate the activity of neurons in the brain – “sonogenetics” uses sound waves to do just that.
  • creating gaseous nanovesicles (really, really, really small vesicles) derived from microbes that can be introduced into the brain to view the brain, particularly in its deeper levels.
  • a wearable FUS cap that’s designed to modulate the activity of overactive sensorimotor regions of the brain

Shhh…..A Quiet TMS – an inaudible TMS (a qTMS or quiet TMS) machine that is more tolerable, safer, more precise and even more effective.

A Walk Down Memory Lane Again? – a new brain stimulation procedure called “HF-Stim” to enhance the hippocampal-cortical networks which enable us to have memories.

UNDERSTANDING THE BRAIN

The Inflammation Behind Neuroinflammation – DREADDS ( Designer Receptors Exclusively Activated by Designer Drugs) to determine which kinds of cells are producing neuroinflammation.

Good Vibes – Virtual Brain Electrode project will load red blood cells with magnetic particles in order for researchers to indicate exactly which part of the brain those pathogenic EEG signals are coming from.

fMRI – new technology to tell which kinds of neurons (inhibitory/excitatory) or glial cells are causing problems, which will help determine which kinds of treatment might be best.

Microscopic Resolution – combining fMRIs with other brain imaging technologies to provide three-dimensional maps at the microscopic level of the brain when it is active.

Read more about these projects and how they might benefit people with ME/CFS and FM in the full article at Health Rising.

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The association of fecal microbiota & fecal, blood serum & urine metabolites in ME/CFS

Posted on 01/13/2017 by wames

Research abstract:

INTRODUCTION:

The human gut microbiota has the ability to modulate host metabolism. Metabolic profiling of the microbiota and the host biofluids may determine associations significant of a host–microbe relationship. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a long-term disorder of fatigue that is poorly understood, but has been linked to gut problems and altered microbiota.

OBJECTIVES

Find changes in fecal microbiota and metabolites in ME/CFS and determine their association with blood serum and urine metabolites.

METHODS

A workflow was developed that correlates microbial counts with fecal, blood serum and urine metabolites quantitated by high-throughput 1H NMR spectroscopy. The study consists of thirty-four females with ME/CFS (34.9 ± 1.8 SE years old) and twenty-five non-ME/CFS female (33.0 ± 1.6 SE years old).

RESULTS

The workflow was validated using the non-ME/CFS cohort where fecal short chain fatty acids (SCFA) were associated with serum and urine metabolites indicative of host metabolism changes enacted by SCFA.

In the ME/CFS cohort a decrease in fecal lactate and an increase in fecal butyrate, isovalerate and valerate were observed along with an increase in Clostridium spp. and a decrease in Bacteroides spp. These differences were consistent with an increase in microbial fermentation of fiber and amino acids to produce SCFA in the gut of ME/CFS patients. Decreased fecal amino acids positively correlated with substrates of gluconeogenesis and purine synthesis in the serum of ME/CFS patients.

CONCLUSION

Increased production of SCFA by microbial fermentation in the gut of ME/CFS patients may be associated with deleterious effects on the host energy metabolism.

The association of fecal microbiota and fecal, blood serum and urine metabolites in myalgic encephalomyelitis/chronic fatigue syndrome, by Christopher W. Armstrong, Neil R. McGregor, Donald, P. Lewis, Henry L. Butt, Paul R Gooley in Metabolomics, January 2017 13:8 [Published online 12 Dec 2016]

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The great NIH exercise initiative: a boon for ME/CFS & FM?

Posted on 01/12/2017 by wames

Health rising forum post, by Cort Johnson, 3 January 2017: The Great NIH Exercise Initiative: A Boon for Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia?

“This physical activity initiative aims to fundamentally change our understanding of what happens to the body on the molecular level when we exercise,” said James M. Anderson, M.D., Ph.D.

In Part II of a three-part look at recent major NIH efforts that may significantly impact chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) we find the NIH bringing its big guns to bear on the most problematic area of all for ME/CFS patients – exercise.

Few diseases, if any, are as defined by problems with physical activity as chronic fatigue syndrome (ME/CFS), and few diseases affect physical activity as dramatically as does fibromyalgia. Nobody, of course, knows why mild exercise can cause such relapse in ME/CFS or why more serious exercise can cause such pain in FM.

Maybe that’s not such a surprise. It turns out that researchers know surprisingly little about what happens when we exercise. Sure they know what happens to the heart rate, blood flows, air intake, oxygen usage, etc., when we exercise but we know very little about what happens to the body at the molecular level. That’s important, not just for exercise physiologists, but for ME/CFS and FM as well; it’s at the molecular level where the key to ME/CFS and FM probably lies.

Our understanding of the molecular changes that occur during exercise is going to entirely change – and probably fairly rapidly – when the NIH’s Molecular Transducers of Physical Activity in Humans Program (MoTrPAC; Motor…Pac – get it? Kind of?) gets rolling.

MotrPAC is going to take a deep dive into the world of exercise. By the time they’re done we’re going to have new ways to analyze what the heck goes wrong during exercise in ME/CFS.

You don’t think Dr. Collins wasn’t thinking of chronic fatigue syndrome (ME/CFS) when he said this:

“The development of a so-called molecular map of circulating signals produced by physical activity will allow us to discover, at a fundamental level, how physical activity affects our health. This knowledge should allow researchers and doctors to develop individually targeted exercise recommendations and better help those who are unable to exercise.”                                                  Francis Collins

I do… In fact, the optimist in me wonders if the fatigue RFA grant Collins was reportedly considering for ME/CFS morphed into this $170 million dollar (not completely funded) project. (Why would Collins do this kind of run-around? Because he can get buy-in from the Institutes to spend a ton of money to study exercise. He can’t get buy-in to spend that kind of money on ME/CFS.)

This is a biggie: it contains seven clinical sites, seven chemical analysis sites, animal models, a bioinformatics center, a coordination center, and finally and perhaps most importantly for diseases like chronic fatigue syndrome and fibromyalgia, the open sourced data information center.

Two of the 19 grants (Ron Davis and Dr. Montoya, take note) are going to two Stanford researchers (Michael Snyder, Stephen Montogomery) to identify and characterize all the molecules that form during or after exercise. Yes, that’s after exercise as well…what an opportunity to study post-exertional malaise in ME/CFS.

At the end of this huge grant ($15.7 million – equal to the entire budget of the upgraded NIH ME/CFS program) these two Stanford researchers will know more about genomic, transcriptomic and epigenomic effects of exercise than anyone else alive…and it’s all going to happen in the next five years.

One imagines that Nancy Klimas and Gordon Broderick with the multiple data points they’ve collected before, during and after exercise might have something to say to Drs. Michael Snyder and Stephen Montgomery, PhD. Of course, Dr. Montoya is using exercise in his immune studies at Stanford as well. One might think these researchers might be interested in the growing exercise data collected on the most exercise challenged illness group there is.

What an excellent control group ME/CFS patients would be (!). How better, after all, to explicate what goes right in exercise than by understanding what can go so wrong? Lead Stanford researcher Michael Snyder might very well agree:

“A lack of physical activity is a major factor in multiple diseases. This program provides an exciting opportunity to learn the molecular mechanisms underlying physical activity, with the goal of enabling new approaches to improving or maintaining individual health.”                                  Michael Snyder

Personally, I would put finding ways to enable ME/CFS patients to finally do the exercise they’ve been yearning for so many years as a top priority. One wonders how many ex-athletes – Jamison Hill’s and others – are out there? (Please take the survey.) Anecdotal reports suggest they abound in ME/CFS. Some people think ex-athletes may be over-expressed in ME/CFS. Thirty-seven years ago I was an avid runner and exerciser. Never did I dream such a fundamental part of my life could be taken away so completely.

Even if the Stanford group can’t find a way to include a few ME/CFS patients in their huge study, within five years or so we should have a bevy of molecular targets that Ron Davis, Derya Unutmaz, Patrick McGowan,Ian Lipkin, Gordon Broderick, Zaher Nahle or other ME/CFS researchers interested in the molecular roots of this disease should be able to analyze.
Stanford isn’t the only possible ME/CFS connection. Marcas Bamman at the University of Alabama at Birmingham’s “Center for Exercise Medicine” will lead one of the clinical centers. One wonders if he might be interested in what’s happening in Jarred Younger’s Neuroinflammation, Fatigue and Pain Lab on the same campus.

Plus, included in those omics’ (genomics, epigenomics, transcriptomics, proteomic’s) analyses are extensive metabolomics studies as well. MoTrPAC isn’t just whistling dixie with regard to metabolomics either. The Emory Chemical Analysis Center in Georgia appears to be almost entirely devoted to metabolomics. Boasting a “state-of-the-art ultra-high resolution accurate mass high-field Orbitrap tandem mass spectrometer”, the group will use “global, targeted and spatially resolved metabolomics” to produce “unequivocal chemical identification(s) of novel molecular transducers”. The Mayo Rochester site will also attempt to fuse proteomics and metabolomics date to generate molecular maps of physical activity.

What a serendipitous project this is. Just as ME/CFS research at the NIH starts to finally begin to ramp up (expect an announcement on that in the next couple of weeks) it embarks on an ambitious project to understand the molecular roots of the most problematic activity of all in ME/CFS – exercise. For once we have good timing.

Health Rising is a website with news blog and forums dedicated to providing timely, accurate information to people with chronic fatigue syndrome (ME/CFS) and fibromyalgia.

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Twins needed for ME/CFS research

Posted on 01/11/2017 by wames

National ME/FM Action Network announcement:

A senior Canadian researcher has been looking for genetic factors in people with ME/CFS for several years. His studies have already yielded promising results. The next stage of his study involves looking at identical twins where both twins have ME/CFS (“concordant”) or one of the twins has ME/CFS and the other does not (“discordant”). He has already found three sets of identical twins for his study but hopes to find more.

If you are identical twins with discordant or concordant ME/CFS, please contact Margaret Parlor at mefminfo@mefmaction.com to learn more about the study and what it would involve from you.

I am interested in hearing from identical twins affected by ME/CFS anywhere in the world. There are two reasons.

  • Firstly, while this researcher hopes to find enough cases in countries where he has collaborators (Canada, the US and New Zealand), he might need additional cases and might be able to work out suitable arrangements for twins in other locations to participate as well.
  • Secondly, I suspect that other researchers will want to do twin studies. This will give us an indication of how easy or difficult it is to find volunteers and a list of possible volunteers. Please note that if a researcher asks me for names of twins, I will notify you about the study and ask you for permission to share your names; I will not give your names to researchers without notifying you and receiving your permission.

Please share this request widely. And if you know identical twins in this situation, please encourage them to contact me. Thank you!

Margaret Parlor, President, National ME/FM Action Network

mefminfo@mefmaction.com

 

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Differing case definitions point to the need for an accurate diagnosis of ME/CFS

Posted on 01/11/2017 by wames

Research article:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterised by unexplained and persistent or recurrent incapacitating fatigue accompanied by a variety of symptoms and substantial reductions in previous levels of occupational, educational, social and/or personal activity [1,2]. Given the absence of biomarkers for diagnosis, ME/CFS is defined by a combination of symptoms, most of which are non-specific and common to a number of diseases and conditions.

Over 20 case definitions have been proposed, leading to large variations in sensitivity and specificity of diagnosis. These diverse sets of diagnostic criteria and distinct ways in which they have been applied pose significant problems, as research results may vary considerably according to which definition is used. A particular problem occurs when overly inclusive criteria are used, since their lack of specificity may lead to considerable selection bias [3,4].

Unfortunately, many studies, clinical trials in particular, have used broad case definitions such as the Oxford criteria [5], which requires little more than the presence of persistent significant fatigue for over six months and the exclusion of conditions that could explain symptoms, for a diagnosis to be made.

This problem has been highlighted by the Agency for Healthcare Research and Quality (AHRQ) review of evidence for the NIH Pathways to Prevention Workshop [4], which showed significant changes to the interpretation of evidence for treatment, when studies using broad case definitions, such as the Oxford criteria, are excluded from the analysis. The implications for clinical practice suggest that fit-for-all management approaches to ME/CFS, may be inadequate for patients who fulfil better targeted case definitions.

For patients selected using more restrictive definitions, cognitive behavioural therapy (CBT), graded exercise therapy (GET) and other forms of non-drug management approaches to ME/CFS are most appropriate as adjunct therapies rather than restorative treatments, when provided by therapists with a good understanding of ME/CFS. These forms of behavioural intervention have been shown to support the well-being and rehabilitation of those suffering from many chronic and disabling conditions [6]. However, it is very important that the use of behaviourally based management strategies does not deter researchers, physicians and other health professionals from the overarching goal of investigating the causes and pathophysiology of ME/CFS in various sub-groups and the development of specific treatments.

Read more:

Differing case definitions point to the need for an accurate diagnosis of myalgic encephalomyelitis/ chronic fatigue syndrome by Luis Nacul, Caroline C. Kingdon, Erinna W. Bowman, Hayley Curran & Eliana M. Lacerda in Fatigue: Biomedicine, health & behaviour [Published online 8 Jan 2017]

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Making drugs obsolete: the electroceutical revolution – FM & ME/CFS perspective

Posted on 01/10/2017 by wames

Health rising blog post, by Cort Johnson, 2 Jan 2017: Making Drugs Obsolete: The Electroceutical Revolution – A Fibromyalgia and ME/CFS Perspective

This is the first of three blogs looking at major NIH projects which, while not being aimed at fibromyalgia or chronic fatigue syndrome (ME/CFS), could profoundly affect how they are understood and treated.

The NIH’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) is exploring an entirely new way of treating disease. It proposes to tweak the electrical circuits (nerves) in our bodies to return people to health.

These nerves (every nerve outside the brain and spinal cord) control the health and functioning of every organ in the body. SPARC is slated to spend $250 million over the next seven years in an attempt to learn how to manipulate these nerves to reduce pain, relieve inflammation, heal heart problems, fix gut disorders and more.

Nobody knows if the self-proclaimed “high-risk” project will be successful, but if it is it could usher in a new, side-effect free way of treating illnesses that could put drugs to shame.

The peripheral nervous system is stunningly complex but the general idea is not. It simply consists of using some sort of generator to send electrical impulses down a nerve, causing it to fire. The crude technology used today employs a kind of scattershot approach which ends up activating bunches of nerves.

The “Electroceutical” Revolution?

But with better nerve maps and more refined tools it should be possible to activate just the right fibers in the right nerves to, say, stop some inflammatory processes in their tracks. Or to tweak nerves to fix gut problems, reduce pain, reverse heart failure, or treat diabetes. These are just a few of the possibilities proponents of the electroceutical revolution can envision.

These electroceuticals are either placed on the skin or are surgically implanted where they emit electrical impulses that either fire up or silence nerves. They need not be near the organ of interest at all; one device for patients with bladder problems is placed on the soles of their feet.

Read more about the technology, vagus nerve stimulation and possible effect on reducing inflammation in the ME/CFS immune system

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Fuel shortage: Norwegian study expands on energy problem in ME/CFS

Posted on 01/09/2017 by wames

Health rising blog post, by Cort Johnson, 27 Dec 2016: Fuel shortage: Norwegian study Expands on Energy Problem in Chronic Fatigue Syndrome (ME/CFS)

Fluge and Mella seem to be working at almost lightning speed. Besides managing their huge Rituximab study (and all the sub-studies within it) and the cyclophosphamide trial, they’re also carrying out large research studies.

For years, of course, some researchers and doctors championed the idea that problems with mitochondrial energy production were at the heart of ME/CFS. For many, though, the idea seemed almost too simple…too easy in a way. The body throws too many curves at us for something so obvious to be the cause. But it may be.

The work of Bob Naviaux of UCSD, Ron Davis of the Open Medicine Foundation, McGregor and Armstrong et. al. in Australia, Maureen Hanson at Cornell, and Fluge and Mella in Norway suggest that problems producing energy could, in fact, be causing the physical and mental fatigue in (ME/CFS).

Of course, it’s going to be complex. Exercise studies and other studies have suggested that the aerobic energy production pathways are severely blunted in a significant number of ME/CFS patients. Thus far, though, the metabolomics data suggests that the breakdown comes not in the aerobic energy production pathway but just before it.

Some key facts – such as I understand them.

  • Key Factor in Glycolysis – Pyruvate –  Pyruvate is produced by glycolysis and then gets broken down into acetyl-CoA for use in the mitochondria. When oxygen levels are low, the same process is used to produce ATP anaerobically. Anaerobic energy gets its bad rep because it produces toxins like lactate which build up and cause pain and fatigue. All this occurs in the cell’s cytoplasm.
  • Key Factor in Aerobic Energy Production – Acetyl-CoA – The first goal in aerobic energy production is to produce acetyl-CoA. This occurs in three ways: preferentially by converting pyruvate and/or by converting fatty acids or amino acids. The acetyl-CoA is then broken down further to produce ATP by a process called oxidative phosphorylation. All aerobic energy production occurs in the cell’s mitochondria.

The Study
At 302 patients (200 ME/CFS patients and 102 healthy controls) this was a nice big study. A different type of study than the recent metabolomic studies, it used a mass spectrometer to measure the levels of 20 amino acids involved in energy metabolism in the blood.

QT-RCT PCR was used to examine gene expression. Cells were also cultured, dropped in ME/CFS or healthy control’s serum (blood), tweaked with metabolic factors, and their lactate production and cellular respiration was measured.

Results
Amino Acid Results
Fluge and Mella did a simple but telling thing with the 20 amino acids by dividing them into one of three energy production pathways:

Glycolytic Amino Acids – Amino acids used in the glycolysis pyruvate producing pathway which require PDH to be metabolized (alanine (Ala), cysteine (Cys), glycine (Gly), serine (Ser), and threonine (Thr))

Aerobic Amino Acids – Amino acids that fuel aerobic energy production but which do not require PDH to be broken down((isoleucine (Ile), leucine (Leu), lysine (Lys), phenylalanine (Phe), tryptophan (Trp), and tyrosine (Tyr)) – mostly ketogenic amino acids

Other Amino Acids – not found in the first category but which are essential to aerobic energy production (anaplerotic – methionine (Met), valine (Val), histidine (His), glutamine (Gln), glutamate (Glu), and proline (Pro), aspartate (Asp), (Asn + Asp = Asx))
Chronic Fatigue Syndrome (ME/CFS) – A Pyruvate Dehydrogenase Disease?

Fluge and Mella found no difference in the levels of the amino acids used in glycolysis – pyruvate production is fine – but reductions in the levels of the ketogenic amino acids used to power aerobic energy production.

Our cells much prefer using glucose to produce energy but the results and the Aussie study suggest that our cells are turning elsewhere.

Remember that our cells – use three different substrates (pyruvate, fatty acids and amino acids) to produce acetyl-CoA but they much prefer glucose.  If pyruvate isn’t being broken down into acetyl-CoA, however, then our cells will turn to another energy source; in this case amino acids. The fact that virtually all the amino acids used to produce acetyl-CoA were depleted in the female ME/CFS patients suggested that their cells, starved of metabolized pyruvate, were turning to and using up amino acids to to produce energy.

Amino acids, unfortunately, are kind of like the body’s last straw for energy production. Our cells would much prefer to use glucose, but even fatty acids are a better source of energy than amino acids. In order for body to use amino acids it has remove an amino group (producing ammonia) and turn them into a sugar.  (The fact ME/CFS patients appear to be turning to amino acids might suggest that they’re having problems with fatty acid metabolism as well.)

There’s another problem, though. If all this unused pyruvate is hanging around, it has to go somewhere. Unused pyruvate gets converted into lactate – a toxin responsible for much of the fatigue and pain associated with exercise. Lactate ultimately gets dumped into the blood stream. Fluge and Mella believe lactate accumulations are probably a key problem in ME/CFS as well. High lactate levels in ME/CFS patients’ brains have been found in several studies but reports on lactate accumulations in the blood are mixed.

Since pyruvate production doesn’t appear to be the problem, the problem must lie in the pyruvate dehydrogenase enzyme complex (PDH) which breaks down pyruvate to produce acetyl-CoA.

Or a Pyruvate Dehydrogenase Kinase Disease?
Fluge and Mella then asked why pyruvate dehydrogenase is not working in ME/CFS and may have found an answer in the increased gene expression (or activity) of the enzymes (PDH kinases (PDK)) that inhibit PDH. Rather encouragingly, they found that increased expression of one form of the PDK enzyme (PDK1) was associated with increased severity and longer duration patients.

Fluge and Mella uncovered numerous irregularities that could be affecting the pyruvate dehydrogenase enzyme in ME/CFS

Digging deeper still they found increased gene expression of the transcription factor (PPAR) which upregulates PDH kinase in ME/CFS patients as well.  Then they discovered that the gene expression levels of another enzyme (SIRT4) that limits pyruvate dehydrogenase production were increased as well.

Things were really humming along; Fluge and Mella’s findings suggested that every step in the chain needed to limit pyruvate dehydrogenase levels were activated in ME/CFS. Their consistently positive findings suggested that an inhibited PDH enzyme really may be a problem in ME/CFS.

Read more about the results of the study

Not just tired: further research suggests cell energy production impaired in ME, by Emily Beardall, 23 Dec 2016 [blog post: A Prescription for M.E. My blog from the intersection of patient & pharmacist]

TV2 interview: New study on pathological mechanisms in ME from researchers in Norway [in Norwegian, subtitles in English]

ME Action blog post: Fluge, Mella and Armstrong: more support for disordered metabolism in ME patients, by Jaime S, 23 Dec 2016

 

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