The “Starvation” Disease? metabolomics meets CFS down under

Posted on 11/17/2016 by wames

Health rising blog post: The “Starvation” Disease? Metabolomics Meets Chronic Fatigue Syndrome Down Under, by Cort Johnson, 10 November 2016

“The pathological nature of the fatigue experienced by ME/CFS sufferers is its inexplicable persistence, severity and its inability to be sufficiently relieved by rest.” Armstrong et. al.

The Naviaux metabolomics study with its findings suggesting that a hypometabolic state is present in chronic fatigue syndrome was thrilling, but it wasn’t the first or even nearly the first ME/CFS metabolomics study. The Aussies (McGregor, Gooley, Butt, and more recently Armstrong) have been plugging away at metabolism and metabolic work for years, and their 2015 study – ignored by most – was as exciting as the Naviaux paper. Ron Davis glommed onto it early and  praised it. Looked at in light of Bob Naviaux’s work, the paper, with its similar core findings and somewhat different interpretations, is exciting indeed.

The Core Problem in Chronic Fatigue Syndrome Identified? Naviaux’s Metabolomics Study Breaks Fresh Ground

metabolomics-armstrong-smci-webinarFrom the Amstrong SMCI webinar

Christopher Armstrong, the lead author, is an example of the kind of young researcher this field needs so much. An Australian researcher working with Neil McGregor – a metabolomics pioneer in the ME/CFS field  – Armstrong represents hope for the future.

Armstrong was not at IACFS/ME conference but Dr. McGregor was. McGregor’s mostly been working in the shadows for years but he’s out of the shadows now and appears to be in considerable demand. He was not being totally ignored before; a year or so ago the Australian group’s work caught the eye of an ME/CFS researcher – Dr. Fluge – who doesn’t miss much.  Dr. Fluge’s subsequent metabolomics work was one of the highlights of the IACFS/ME Conference.

When I asked Armstrong how he got involved in chronic fatigue syndrome (ME/CFS), he noted that Dr. McGregor and Dr. Henry Butt have studied ME/CFS since the early 1990s. After Butt and Gooley published a paper on gut microbes in ME/CFS. Armstrong’s Ph.D. study examined D-lactate in blood, fecal and urine samples. He then got funded for the larger study that was published in 2015.

Continue reading this article for more about Dr Armstrong’s work

Solve ME/CFS webinar with Christopher Armstrong, 20 October 2016

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ME Association’s Metabolomics study appeals for funds

Posted on 11/17/2016 by wames

ME Association: Make ME Better! appeal

Our Make ME Better campaign aims to raise £50,000 to fund scientific research which we hope could lead to a breakthrough in diagnosis and treatment of ME/CFS.

Led by Dr Karl Morten, scientists from the University of Oxford and Newcastle University wish to spend 12 months analysing nearly 300 blood samples, looking at metabolomics – chemical clues that are left behind after changes in cells. Put simply, they’re on the hunt for a smoking gun.

The British research will pick up the gauntlet of the groundbreaking Naviaux study released by the University of California earlier this year, which suggested that ME/CFS could be the body going into a state of semi-hibernation.

Dr Morten will be working alongside Dr James McCullagh, Associate Professor in Mass Spectrometry at the University of Oxford, and Professor Julia Newton, Dean for Clinical Medicine at Newcastle University.

Many of the blood samples will come from the ME/CFS Biobank – the first significant time they have been used by external researchers – and will be compared to those from a control group.

IT’S A BIG TARGET BUT PLEASE HELP US REACH IT!

You can support MAKE ME BETTER

For the first time ever, you can involve all your friends and family in fundraising for this appeal – a Santa dash, Christmas party, or community Christmas card……

Once you’ve decided what you want to do, simply click on the ‘Start fundraising’ tab of the campaign page to get started.

Please support our campaign to MAKE ME BETTER in whatever way you can.

Helen Hyland
Fundraising Manager
ME Association

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B cell functional changes & Ca2+dysregulation in ME/CFS

Posted on 11/16/2016 by wames

Research abstract:

Single nucleotide polymorphisms and genotypes of transient receptor potential ion channel and acetylcholine receptor genes from isolated B lymphocytes in myalgic encephalomyelitis/chronic fatigue syndrome patients, by Marshall-Gradisnik S, Johnston S , Chacko A , Nguyen T , Smith P , Staines D 3 in J Int Med Res. 2016 Nov 10. pii [Epub ahead of print]

OBJECTIVE:
The pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is unknown; however, a small subgroup of patients has shown muscarinic antibody positivity and reduced symptom presentation following anti-CD20 intervention. Given the important roles of calcium (Ca2+) and acetylcholine (ACh) signalling in B cell activation and potential antibody development, we aimed to identify relevant single nucleotide polymorphisms (SNPs) and genotypes in isolated B cells from CFS/ME patients.

METHODS:
A total of 11 CFS/ME patients (aged 31.82 ± 5.50 years) and 11 non-fatigued controls (aged 33.91 ± 5.06 years) were included. Flow cytometric protocols were used to determine B cell purity, followed by SNP and genotype analysis for 21 mammalian TRP ion channel genes and nine mammalian ACh receptor genes. SNP association and genotyping analysis were performed using ANOVA and PLINK analysis software.

RESULTS:
Seventy-eight SNPs were identified in nicotinic and muscarinic acetylcholine receptor genes in the CFS/ME group, of which 35 were in mAChM3. The remaining SNPs were identified in nAChR delta (n = 12), nAChR alpha 9 (n = 5), TRPV2 (n = 7), TRPM3 (n = 4), TRPM4 (n = 1) mAChRM3 2 (n = 2), and mAChRM5 (n = 3) genes. Nine genotypes were identified from SNPs in TRPM3 (n = 1), TRPC6 (n = 1), mAChRM3 (n = 2), nAChR alpha 4 (n = 1), and nAChR beta 1 (n = 4) genes, and were located in introns and 3′ untranslated regions. Odds ratios for these specific genotypes ranged between 7.11 and 26.67 for CFS/ME compared with the non-fatigued control group.

CONCLUSION:
This preliminary investigation identified a number of SNPs and genotypes in genes encoding TRP ion channels and AChRs from B cells in patients with CFS/ME. These may be involved in B cell functional changes, and suggest a role for Ca2+dysregulation in AChR and TRP ion channel signalling in the pathomechanism of CFS/ME.

 

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A polysaccharide from Schisandra chinensis fruit might relieve fatigue in CFS?

Posted on 11/16/2016 by wames

Research abstract:

Schisandra chinensis fruits are a famous traditional Chinese medicine to treat all kinds of fatigue. This study aimed to investigate the therapeutic effect and metabolic mechanism of a polysaccharide (SCP) from Schisandra chinensis fruits on chronic fatigue syndrome(CFS).

SCP was isolated and the physicochemical properties were analyzed. A CFS model of rats was established and the urinary metabonomic studies were performed using gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) in combination with multivariate statistical analysis. The results showed that SCP is a protein-bound polysaccharide. The amino acid composition of SCP consisted of 12 amino acids.

The growth and the behaviors of the rats in the CFS model group were worse than those in the control group and improved after SCP treatment. Analysis of the GC-TOF-MS revealed that twelve metabolites were significantly changed, and six metabolites were oppositely and significantly changed after the SCP treatment. The TCA cycle metabolic pathways and the alanine, aspartate and glutamate metabolism were identified as significant metabolic pathways involved with SCP. The therapeutic mechanism of SCP against CFS was partially due to the restoration of these disturbed pathways.

Metabolic mechanism of a polysaccharide from Schisandra chinensis to relieve chronic fatigue syndrome, by A Chi, Y Zhang, Y Kang, Z  in Int J Biol Macromol. 2016 Aug 18;93(Pt A):322-332 [Epub ahead of print]

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Countess of Mar complains about BBC portrayal of FITNET trial

Posted on 11/15/2016 by wames

The Countess of Mar has written to the Director General of the BBC with a formal complaint about its portrayal of the FITNET trial from 1 Nov 2016 onwards.

3rd November 2016

Dear Lord Hall
Formal Complaint to the BBC re: the purveying of mis-information on 1st November 2016

This is brought to your personal attention because it is such a serious matter.

The BBC is required to be accurate and impartial, but James Gallagher (the BBC News
website Health and Science reporter who was responsible for the item that made the BBC
headlines from 5.30am on 1st November 2016) was neither accurate nor impartial.
On BBC News 24 the breaking news ticker headline repeatedly announced across the screen:

“A successful treatment for children with CFS is being trialled by the NHS.”

The BBC’s Charter says that its primary function is to inform, educate and entertain, but the BBC breached its own Charter by its 24-hour non-stop promotion of a study of myalgic
encephalomyelitis/chronic fatigue syndrome in children and adolescents (the £1 million
FITNET trial, which stands for Fatigue In Teenagers on the interNET) and which claims
success for a behavioural modification intervention when there is no objective evidence of
any such success in either children, adolescents or adults.

Moreover, the study had not even started to recruit participants: this was not made clear and it was heralded as “Landmark chronic fatigue trial could cure two-thirds” but that was later changed to the nonsensical “Landmark chronic fatigue trial could treat two-thirds“. Chronic fatigue is not the same as ME/CFS.

The item was described thus:

“the BBC and their scientifically illiterate journalists imaginatively and dishonestly spun this as a 2/3 cure rate”.

The letter goes on to look at specific aspects of the complaint and then ends:

I ask that you ensure that the BBC issues a prominent retraction of its endorsement of and
support for the FITNET study and, to counter-balance its support for behavioural
interventions for a proven and classified neuroimmune disorder, the BBC offers a
commensurate right of reply to those with an understanding of the biomedical nature of the disease.

Read full letter

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Targeting serotonin and insulin-like growth factor in CFS

Posted on 11/15/2016 by wames

Thesis outline:

Given the controversies and uncertainties surrounding these potentially important mediators in CFS, we decided to investigate the role of tryptophan, 5-HT and IGF-1 in CFS in this thesis. Our studies aim to obtain a deeper insight into the pathophysiology of CFS by investigating the efficacy of three biological interventions for CFS.

The effect of Granisetron, a 5-HT3 receptor antagonist, in CFS – In chapter 2 we asked the question whether treatment with a 5-HT3 receptor antagonist is effective in CFS. Studies and clinical observations suggested a role for 5-HT3 receptor antagonism in the treatment of chronic fatigue associated with chronic liver disease and fibromyalgia. The effect of 5-HT3 receptor antagonists in CFS patients had not been investigated in CFS patients before, hence a pilot study was carried out to investigate the effect of Granisetron.

The effect of Ondansetron, a 5-HT3 receptor antagonist, in CFS– In chapter 3 we addressed the same question based on positive findings found in the pilot study described in chapter 2. A randomised double-blind controlled trial was performed. Because granisetron was no longer available at that time, due to a merge of pharmaceutical manufacturer SmithKline Beecham with Glaxo Wellcome, the 5-HT3 antagonist Ondansetron (Zofran) was used to further investigate the effect of 5-HT3 receptor antagonism in CFS.

The effect of Acute Tryptophan Depletion in CFS – Besides intervention with selective serotonin antagonists, we also investigated the effect of Acute Tryptophan Depletion (ATD), a well-known intervention in major depressive disorder The results of a placebo-controlled cross-over ATD study are presented in chapter 4.

Based on the hypothesis that CFS represents a hyperserotonergic state, we used ATD to decrease central serotonin availability, and assessed the effects on fatigue severity, concentration and mood.

The effect of Acclydine in CFS – In chapter 5 we investigated whether CFS patients have lower IGF-1 levels than age, weight and gender matched neighbourhood controls.

Based on the idea that the growth hormone metabolism is disrupted in CFS, De Meirleir in 2001 reported that treatment with Acclydine, a plant-sourced alkaloid, is effective in modifying growth hormone/

IGF-1 status in adult CFS patients and reverts complaints. In 2002, the CFS patient organisation reported in their ‘MEdium Journal’ that the manufacturer of Acclydine had found that 75-80% of CFS patients have a growth hormone deficiency.

Double-blind randomised controlled trials were needed. Acclydine was an expensive treatment and is available on the internet without a prescription. It had been mentioned on the news that Acclydine was recommended for cancer patients with chronic fatigue, and that there were conflicts in Acclydine research. Acclydine was administered to vulnerable patients, but the scientific evidence for efficacy was lacking. The effect of Acclydine, officially a food supplement, was thus evaluated in a randomised controlled clinical trial. We evaluated whether Acclydine is effective in CFS by increasing biologically active IGF-1 levels. Results of a randomised controlled trial are presented in this thesis.

[Comment from M Fluks: Chapter 5 debunks Acclydine therapy. In The Netherlands and Belgium problems arose after Acclydine was sold to PWCs, PWFMs, and Cancer patients (Cancer patients even died due to lack of treatment). Afterwards, things would never be the same: Acclydine therapy marked the beginning of the end of CFS in The Netherlands  and Belgium.]

Discussion and future prospects – In chapter 6 I will discuss the main results and implications of the investigations performed, and present recommendations and prospects for future studies.

Chronic Fatigue Syndrome: Targeting Serotonin and Insulin-like Growth Factor, by Gerard Kong Han The. Thesis from Radboud University Nijmegen Medical Centre, 1 Nov 2016

http://repository.ubn.ru.nl/handle/2066/160772

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Low putamen activity associated with poor reward sensitivity in childhood CFS

Posted on 11/14/2016 by wames

Research abstract:

Mizuno K, Kawatani J, Tajima K, Sasaki AT, Yoneda T, Komi M, Hirai T, Tomoda A, Joudoi T, Watanabe Y. Low putamen activity associated with poor reward sensitivity in childhood chronic fatigue syndrome. Neuroimage Clin. 2016 Sep 26;12:600-606. eCollection 2016

Motivational signals influence a wide variety of cognitive processes and components of behavioral performance. Cognitive dysfunction in patients with childhood chronic fatigue syndrome (CCFS) may be closely associated with a low motivation to learn induced by impaired neural reward processing. However, the extent to which reward processing is impaired in CCFS patients is unclear. The aim of the present functional magnetic resonance imaging (fMRI) study was to determine whether brain activity in regions related to reward sensitivity is impaired in CCFS patients.

fMRI data were collected from 13 CCFS patients (mean age, 13.6 ± 1.0 years) and 13 healthy children and adolescents (HCA) (mean age, 13.7 ± 1.3 years) performing a monetary reward task. Neural activity in high- and low-monetary-reward conditions was compared between CCFS and HCA groups. Severity of fatigue and the reward obtained from learning in daily life were evaluated by questionnaires. Activity of the putamen was lower in the CCFS group than in the HCA group in the low-reward condition, but not in the high-reward condition. Activity of the putamen in the low-reward condition in CCFS patients was negatively and positively correlated with severity of fatigue and the reward from learning in daily life, respectively.

We previously revealed that motivation to learn was correlated with striatal activity, particularly the neural activity in the putamen. This suggests that in CCFS patients low putamen activity, associated with altered dopaminergic function, decreases reward sensitivity and lowers motivation to learn.

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Support for the microgenderome invites enquiry into sex differences in ME/CFS

Posted on 11/14/2016 by wames

Research abstract:

The microgenderome defines the interaction between microbiota, sex hormones and the immune system. Our recent research inferred support for the microgenderome by showing sex differences in microbiota-symptom associations in a clinical sample of patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).

This addendum expands upon the sex-specific pattern of associations that were observed. Interpretations are hypothesised in relation to genera versus species-level analyses and D-lactate theory.

Evidence of sex-differences invites future research to consider sex comparisons in microbial function even when microbial abundance is statistically similar. Pairing assessment of clinical symptoms with microbial culture, DNA sequencing and metabolomics methods will help advance our current understandings of the role of the microbiome in health and disease.

Support for the Microgenderome Invites Enquiry into Sex Differences, by Amy Wallis, Henry Butt, Michelle Ball, Donald P. Lewis & Dorothy Bruck in Gut Microbes, 3 November 2016 [Epub ahead of print]

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Robust evidence of an underlying biological process in ME/CFS

Posted on 11/11/2016 by wames

Miriam Tucker reports on the overwhelming evidence for the biological basis for ME/CFS which was presented at the IACFS/ME conference in the USA in October 2016:

Biomarker Research Advances in ‘Chronic Fatigue Syndrome’, by Miriam E. Tucker in Medscape Medical News, November 08, 2016

Extract:

The symptom heterogeneity, combined with the lack of specific biomarker, has resulted in skepticism among some clinicians that the condition is biologically, rather than psychologically, based.

However, studies during the last decade point to biological underpinnings. At the biennial IACFSME conference, more than 100 papers were presented that contribute further to the evidence base, according to Anthony L. Komaroff, MD, professor of medicine at Harvard University, Boston, Massachusetts, and editor-in-chief of the Harvard Health Letter.

“Case-control studies comparing patients with ME/CFS to both disease comparison groups and healthy control subjects find robust evidence of an underlying biological process involving the brain and autonomic nervous system, immune system, energy metabolism, and oxidative and nitrosative stress,” Dr Komaroff said in a conference summary at the end of the meeting.

He added, “To those people out there who still question whether there is really anything wrong in this illness, my advice to them would be try consulting the evidence.”

Read the full article – you may need to register with Medscape first

Margaret Williams comments on Miriam Tucker’s article:

Professor Hornig told Medscape Medical News: “in addition to accelerating research on causes and treatment, we critically need to find ways to educate medical professionals about the disorder”.

Attempting to educate the UK medical profession, the DWP and benefits decision-makers,
the media and local authorities about ME/CFS has proved impossible for the last 30 years.

Since the psychosocial model is demonstrably wrong, to continue treating ME/CFS as a
behavioural disorder is both unethical and harmful, and is wasteful of tax payers’ money.
Thirty years of behavioural research and interventions have yielded a null result.

The stranglehold of the psychosocial school in the UK over this disorder must be broken so
that actual progress can be made.

How can so much evidence be ignored by so many people for so long?

Read the article: Extracts from Medscape Medical News: “Biomarker Research Advances in ‘Chronic Fatigue Syndrome’ ” by Miriam Tucker, 8th November 2016 – Comment by Margaret Williams 9th November 2016

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Investigation of the effects of vanilloids in animal model of chronic fatigue

Posted on 11/10/2016 by wames

Research abstract:

AIM OF THE STUDY: To assess the effectiveness of TRPV1 modulators in animal model of Chronic fatigue syndrome (CFS). To assess central and peripheral behavioral activity of TRPV1 modulators.

MATERIAL AND METHODS: CFS was induced by forcing the rats to swim for 10min for 21 consecutive days. The rats were treated with capsaicin (TRPV1 agonist, 2.5mg/kg) and n-tert-butylcyclohexanol (TRPV1 antagonist, 10mg/kg) for 21 days 30min before the exposure to stress procedure. The behavioral consequence of CFS was measured in terms of immobility time, grip strength, locomotor activity, and anxiety level using Rota rod, Actophotometer, and Elevated plus maze model respectively. The other parameters include Plasma corticosterone, adrenal gland and spleen weight, complete blood count, blood urea niterogen (BUN), Lactate dehydrogenase (LDH), Lipid peroxidation, catalase and reduced glutathione (GSH).

RESULTS AND DISCUSSION: TRPV1 modulators reversed (p<0.05) the increase in immobility period, anxiety, spleen weight, BUN and LDH levels, and MDA levels along with decrease in grip strength, locomotor activity, plasma corticosterone, adrenal gland weight, catalase, and GSH. There was also significant increase in total WBC count when compared with the disease control group. The reversal was attributed to modulation of HPA axis, oxidative stress, anaerobic respiration product, muscle degradation product.

CONCLUSION: The present study reveals the effectiveness of n-tert-butylcyclohexanol and capsaicin against chronic fatigue syndrome. The mechanism of action can be attributed to inhibition of TRPV1 channel and thereby modulating pain perception, neuroendocrine function, oxidative stress and immune function.

Investigation of the effects of vanilloids in chronic fatigue syndrome by Kuldeep Sarvaiya, Sunita Goswami in Brain Res Bull. 2016 Sep 28;127:187-194 [Epub ahead of print]

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