Tuesday, 24 July 2012

New ME/CFS highlight notice issued by the UK Medical Research Council


The Medical Research Council (MRC) has put out a new call for ME/CFS research applications in a revised ‘highlight notice’ that went up on its website today (23 July 2012).

The notice says that the MRC wants to receive bids for projects that were not well-covered in the last funding round – which resulted in £1.6m being awarded to five projects just before Christmas last year. The lion’s share went to two studies at the University of Newcastle, where lead investigators Dr Wan Ng and Professor Julia Newton received over £900,000 between them.

“Some areas considered important and tractable for research by the MRC CFS/ME Expert Group (chaired by Professor Stephen Holgate), and highlighted in that call, were not well covered in the funded applications. These are highlighted below, alongside the other call topics, and now our Research Boards would particularly welcome applications in these areas,” the notice says.

Areas that will be considered are:

Immune dysregulation: There is evidence for a disturbance in innate and adaptive immunity in CFS/ME including alterations in cytokine profile, absolute and functional alterations in T cells and NK cells and occurrence of autoantibodies and allergic reactions that may explain some of the manifestations such as fatigue and flu-like symptoms. A number of infectious and environmental exposures have been associated as triggering these changes.

Pain: Headache, facial pain and myalgia are reported symptoms of CFS/ME that may involve altered sensory and/or cognitive processing in the relevant neural pathways.

Improved sub-phenotyping and stratification of CFS/ME: CFS/ME is often considered a broad spectrum disorder or syndrome and, as in other disease areas, it may be that the causes and mechanisms underpinning diverse symptom profiles are different. Better patient phenotyping and stratification could provide valuable new insights into the natural history of the disease and enable the development of more effective, better targeted treatments.

Mechanisms of CFS/ME in children: The manifestations of CFS/ME in children represent a major clinical management challenge. There is a need for research aimed at improving understanding of the mechanisms that lead to the early onset of the disease; this knowledge can then be used for the development and evaluation of new treatment options, as a prelude to their assessment in large-scale clinical trials.

Neuropathology: There is now preliminary evidence supporting the view that inflammatory mechanisms in the brain and spinal cord may underlie the pathophysiology of some severe disease CFS/ME phenotypes. Biobanks are now becoming available and create a unique opportunity for interrogation.

The MRC explains in its notice that it is hoping to tease out applications from investigators new to the field of ME/CFS studies as well as wanting to help established investigators build up their own ME/CFS research portfolios. The organisation also wants to encourage partnerships with other funders.

And this time the notice is ‘cross-board’ – which means that applications can be sent to any of the MRC’s four main Research Boards. They are (1) the Infections and Immunity Board, (2) the Molecular and Cellular Medicine Board, (3) the Neurosciences and Mental Health Board and (4) the Population and Systems Medicines Board.

Monday, 16 July 2012

Update On The PACE Trial


Professor Malcolm Hooper

11th July 2012

Many people have submitted formal complaints about the flawed methodology of the £5 million publicly-funded PACE Trial; these include complaints about the with-holding of the recovery statistics, the mis-reporting of the results by Principal Investigators themselves and by the media through the auspices of the Science Media Centre, and the apparent manipulation of the raw data, widely believed to be an attempt by the Investigators to salvage a trial that could not be allowed to fail.

Those complaints have been made to the Medical Research Council (MRC), whose Head of Corporate Governance and Policy, Dr Frances Rawle, chose not to address the issues raised and then to mock the complaint (BMJ 22nd June 2011); to The Lancet, whose editors admitted in writing that its erroneous reporting of the trial results must be corrected but almost 18 months later have still not done so and who – against the Elsevier complaints protocol -- dismissed a formal complaint entirely; to the Secretary of State (who referred it back to the MRC); to the editors of numerous newspapers who mis-reported the trial results (the way in which ME/CFS patients have been vilified in the press has just been put before Lord Leveson’s Inquiry by the Neuroimmune Alliance), and to the Royal Statistical Society, who enthusiastically requested an analysis of the statistics but then refused to publish it but provided no reason.

All complaints and concerns were ignored or dismissed and met with determined refusal to address the issues raised.

The redoubtable Countess of Mar therefore tabled a number of questions on 9th May 2012 and replies to her questions were provided by Baroness Wilcox, Parliamentary Under-Secretary of State in the Department for Business, Innovation and Skills (the Department responsible for the MRC).

Those replies were widely regarded as being unsatisfactory and Lady Wilcox was clearly anxious about the situation; following discussions between Lady Mar and Lady Wilcox, the latter offered Lady Mar a meeting with BIS officials to discuss the concerns, which Lady Mar accepted. It was anticipated that four prominent people from the ME community would accompany Lady Mar to that meeting with officials from the MRC and BIS.

Consequently, the attached document “Briefing Notes for meeting with BIS officials about incorrect answers to Parliamentary Questions re: the MRC-funded PACE Trial and ME/CFS” was compiled.

Given that it was accepted that BIS officials would have little knowledge of the situation, the document was written in plain English and was in five easy-to-understand sections: (i) Objectives of meeting with officials from the Department for Business, Innovation and Skills (BIS); (ii) Essential background information about ME/CFS (iii) Problems with the replies to Parliamentary Questions (PQs) of the Parliamentary Under Secretary of State in the Department for Business, Innovation and Skills (Baroness Wilcox); (iv) Problems with the Medical Research Council’s role in the PACE Trial and its repeated denial of accountability and (v) Failure of the PACE Trial Principal Investigators (PIs) to report primary outcome measures as set out in the Trial Protocol; evidence of misrepresentation of the data and evidence of unacceptable selectivity in the results of the trial published in The Lancet.

However, on 21st June 2012, Lady Wilcox informed Lady Mar that the BIS officials were “concerned” about Lady Mar’s “associations” and suggested that she and Lady Mar should have tea together to enable her to get a handle on the problem before the full meeting with BIS officials.

Before any such discussions could take place, on 25th June 2012 Jamie Ballantyre, Assistant Private Secretary to Baroness Wilcox, wrote to the Countess of Mar asking if she would be available to meet Baroness Wilcox, Officials from the MRC and Officials from BIS at 16.30 on 12th July 2012. The letter was specific: “This meeting would be to discuss MRC funding opportunities for CFS/ME and the actions the MRC has taken to try to build capacity in this area…It will not be possible for the technical details of the trial or interpretation of the data to be discussed”. The reasons given were (i) “The research itself has been conducted independently of government and results of the trial, following peer review, have been published (ii) Although funding for the trial was provided by the MRC, this decision to fund would have been made based on peer review. In line with the Haldane Principle of scientific independence, the department would not and should not have any influence on this process (iii) None of the officials who will be present have the relevant technical expertise and knowledge”. The letter continued: “It is important to note that there are channels for challenging scientific results through journals and other publications, speaking at conferences, further research work etc”.

Not only was the DWP a co-funder of the PACE Trial (so it cannot be argued that the trial was independent of government, which has a strong vested interest in getting people with ME/CFS off state benefits and back to work, this being the non-clinical rationale for the “clinical” trial), it has been acknowledged that the PACE Trial protocol that was published in BMC Neurology on 8th March 2007 (BMC Neurology 2007, 7:6 doi:10.1186/1471-2377-7-6) was not peer-reviewed by the journal before publication (“This study protocol was not peer reviewed by the journal because it had already received ‘ethical’ and funding approval by the time it was submitted….We strongly advise readers to contact the authors or compare with any published results article(s) to ensure that no deviations from the protocol occurred during the study” -- Editor’s comment 31st January 2007:
http://www.biomedcentral.com/imedia/2095594212130588_comment.pdf ).

In the case of the PACE Trial, The Lancet’s peer review process has patently failed, since no non-biased peer-reviewer would have approved such a significant deviation from the published Protocol including the highly selective publication of results, the abandonment of primary end-points and the shifting of goal posts such that the post-hoc “normal range” overlapped with the entry criteria.

It seems remarkable that officials from the MRC would not have the relevant knowledge to discuss very basic concerns about the methodology of one of its own clinical trials or its own role in that trial.

Moreover, the Haldane Principle (ie. that decisions about how research funds should be spent should be made by researchers and not by politicians) has nothing to do with the issues raised: the key issue is that BIS is responsible for the MRC’s failure to adhere to elementary rules of scientific procedure that occurred in the PACE Trial and as a result of the MRC’s failure, sick people continue to be put at risk of iatrogenic harm.

What is at stake here is the fact that the PACE Trial is scientifically flawed and the results have been misrepresented so NICE, insurance companies, the DWP and private companies contracted by the government (including Atos) are relying on false interpretation of the data to the serious detriment of very sick people.

Lady Mar’s response was that such a meeting would “get us nowhere” and that she would meet Baroness Wilcox privately and explain the situation to her.

A private meeting between the Countess of Mar and Baroness Wilcox took place on 11th July 2012, at which Lady Wilcox agreed that the best way to deal with the situation would be a debate in the House of Lords; this will be arranged for October when the House returns after the recess.

At the conclusion of that meeting, Lady Mar gave Lady Wilcox a copy of the attached Briefing Notes, so there can be no argument that she did not receive a copy.

These facts are being made publicly known in accordance with the government’s keenness for transparency and accountability.

To read the Briefing Notes mentioned, click on the link

For further information about the PACE Trial, please read Magical Medicine: How To Make A Disease Disappear by Prof Malcolm Hooper. A PDF file is available here (442 pages, 6Mb file size).

Monday, 9 July 2012

Little Things

Another poem from “Echoes of Eternity” by Michael R Abbott; used with permission

Little Things

Daisies for the Children
Deck the carpets green;
Even in the little things,
The hand of God is seen.
All our needs supplying,
By His tender care,
Riches more to us He gives
And love beyond compare.

Flowers clothed in yellow,
Red, pink, white and blue,
Painted by the Master's hand
In every glorious hue.
Solomon, in glory,
Was not so arrayed;
With God as our Provider,
We need not be afraid.

Just a little sparrow,
Falling from its nest,
Comes to the Lord's attention:
His watch doth never rest.
By His hand He feeds them
With a bounteous fare;
Why should we not trust in Him,
Who lavishes such care?

Early in the morning,
Dew lies on the ground;
The treasures of creation
In morning light abound.
He who formed the creatures,
Herbs, and flowers, and trees,
In His life upon this earth
Took children on His knees.

Seeing then His glory
And His love made known,
Let us come with thankful hearts
And fall before His throne;
Let us trust Him fully
For our daily bread,
Lying down in peace to sleep
At night upon our bed.

Monday, 2 July 2012

Research: Mitochondrial dysfunction and the pathophysiology of CFS/ME


by Tony Britton on June 30, 2012

Int J Clin Exp Med 2012;5(3):208-220

http://www.ijcem.com/ ISSN:1940-5901/IJCEM1204005 Full text available HERE.

Mitochondrial dysfunction and the pathophysiology of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)

Norman E Booth (1), Sarah Myhill (2), John McLaren-Howard (3)

(1) Department of Physics and Mansfield College, University of Oxford,Oxford UK;

(2) Sarah Myhill Ltd, Llangunllo, Powys UK;

(3) Acumen, Tiverton, Devon UK


The objectives of this study are to test the hypothesis that the fatigue and accompanying symptoms of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis are in part due to defects in energy provision at the cellular level, and to understand the pathophysiology of the defects so that effective medical intervention can be implemented.

We performed an audit of 139 patients (ages 18-65) diagnosed with CFS/ME and attending a private practice.

The patients and 53 normal, healthy controls had the ATP Profile test carried out on neutrophils from a 3-ml venous blood sample. This test yields 6 numerical factors that describe the availability of ATP and the efficiency of oxidative phosphorylation in mitochondria. Other biomedical measurements, including the concentration of cell-free DNA in plasma, were made.

The results of the audit are compared with the controls and a previous cohort of 61 patients. We find that all patients tested have measureable mitochondrial dysfunction which correlates with the severity of the illness. The patients divide into two main groups differentiated by how cellular metabolism attempts to compensate for the dysfunction.

Comparisons with exercise studies suggest that the dysfunction in neutrophils also occurs in other cells. This is confirmed by the cell-free DNA measurements which indicate levels of tissue damage up to 3.5 times the normal reference range.

The major immediate causes of the dysfunction are lack of essential substrates and partial blocking of the translocator protein sites in mitochondria. The ATP Profile is a valuable diagnostic tool for the clinical management of CFS/ME.