Science at the UK CMRC Conference, 1-2 Sept 2014

Scarecrow

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Did Dr Crawley explain the science that leads to 'fatigue' clinics declaring children whose symptoms are completely unchanged as recovered from myalgic encephalomyelitis, then rediagnosing them with persistent refusal syndrome? The scientific research that has gone into that must be startling.
I think you know she didn't!
 

Simon

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I'm not really replying to this, just savouring the best bits! Wonderful news. Thanks @Jonathan Edwards for taking part and for the reporting.
Maybe the most important thing is that there was a really clear consensus about the methodological issues that get discussed here on PR.
:)

Homing in on local events in the brain and probably microglia looks the way a lot of people are thinking. Interferons continue to look interesting.
More on microglia here (sorry, couldn't miss the opportunity to plug):
Brain Cells Making us Sick? The microglia connection in ME/CFS & Fibromyalgia (& Part 2)

And although we must, as Sasha said, keep this to the science I was very encouraged by the political atmosphere. this was overwhelmingly a conference about neuroimmunology. The word biopsychosocial was used precisely twice and the second time for the purpose of saying that the word was completely meaningless and unhelpful. It was clear that almost everyone present was in strong agreement. The word suggested to replace it is just 'biological'.
This feels like a real momentum shift. Especially given that this was a conference open to all types of researchers, and was funded by the MRC. Hopefully future research funding from the MRC (+ NIHR & Wellcome Trust, who I gather were also there as observers) will move in this direction too.

Interestingly, apart from the Lipkin/Hornig lab and the Newton lab the science this week was all different from that at IiME. The two meetings complemented each other for me very nicely. We have now had a really broad exposition of the best science at UK meetings this year and new collaborations are sprouting like weeds. It all looks very exciting to me.
I've been ill for nearly two decades, and the research scene has never looked remotely like this before.
 
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I am only just back from London where Ian Lipkin (with his broken leg) gave an excellent presentation to a patient meeting at Allen and Overy this morning

Ian then went off to speak to the press at the Science Media Centre: http://www.sciencemediacentre.org/expert-encounter-prof-ian-lipkin-columbia-university/

This is the current list of those attending the press briefing:
Associated Press
Bloomberg TV
Daily Mail
New Scientist
Radio 4 Today
Reuters

The journalists will, of course, have wanted to talk to Ian about a range of medical topics that he is involved with in addition to ME/CFS

So please watch out for reports from now on…

Ian then flew back to New York this afternoon

So thanks to everyone who helped us to pay for Ian's trip to London - it was money very well spent!

The first UKRC Bristol conference was outstanding - and this is the feedback that we are also receiving from both our overseas speakers (Ian, Robert Dantzer, Andrew LLoyd) and a considerable number of researchers who attended or participated in the meeting
It was great to see Prof Jonathan Edwards there as well and I understand that he has been reporting on some of the content already
The patient meeting was also full on Monday afternoon and resulted in some lively and thoughtful discussion on the challenges facing ME/CFS research
As for content, I can assure the internet sceptics that this was a very biomedical conference looking at infection, immunology, neurology, neuroinflammation and microglia (which had lots of mentions!), muscle and mitochondrial pathology, genetics, neuroimaging (and how they all link up), pain, sleep, and all the new technologies (genomics, proteomics) that we need to make use of

The abnormal illness beliefs and behaviour model wasn't even mentioned...…

Professor Stephen Holgate made it clear in his closing remarks that we are dealing with a serious MULTISYSTEM DISEASE and that we must now go out and bring in new researchers to follow up the all leads and exciting new findings that were discussed over the past two days
I will be preparing a detailed and thoughtful report over the next week or so for the MEA website
And am happy to answer questions in the meantime
But this will have to wait till tomorrow - it has been a very hectic six days starting with my daughter's wedding last weekend, then Bristol and London, and I'm just home today in time for our wedding anniversary!
 

Simon

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So thanks to everyone who helped us to pay for Ian's trip to London - it was money very well spent!

The first UKRC Bristol conference was outstanding - and this is the feedback that we are also receiving from both our overseas speakers (Ian, Robert Dantzer, Andrew LLoyd) and a considerable number of researchers who attended or participated in the meeting

It was great to see Prof Jonathan Edwards there as well and I understand that he has been reporting on some of the content already

The patient meeting was also full on Monday afternoon and resulted in some lively and thoughtful discussion on the challenges facing ME/CFS research

As for content, I can assure the internet sceptics that this was a very biomedical conference looking at infection, immunology, neurology, neuroinflammation and microglia (which had lots of mentions!), muscle and mitochondrial pathology, genetics, neuroimaging (and how they all link up), pain, sleep, and all the new technologies (genomics, proteomics) that we need to make use of

The abnormal illness beliefs and behaviour model wasn't even mentioned...…

Professor Stephen Holgate made it clear in his closing remarks that we are dealing with a serious MULTISYSTEM DISEASE and that we must now go out and bring in new researchers to follow up the all leads and exciting new findings that were discussed over the past two days

I will be preparing a detailed and thoughtful report over the next week or so for the MEA website
Thanks, Charles to you and the MEA for this report, the one promised and for organising the funding to bring Ian Lipkin over here. I don't think ME/CFS researchers normally attract the media A list like that (hope they cover Ian Lipkin's ME/CFS research as well as his more glamorous work).

It sounds to me like this is ME/CFS reaching the mainstream in a big way. I've been ill for nearly two decades and have been constantly frustrated by the low levels of biomedical research. It feels like all that is in the process of changing. Rapidly.
 
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NK17

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Thank you @charles shepherd for bringing us the latest from today's conference and press briefing.

All PWME around the world are finally starting to get the right attention.

I'm proud and humbled by the hard work done by my fellow sufferers to raise awareness and by those few doctors and researchers who have been listening to us.

Congrats on your daughter's wedding and your anniversary.

A virtual toast for a brighter future for all of us!

Keep up the good work!
 
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I am still trying to gather thoughts but I have drafted a perspective on the first day at least. I will feed in this, and then day two, in bite sized chunks over the next couple of days.

CMRC Bristol Meeting – my perspective

Day 1
Welcome by Professor Holgate

Stephen Holgate did not give a formal presentation but made general remarks at the beginning and at the end of the conference, and also interspersed amongst talks as the meeting progressed. The salient things for me were:

1. An emphasis on how much ME/CFS had been neglected, how disabling it can be and how much it needs more attention with high quality research, which is now beginning to get off the ground.

2. The idea that the syndrome of CFS must be caused by several different processes. Like me, he is convinced that there are lots of equally important 'ME' diseases here, just as there are for arthritis or MS or asthma.

3. The recognition that it has been pressure from patients that has got research out of the doldrums.

4. The admission that there had been a breakdown in trust between doctors and patients and that this has to be faced head on and put behind us.

5. The value of capitalising on patient involvement by having meetings where patients and researchers meet together.

In this last respect I think the meeting worked extremely well. We all had the same name badges and there was ample time for patients and researchers to talk over refreshments. There was quite a PR contingent. Some sessions may have been for ‘researchers’ only, as was the dinner in theory, but in reality this included many people from the charities, and also in fact scientists, who were either patients or carers. I don’t think anyone was told they were not welcome at a session. Moreover, there was an expert science panel session specifically for taking questions from patients and carers rather than scientists.

An interesting point made to me by two people from the charities involved was that those within the collaborative were well aware that IiME had beaten them to it in setting up this sort of meeting. In fact the patient/researcher mix was very similar (something I have never come across before at medical meetings). The style of the meeting was different in other ways but the message seemed to me to be the same – let’s get on with some biological research.
 
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Anne Faulkner Lecture: Robert Dantzer on neuroimmune basis of fatigue


Dr Dantzer gave us a historical overview of how we have come to understand the way cytokines cause what is called ‘sickness behaviour’. He has worked particularly on fatigue in cancer. He very much set the scene in terms of trying to understand how fatigue is mediated on a broad front.

Dr Dantzer tended to focus on the traditional ‘inflammatory’ cytokines like TNF, IL-1 and IL-6, but also talked of gamma interferon. Specifically he spent part of his talk on hypocretin and leptin. He emphasised that cytokines and the nervous system can interact at almost all points, and in both directions. For the brain to control the immune response it has to get signals from the immune response and those pathways are recognised both through HPA axis and higher brain centres.

He also discussed the overlap and difference between ‘fatigue’ behaviour in terms of loss of motivation, in the sense of being able to summon effort under stress, and the mood change of depression per se. Much of this was related to animal experiments which may not seem entirely relevant, but later in the meeting we had a similar story from patient studies about how fatigue and depression can overlap but can also be separated out.

I learnt a lot from this lecture but I was left with the thought that maybe the idea that all fatigue is due to the same old circulating cytokines, like TNF, is too easy. Other people were obviously thinking the same. To be fair, Dantzer does not work on ME; he was giving us the broad perspective on what we know rather than what we hope to find out. As things progressed we had some fine tuning from people more directly involved with ME and chronic pain symptomatology. As Dr Lipkin said in Q&A, we need to start broad and then parse out the different components.
 

Sasha

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I learnt a lot from this lecture but I was left with the thought that maybe the idea that all fatigue is due to the same old circulating cytokines, like TNF, is too easy. Other people were obviously thinking the same.
Cort has just posted about Japanese work on fatigue - the Japanese have been tackling fatigue (zooming in from a broad scope and including specific work on CFS) because of its effects on their economy:

http://www.cortjohnson.org/blog/201...panese-brain-damage-chronic-fatigue-syndrome/

Wondering whether any of that kind of stuff was included in Dr Danzer's overview or whether people at the conference seemed aware of it. I don't know whether language issues tend to keep much Japanese work out of the mainstream literature these days. I don't think I've ever heard of a Japanese researcher attending an ME conference outside Japan.
 
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Kati

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The networking style of this meeting fits very well with what has been my experience with 'patient engagement' efforts that has been occuring in my province.

Patient engagement is huge, suddenly there is this realization that patients do have something to contribute that is meaningful, that paternalistic model of health care is not working anymore, and that an engaged and empowered patient is a healthier patient.

For physicians, it may take a little while to get used to it. However in the long run, everybody wins.

Edit to add: Patient engagement opportunities exist on many levels of health care, from participating in shaping of the health care system to providing feedback to a hospital or a clinic to taking part in an advisory committee. You can also make your own 'engagement' by writing letters to your governments and political representant and following up with a phone call. The more engaged and connected patients are, the better for all of us.
 
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Sean

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So many likes to give,…

Probably easier to just put a pile of them here to be used as required.

Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like. Like.

:thumbsup: :hug: :balloons:
 
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Neil Harrison: Interferon alpha rapidly changes brain microstructure

This was a fascinating presentation of early results from a study of brain fMRI changes after giving alpha interferon to people with hepatitis C. Alpha interferon produces fatigue in a high proportion of people treated, within 4 hours. Dr Harrison admitted that he did not yet have formal controls but he had picked up a very interesting finding. On an analysis called qMT patients developed hot spots over the basal ganglia and particularly on the left hand side 4 hours after treatment. qMT assesses the extent to which protons (hydrogen atoms) are present in the randomly behaving form present in water and how much in a more regularised form in larger molecules. It is not clear what the changes he found would mean biochemically but it is interesting that other researchers have found changes on the left side in basal ganglia in a related experiment using a different type of analysis. What I like about this is that it does not seem to be just ‘cytokines causing inflammation’ but something much more specific.


Alice Russell: Interferon alpha induced fatigue

This study looked at 25 patients receiving interferon alpha for hepatitis C and followed changes in the blood over a period of 6 months. A large number of gene products were studied. Downstream effects of interferon alpha on a range of signalling molecules involved in inflammatory pathways were identified. Patients with CFS/ME were used as controls. The long term aim was to asses whether interferon alpha treatment was a good model for cytokine changes in CFS/ME.


These two papers on alpha interferon highlighted for me the possibility that fatigue in MEs may not necessarily be mediated by the typical ‘inflammatory’ cytokines like TNF but may either involve something specific, like an interferon, that is not necessarily in itself ‘inflammatory’ or that the site of production and action of the cytokine may be very localised. Again, this seemed to be on other people’s minds. This is where I come back to a comment I have made before, that the idea that cytokines are either ‘inflammatory’ or ‘anti-inflammatory’ looks now to be unhelpful. I am not convinced that we are even looking for true ‘inflammation’ of the sort I know in rheumatoid arthritis. The key message from these studies for me was that you can get severe fatigue with just one cytokine that is not directly involved in cell migration or tissue swelling. Interferon alpha may not be the right one for MEs but it illustrates the fact that there are several options.
 
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Lisa Blundell: Systematic review of blood cytokine concentrations in CFS.

This was purely a ‘paper’ study, reviewing the literature on blood cytokines in CFS, but still very interesting. The simple message was that there did not seem to be any consistent evidence for a rise in blood cytokine levels in CFS, in 29 papers found, except perhaps TGFbeta.

This might seem to dampen down enthusiasm for cytokines causing fatigue. However, as Maria Fitzgerald pointed out, almost certainly nobody should have expected to find cytokines free in the blood. I know from rheumatoid arthritis, which is perhaps the grossest inflammatory disease of all, that finding cytokines in blood is far from easy, even when the cytokine responsive CRP protein is showing sky high. The reason may be that in RA the cytokines raising the CRP are made inside the liver in Kuppfer cells, right next to where the CRP is made. The important lesson was learnt when RA patients were given anti-TNF and it worked – the cytokine is there but acting locally. As the meeting progressed this became a consistent theme.

And maybe TGFbeta is more important than we thought. TGFbeta does not get talked about much but 5 out of 7 studies got a result for TGFbeta. This might actually make sense because this is a cytokine that gets involved in response threshold setting. If there is a stimulatory pathway acting locally that we cannot find in the blood there might still be a general feedback response through TGFbeta that did show up in blood.

And note that this was a molecular paper from a psychiatry department.



Kate Earl: Resveratrol treatment on TNF-induced cytokine release

This study was about the effects on TNF in cultured muscle cells of a rather interesting compound derived (I think) from cocoa called resveratrol. TNF seems to be important for muscle cells in that not only does it affect them but it may stimulate them to make their own ‘inflammatory’ (?!) cytokines in a vicious cycle. The effect acts on basic respiratory mechanisms involving reactive oxygen species. Resveratrol was found to reduce the ability of TNF to stimulate release of other cytokines from the muscle cells.

It was intriguing to see a compound found in normal diet having an effect on cell cytokine handling in this way. Together with the later presentation from Anne McArdle (from the same group) these were the only data looking specifically at muscle. One might ask the question whether muscle is really the target in MEs, since a lot of other groups seem to place the problem more centrally in the brain. However, taking Stephen Holgate’s multiple (and multisystem) disease idea to heart I think it is good to see all these potential targets under study. Muscle may be targeted directly in some cases and brain in others, or the problem may be a general one that affects cell metabolism across the board. Anything non-toxic that alters cytokine production is going to be of interest wherever it can act, I think.
 
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Workshops

After lunch we had workshops to look at research strategies. I went to a workshop on sleep disturbance run by Sue Wilson. In fact Sue was the only real sleep research expert in the group and for me the value was in hearing about the methodology she had for studying sleep and its relevance to ME and shifts in sleep patterns. She presented her approach on the Tuesday and I will discuss it under that session. There was, at least, enthusiasm for pursuing sleep research because it did seem to be an important problem, perhaps particularly for adolescents who may be most responsive to having their sleep cycle regularised by treatment.

There was a specific session for patient/researcher interaction on research priorities that seemed to be very successful. There is supposed to be a report coming out in due course – which may be on the MEA site I think.



Panel Discussion

The panel discussion was an opportunity for researchers to pick out what they thought was important in general terms and for patients and carers to ask questions. Perhaps the most important dialogue related to diagnostic categories and how we should relate them to research. Dr Lipkin made the important point that we want to study all fatigue partly because that will draw in more interested parties and partly because we need to study general mechanisms first. We then have to separate out the different problems that cause fatigue.

Another important point that was made was that diagnostic categories for research purposes are quite different from diagnostic labels for clinical care. I know this very well from arthritis. The diagnostic criteria for RA for research work have no relevance to whether or not it is useful to make a diagnosis in the clinic and treat on that basis. This is often hard for patients to understand but it makes sense.

Everyone seemed to agree, as Andrew Lloyd said later, that we are not looking for perfect criteria for ‘CFS’ or for ‘ME’. CFS is just the general symptom pattern we want to try and alleviate, it is not ‘a disease’. And the causes of that will be multiple so there is no point in looking for one ‘ME’ either. Other branches of medicine have learned this lesson. There is no disease called ‘asthma’. Yet the researchers still appreciate fully that it is important for patients to have a diagnosis they can relate to. Everyone agrees that the current situation is unsatisfactory but that the priority is for finding out what is really going on so that we can use some more intelligent words when we know what we are talking about.


End of Day 1
 

lansbergen

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I am not convinced that we are even looking for true ‘inflammation’ of the sort I know in rheumatoid arthritis.
I have been saying for years the inflammation does not show like doctors know it. Not only in me but also in animals. And I have seen a lot of animals with it.

How can it be autoimmunity when a large animal group known for their good health get it all at the same time?