Science at the UK CMRC Conference, 1-2 Sept 2014
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lansbergen
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Good thinking.
I have no doubt brain and muscles are both involved.
What do ypu think will happen when axon ends are attacked?
I think we may have hit the nail on the head when we talk about the two conferences.
IiME choses doctors from several areas and in particular the group that stands out for me are the "treaters". We have had Cheney, Peterson, Lerner and other doctors who have been trying to both understand and treat ME or CFS for a long time now.
Would I be mistaken if I said that the CMRC conference didn't involve any treaters or even invite any treaters?
IiME choses doctors from several areas and in particular the group that stands out for me are the "treaters". We have had Cheney, Peterson, Lerner and other doctors who have been trying to both understand and treat ME or CFS for a long time now.
Would I be mistaken if I said that the CMRC conference didn't involve any treaters or even invite any treaters?
Resveratrol comes from the skins of red grapes and some other fruits and is in red wine and (yippee!) chocolate. You can buy it as a food supplement. I think a few PR members have tried it but I don't know what kind of results they've had.
It has become well-known for alleged cardiovascular benefits but:
http://www.nhs.uk/news/2014/05May/Pages/Resveratrol-red-wine-chemical-overhyped.aspx
That's interesting, given Julia Newton's findings on cultured muscle from PWME:
http://www.meassociation.org.uk/201...ope-for-me-sufferers-the-times-23-april-2013/
In the study, scientists took muscle biopsies from ten patients and ten healthy but sedentary volunteers.
The muscle cells were grown into small pieces of muscle and then subjected to “exercise” in the form of electrical impulses.
The cells from ME patients produced on average 20 times as much acid when exercised, suggesting an underlying cause for the aching muscles that patients often experience as soon a they begin to exercise.
The cells also showed other abnormalities, such as reproducing more slowly.
In the study, scientists took muscle biopsies from ten patients and ten healthy but sedentary volunteers.
The muscle cells were grown into small pieces of muscle and then subjected to “exercise” in the form of electrical impulses.
The cells from ME patients produced on average 20 times as much acid when exercised, suggesting an underlying cause for the aching muscles that patients often experience as soon a they begin to exercise.
The cells also showed other abnormalities, such as reproducing more slowly.
Maybe we're looking at subgroups again.
Jonathan Edwards
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Not sure which animals these are? Nobody is suggesting, I think, that all MEs are autoimmune based. The Norwegian study suggests that maybe half of human cases might be. 'Epidemics' either in humans or animals are less likely to be autoimmune to my way of thinking. I think we run into trouble if we argue that one size fits all.
Jonathan Edwards
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I am coming to that! A few more sessions to go yet.
I was wondering how consistent a picture we would expect from these 29 papers. For example, are all cytokines known or is there potential for new ones associated with fatigue to be found. Also if there are multiple different diseases and cytokines are involved would you expect them to be the same ones or a mixture of different ones? I'm guessing if the answer to the last question is that different cytokines could be involved this could lead to confused results particularly with small studies - my guess is there could be clusters in larger studies.
Jonathan Edwards
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CMRC Bristol Meeting – my perspective continued
Day 2
Stuart Watson: Autonomic dysfunction in CFS
Dr Watson presented research from the Newcastle group, covering endocrine, cytokine and autonomic studies. A cohort of patients had been recruited for multiple studies. This cohort was deliberately restricted to those without significant affective symptoms (overt depression). He felt this was important as their findings contrasted with some other previous studies. For instance they failed to find association between CFS and adverse life events in childhood.
He described studies of dexamethasone suppression of cortisol and reported that a subgroup of CFS patients showed reduced cortisol suppression, in contrast to previous reports.
In line with other groups he described a lack of evidence in their studies for abnormal cytokine levels.
He also described ongoing studies looking at blood volume control using liver imaging and other modalities.
For me the interesting aspect here was the evidence of neuroendocrine imbalance, together with clinical evidence of autonomic disturbance, in the absence of blood cytokine changes. The implication for me is, again, that central nervous signalling pathways can be measurably abnormal without there being any peripheral cytokine evidence.
Of note, Dr Watson is a psychiatrist working together with Dr Newton on a wide range of aspects of ME/CFS, and their collaboration seems to be doing much to clear the air and fit everything together in a unified biological model.
Fai Ng: Biological fingerprints of fatigue
Dr Ng described studies looking for a ‘serological fingerprint’ for fatigue based on RNA extraction from while blood. His studies included patients with primary Sjogren’s syndrome, some of whom have major fatigue and some of whom do not. Interestingly he found a pattern of change in gene expression in Sjogren’s patients but this tended to be more marked in those with less fatigue. Sjogren’s patients were drawn from a cohort within which a trial of rituximab is taking place and it is hoped that response to treatment can be correlated with the serological fingerprint.
Again, this study emphasised to me the fact that different facets of a single disease may be mediated by different pathways. It rather looks as if fatigue in Sjogren’s syndrome is mediated by pathways that are not involved in the production of other features of the disease.
Day 2
Stuart Watson: Autonomic dysfunction in CFS
Dr Watson presented research from the Newcastle group, covering endocrine, cytokine and autonomic studies. A cohort of patients had been recruited for multiple studies. This cohort was deliberately restricted to those without significant affective symptoms (overt depression). He felt this was important as their findings contrasted with some other previous studies. For instance they failed to find association between CFS and adverse life events in childhood.
He described studies of dexamethasone suppression of cortisol and reported that a subgroup of CFS patients showed reduced cortisol suppression, in contrast to previous reports.
In line with other groups he described a lack of evidence in their studies for abnormal cytokine levels.
He also described ongoing studies looking at blood volume control using liver imaging and other modalities.
For me the interesting aspect here was the evidence of neuroendocrine imbalance, together with clinical evidence of autonomic disturbance, in the absence of blood cytokine changes. The implication for me is, again, that central nervous signalling pathways can be measurably abnormal without there being any peripheral cytokine evidence.
Of note, Dr Watson is a psychiatrist working together with Dr Newton on a wide range of aspects of ME/CFS, and their collaboration seems to be doing much to clear the air and fit everything together in a unified biological model.
Fai Ng: Biological fingerprints of fatigue
Dr Ng described studies looking for a ‘serological fingerprint’ for fatigue based on RNA extraction from while blood. His studies included patients with primary Sjogren’s syndrome, some of whom have major fatigue and some of whom do not. Interestingly he found a pattern of change in gene expression in Sjogren’s patients but this tended to be more marked in those with less fatigue. Sjogren’s patients were drawn from a cohort within which a trial of rituximab is taking place and it is hoped that response to treatment can be correlated with the serological fingerprint.
Again, this study emphasised to me the fact that different facets of a single disease may be mediated by different pathways. It rather looks as if fatigue in Sjogren’s syndrome is mediated by pathways that are not involved in the production of other features of the disease.
From MEA FB:
I hope they'll push for that to be annual.
Charles Shepherd Having staged such a successful first UKRC conference at the University of Bristol the plan is to continue with this event in years to come (not sure if it will be every year and where it will be - but we will be discussing this at the UKRC Board meeting later this month) and (amongst other things) make this the main research event of the year where UK research is being strongly highlighted. But we also want to strengthen international input and links in the years to come.
Jonathan Edwards
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Carmine Pariante: Cytokines in depression and fatigue
Dr Pariante discussed in more detail the studies they were doing on interferon alpha treatment for hepatitis C. He reviewed background information on the relation of fatigue to depression. It is clear that there is overlap in some cases but also that there are different determinants of the two problems. In the hepatitis patients depression and fatigue were both problems but they occur at completely different times. Fatigue is almost immediate. Depression comes later. Moreover, some patients have one without the other. And it is not just that depression takes a bit longer to kick in. Fatigue can continue for months or years after treatment in the absence of any depression.
This presentation seemed to show clear evidence for the need to refine our approach to 'sickness behaviour'. Ironically Dr Pariante still talked of 'inflammatory' cytokines, but to my mind 'inflammation' is no longer of any use to us as a concept in the context of MEs. Inflammation is a very curious rag bag concept. It is most obviously about swelling due to increased vascular permabiity and influx of white blood cells. But the spleen is completely full of white blood cells all the time and its blood vessels are always fully permeable but it is not inflamed. Brains almost never have neutrophil white cells (the most specifically 'inflammatory' ones) coming in despite damage from other mechanisms. Progress in understanding diseases like lupus, RA and polymyalgia has been dreadfully slow because people do not think in terms of different processes, like complement activation or cytokine release, but keep just thinking of 'inflammation'. A molecule like leptin can be involved in response to injury or just in not being hungry. It is not an 'inflammatory signal'. Most cytokines we call inflammatory are mostly used to ensure there is no inflammation. Inflammation is a rubbish term we need to bin. The whole debate is at a level too low to get us anywhere.
Rant over.
Dr Pariante discussed in more detail the studies they were doing on interferon alpha treatment for hepatitis C. He reviewed background information on the relation of fatigue to depression. It is clear that there is overlap in some cases but also that there are different determinants of the two problems. In the hepatitis patients depression and fatigue were both problems but they occur at completely different times. Fatigue is almost immediate. Depression comes later. Moreover, some patients have one without the other. And it is not just that depression takes a bit longer to kick in. Fatigue can continue for months or years after treatment in the absence of any depression.
This presentation seemed to show clear evidence for the need to refine our approach to 'sickness behaviour'. Ironically Dr Pariante still talked of 'inflammatory' cytokines, but to my mind 'inflammation' is no longer of any use to us as a concept in the context of MEs. Inflammation is a very curious rag bag concept. It is most obviously about swelling due to increased vascular permabiity and influx of white blood cells. But the spleen is completely full of white blood cells all the time and its blood vessels are always fully permeable but it is not inflamed. Brains almost never have neutrophil white cells (the most specifically 'inflammatory' ones) coming in despite damage from other mechanisms. Progress in understanding diseases like lupus, RA and polymyalgia has been dreadfully slow because people do not think in terms of different processes, like complement activation or cytokine release, but keep just thinking of 'inflammation'. A molecule like leptin can be involved in response to injury or just in not being hungry. It is not an 'inflammatory signal'. Most cytokines we call inflammatory are mostly used to ensure there is no inflammation. Inflammation is a rubbish term we need to bin. The whole debate is at a level too low to get us anywhere.
Rant over.
Jonathan Edwards
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Sue Wilson: Sleep and chronic fatigue
Dr Wilson introduced some fascinating methodology in terms of sleep research and some cogent thoughts about how shifts in sleep patterns may be important targets for therapy. She described the use of a drug called sodium oxybate, which is used in narcolepsy. It increases slow wave sleep in a reproducible and time limited way. She has set up a study of CFS patients who are receiving oxybate and placebo in a cross-over protocol. She is measuring the effect on a variety of measures including daytime sleepiness. The hope is that persistence of fatigue in some cases may be at least partly dependent on a vicious cycle of abnormal sleep rhythm that might be corrected by something like oxybate.
Again, I thought this was fascinating evidence for the need to look at very specific central nervous system pathways if we want to understand fatigue both on a broad basis and broken down into subgroups.
Dr Wilson introduced some fascinating methodology in terms of sleep research and some cogent thoughts about how shifts in sleep patterns may be important targets for therapy. She described the use of a drug called sodium oxybate, which is used in narcolepsy. It increases slow wave sleep in a reproducible and time limited way. She has set up a study of CFS patients who are receiving oxybate and placebo in a cross-over protocol. She is measuring the effect on a variety of measures including daytime sleepiness. The hope is that persistence of fatigue in some cases may be at least partly dependent on a vicious cycle of abnormal sleep rhythm that might be corrected by something like oxybate.
Again, I thought this was fascinating evidence for the need to look at very specific central nervous system pathways if we want to understand fatigue both on a broad basis and broken down into subgroups.
lansbergen
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Jonathan Edwards
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Anne McArdle: Mitochondrial function and skeletal muscle
Dr McArdle gave us an account of how mitochondrial function, generation of reactive oxygen species and ATP handling in muscle are all tied in to signalling through cytokines like TNF. Muscle mitochondria are different from those in other cells in their position and density. She described a range of experimental systems used in Liverpool both in vivo and in vitro to study the ways in which mitochondrial function might be linked in to cytokine changes. She indicated the importance of feedback loops that could potentially set up long term abnormalities of regulation of muscle metabolism.
Dr McArdle gave us an account of how mitochondrial function, generation of reactive oxygen species and ATP handling in muscle are all tied in to signalling through cytokines like TNF. Muscle mitochondria are different from those in other cells in their position and density. She described a range of experimental systems used in Liverpool both in vivo and in vitro to study the ways in which mitochondrial function might be linked in to cytokine changes. She indicated the importance of feedback loops that could potentially set up long term abnormalities of regulation of muscle metabolism.
A.B.
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This is similar to what I have experienced. Fatigue came first and appeared suddenly. Depressive mood came later and slowly. Over the years, the depressive mood went away but the fatigue is still there and has gotten worse. I haven't been depressed for years, and now think the depressed mood was mainly a reaction to my life falling apart (and to all the psychobabble-fueled blaming)
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Daisymay
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The same could surely be said for symptoms like fatigue and pain?
Jonathan Edwards
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Esther Crawley: Epidemiology of CSF/ME in children
Dr Crawley described ongoing studies of incidence, and natural history of CFS in children and adolescents. She found that incidence was similar in boys and girls at 13 but that by 18 it was twice as high in girls. She found that a relatively high proportion of children improve as compared to adults, although not all. She also noted differences in the pattern of symptoms in children, with less sleep disturbance and cognitive dysfunction in the younger groups. Overlap with chronic widespread pain seemed less than previously reported, with evidence for different determinants for the two syndromes. She described the setting up of further studies designed to look at potential risk factors using complex statistical analysis.
There was a lot of useful epidemiological data in this presentation. One thing I did not raise but perhaps should have done is that at least most of the other people presenting (Dr Crawley’s statistics may be more sophisticated) still seemed to be working with the two-component model of genetics and environment. The assumption seems to be that whatever is not genetic must be due to some life event. The major debate is whether that is likely to be an immune or physical insult like infection or injury or whether it may be a psychological event related to social interactions. The overwhelming emphasis in the meeting was on infective or immunological insults. However, my understanding is that a respectable epidemiological model will always be three-component, including a stochastic or random element. You need that for cancer and autoimmune disease so why not for ME. The simple fact is that 90% of the explanation for ME beyond genetics may be due to no environmental factors at all. It may be due to a variable and unpredictable instability of an internal regulatory system. So there is no need to blame anything! There may be nothing to find. But that does not mean we should not be looking like this with detailed statistics, because that is the way to show that there is nothing if there isn’t.
Dr Crawley described ongoing studies of incidence, and natural history of CFS in children and adolescents. She found that incidence was similar in boys and girls at 13 but that by 18 it was twice as high in girls. She found that a relatively high proportion of children improve as compared to adults, although not all. She also noted differences in the pattern of symptoms in children, with less sleep disturbance and cognitive dysfunction in the younger groups. Overlap with chronic widespread pain seemed less than previously reported, with evidence for different determinants for the two syndromes. She described the setting up of further studies designed to look at potential risk factors using complex statistical analysis.
There was a lot of useful epidemiological data in this presentation. One thing I did not raise but perhaps should have done is that at least most of the other people presenting (Dr Crawley’s statistics may be more sophisticated) still seemed to be working with the two-component model of genetics and environment. The assumption seems to be that whatever is not genetic must be due to some life event. The major debate is whether that is likely to be an immune or physical insult like infection or injury or whether it may be a psychological event related to social interactions. The overwhelming emphasis in the meeting was on infective or immunological insults. However, my understanding is that a respectable epidemiological model will always be three-component, including a stochastic or random element. You need that for cancer and autoimmune disease so why not for ME. The simple fact is that 90% of the explanation for ME beyond genetics may be due to no environmental factors at all. It may be due to a variable and unpredictable instability of an internal regulatory system. So there is no need to blame anything! There may be nothing to find. But that does not mean we should not be looking like this with detailed statistics, because that is the way to show that there is nothing if there isn’t.
biophile
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These awesome points are a well overdue and gasping breath of fresh air compared to previous attitudes:
1. An emphasis on how the etiology and pathophysiology of ME/CFS have not been elucidated despite decades of "vigorous" research which found nothing much of interest, so is therefore functional or medically unexplained.
3. Articles and media campaigns about how pressure from patients is destroying research prospects.
4. The denial that doctors and therapists etc had any significant role in the breakdown of trust.
5. That the worst thing for research would be to let the patient rabble contribute to its design or direction.
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alex3619
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I am one of those experimenting with resveratrol on my own health. Its not without side effects, including even worse sleep. However I do feel more energy. Most importantly a lung reactivity problem I have goes away on resveratrol. This is similar to asthma, except its an extreme asthma attack that starts suddenly and finishes the same, with normal lung function in between.
Empirically I found a constant low dose didn't work (300mg per day). A dose of at least 600 mg is necessary for me, but at that dose I don't need another one for two to four days. Once across a threshold it has an impact, under that I see nothing, and that impact is persistent.
However its a blunt instrument as it raises cAMP levels, and so can affect many processes in the body.
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Snow Leopard
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That's a classic right there.
Wow, I've had that argument before (about disease labels), in particular Asthma not necessarily being a single disease. Unfortunately this is one aspect that is not communicated well to the general public.
Most people these days think one disease name=one cause=one treatment that works for everybody (until it is them being treated..)
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