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Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

Discussion in 'General ME/CFS News' started by Sasha, Jul 30, 2013.

  1. ukxmrv

    ukxmrv Senior Member

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    Just want to make the point that we have thousands of ME patients in the UK who were diagnosed by Ramsay and other ME doctors still alive that could be interested in a trial of this drug.

    It's been a long wait for survivors of the Royal Free outbreak for any clinical trial of any drug in the UK. In my local London group we have people who were diagnosed with ME (as per Ramsay and some by Ramsay) with ME who have never been involved with any trial into any drug.

    I'd hate to see a age limit imposed on the trial that would stop known epidemic patients from taking part. Imagine the press, PR and anti-psychiatric lobby milage we could gain from a Royal Free patient finally regaining their health after all they have been through.
     
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  2. Sasha

    Sasha Fine, thank you

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    Hi Kati - you're right, it's a sample size question not a question about why patients would want a trial at all. Earlier in this (now very long thread) we've been asking why the trial would only have 30 patients when the Haukeland study has 140 and Prof Edwards has explained why a bigger sample is not necessarily better in this situation. It will take a bit of trawling back through to find all the elements of the discussion but here's one of the earlier comments:

    http://forums.phoenixrising.me/inde...uximab-trial-30-july.24499/page-6#post-376961
     
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  3. user9876

    user9876 Senior Member

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    He was commenting on a post I made where I was worrying about the size of the trial. Basically I was concerned that with misdiagnosis and non responders that having a small trial might not produce a result due to the mix of patients selected. I subsequently worked through some very simple figures (40% mis diagnosis, 66% responders, and a trial size of 15 being treated) and got a probability of selecting a non treatable group as .0004 which is small so my comment was worrying unnecessarily.
     
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  4. Marco

    Marco Old blackguard

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    I think you've raised a very interesting point there Prof Edwards.

    I've noted previously that ME/CFS case definitions (and the resulting research) tend to emphasise the cardinal symptoms (fatigue, pain etc that are fairly non specific) to the exclusion of 'minor' symptoms that may actually give a better insight into the underlying pathology. My interest was in various manifestations or 'sensory overload' which is rarely mentioned in the literature and under-researched. This seems to be a general tendency in medicine associated with differential diagnosis. 'Co-morbid' symptoms such as anxiety and depression in ME/CFS are also either interpreted as suggesting that ME/CFS is a psychological disorder or (perhaps in response to this) interpreted by patients as an understandable reaction to living with a chronic debilitation illness. An alternative explanation for high levels of such co-morbidities is that they are symptoms to be expected in a neurological disorder.

    Likewise with rheumatoid arthritis, is it possible that, with RA widely accepted as primarily a disease which results in pain associated with joint inflammation that 'minor' symptoms – where they occur - such as fatigue, cognitive dysfunction, 'mood' disorders would be viewed as of minor clinical significance and under-researched or considered to be the result of living with chronic pain (as above) or perhaps resulting from ongoing medication?

    Fatigue, cognitive dysfunction and mood issues do appear to be a problem with RA patients with some indications that they may not just be secondary effects.

    This abstract tested cognitive dysfunction and inflammation markers in RA patients :

    Assessment of biocorrelates for brain involvement in female patients with rheumatoid arthritis.

    http://www.ncbi.nlm.nih.gov/pubmed/21695659

    Interestingly, as previously posted, the same objective measure of cognitive function (P300 ERP) found similar abnormalities in childhood CFS patients but with opposite results for two discrete sub-groups.

    Another pilot study suggests that fatigue and cognitive dysfunction in RA patients may be due to the effects of TNF-a on cerebral blood flow and may be alleviated by anti-TNF-a meds :

    Disease activity and cognition in rheumatoid arthritis: an open label pilot study

    http://arthritis-research.com/content/14/6/R263


    I'm not suggesting that ME/CFS are the same disease or that the same pathology underlies both but the possibility does exist that the same pathological process may result in a wide range of symptoms, not necessarily obviously connected, depending on individual differences (age, gender, genetic predisposition or just plain random). This appears to be increasingly the case in psychiatry where large scale genome studies suggest a shared predisposition may underlie the major psychiatric disorders regardless of how the symptoms present.

    Might it be the case that strict patient selection might be necessary for any Rituximab trial but that any theoretical model should be looking well outside the ME/CFS box?
     
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  5. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    I take your point that there may be no need to invoke environmental factors and that stochastic/random antibody generation may be enough to explain variations, but perhaps the issue of stress during vaccination plays a significant part, by increasing the permeability of the blood-brain barrier, perhaps. This could allow ingress of active components or adjuvants of the vaccine to the CNS which does not occur in non-stressed individuals.

    I have very stark memories of being terrified as a young child in queues of children and parents waiting for the children to be given an injected polio vaccine (probably the Salk type). Whilst other children were quiet until they were injected, then squealed a little, I was screaming and probably hyperventilating all the way. My stress levels must have been through the roof, and I have often wondered whether this could have contributed to my becoming ill over 3 decades later. Of course, stress also alters immune responses, and will also affect responses to drugs, perhaps including biological ones such as rituximab.

    I realise that it may be impossible to ascertain the degree to which randomness is or is not involved though!
     
  6. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    To reprise my last post - stress makes the BBB more permeable. Could this let antibodies in? Some specific aspect of stress or the long-term effects of chronic stress, such as changes in stress hormone levels/patterns of secretion?
     
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  7. Ecoclimber

    Ecoclimber Senior Member

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    Narcolepsy affects about one in 2,000 people. About 20% of the general population carry the exact same HLA subtypes (HLA-DR2, DQB1*0602, etc) but do not get narcolepsy. However, Over 90% of patients with narcolepsy-cataplexy carry HLA-DQB1*0602. So some trigger in the vaccine or T-Cell variant activiates the condition.

    Hypocretin also controls or plays a part in the circadian rhythms (sleep/awake cycle which is so indicative of PWME) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1279673/ The hypocretins (orexins) are recently described hypothalamic neuropeptides thought to have an important role in the regulation of sleep and arousal states1.Hert-1,Hert-2, Orex-A,Orex-B...interchangeable.

    Hypocretin-1" and "hypocretin-2" molecules were found only in the hypothalamus and had some weak resemblance with the gut hormone secretin. Only 10,000-20,000 cells in the entire human brain (out of many billions) secrete these specific hypocretin molecules only in the hypothalamus and had some weak resemblance with the gut hormone secretin. Only 10,000-20,000 cells in the entire human brain (out of many billions) secrete these specific hypocretin molecules. The hypothalamus, a region localized deep in the base of the brain, regulates many basic functions such as the release of hormones, blood pressure, sex, food intake regulation and sleep.

    The team found that a specific variation of a gene belonging to T cells—specialized immune cells that play a role in all immune responses—was present in narcolepsy. HLA and this T cell variant interact in a way that kills off the hypocretin cells. The immune system uses HLAs to differentiate between “self” cells and foreign cells (and attacks those presented as foreign), and most autoimmune diseases are associated with variants of HLA.

    Once these hypocretin cells are wiped out, they cannot be regenerated again. Most autoimmune disorders are associated with specific HLA subtypes. About 70% of the patients with multiple sclerosis have HLA-DR2 for example. Narcolepsy can be used as model for other autoimmune disorder.

    As bio-markers, a genetics test would determine if a patient had the HLA-DR2, DQB1*0602 marker. CSF would determine if the hyocretin levels are normal.
    Joachim Hallmayer is the genetists on the research project while Dr. Emmanuel Mignot is the director of research project at Stanford. Both Dr. Montoya and Dr. Kogelnik are aware of this research.





    On second Note:
    Doctor, in reference to patient selection as mentioned in this thread, Dr. Dusty Miller and I along with his team and lab at the Fred Hutchinson Cancer Research Center were in the beginning stages to conduct a retroviral research project for patients within the ME/CFS community. At the time, we considered that the likely etiology of ME/CFS was pathogenic given the strong evidence during this time period.

    I was in the planning stages to recruit patients for this study. In consultation with Miller, we decided to select patients who met the following criteria: We decided to raised the bar on the patient cohort significantly by dismissing the Fuduka, Holmes, Oxford and CDC cohort as being to inclusive of patients who did not suffer from ME.

    Our patient cohort of 35 had to meet the following conditions:
    1) The CCC (Canadian Consensus Criteria) which included neurological (neuro-cognitive, sensory impairment, processing, brain fog etc.) sleep cycle/insomnia/non-restorative sleep disorder, extreme sharp pain, muscle spasms, debilitating fatigue/exhaustion dysfunction, orthostatic intollerance and Post-Exertional Malaise.
    2) There was a complete absent of a prior history of psycho-somatic disorder and intervention
    3) Patient was extremely robust and quite active in their profession for some time prior to this event
    4) Most importanly their current condition was a direct result from a post viral infection
    5) Ruling out any other possible type of pathogenic or co-pthogenic origins such as Lyme, Lupus, MS etc.
    6) Time and severity of the disability would be considered by using objective measurements. I believe we were going to use the Dr.Lerner's EIPS Energy Index Point Score

    This was the basic selection criteria we would use for our patient cohort for our research project. We felt it was very robust for research needs. The Paper Published Here: Journal of Virology on our primary premise that while exploring potential disease mechanisms, we found that XMRV infection induced apoptosis in SY5Y human neuroblastoma cells, suggesting a mechanism for the neuromuscular pathology seen in CFS. This was the focus of our research on the neurimuscular pathology in CFS!!

    An Added Note: In the Journal PLoS ONE Dr. ShucSteven E. Schutzer, MD, of the University of Medicine and Dentistry of New Jersey -- New Jersey Medical School, and Richard D. Smith, Ph.D., of Pacific Northwest National Laboratory and Dr. Benjamin Natelson
    Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease from Chronic Fatigue Syndrome

    Their research found that each group of ME/CFS and Lyme patients had more than 2,500 detectable proteins. The research team discovered that there were 738 proteins that were identified only in CFS but not in either healthy normal controls or patients with nPTLS and 692 proteins found only in the nPTLS patients

    Unbenownst to the ME Commmunity:
    At the Pacific Lab in Washington, we investigated for Retroviral XMRV Proteins and Intact Retroviral Viruses with Mass Spectrometry using a viral chip on these proteins but came up empty for a retroviral association with XMRV. There is still ongoing research on the CSF proteomes differentiate study.

    Miller, Silverman and Sandra Ruscetti were behind the scenes investigating the retroviral artifact discovered in the lab. Dr. Paul Joilicouer, a well respected retrovirologist researcher in Montreal, was conducting his own ME research on the virus on behalf of the ME/CFS community. His tireless research endeavors was thawrted without the promised co-operation from Mikovits. This information is supported by telephone and email logs.

    Gorssberg has been conducting research over the last decade into the JHK virus, EBV, B-cell in bone marrow as well as other investigators

    http://www.ncbi.nlm.nih.gov/pubmed/23226803

    B-cell depletion with rituximab in relapsing-remitting multiple sclerosis.
    http://www.ncbi.nlm.nih.gov/pubmed/18272891

    Epstein–Barr virus in bone marrow of rheumatoid arthritis patients predicts response to rituximab treatment
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936947/


    Doctor, I hope this will offer some useful information on your RituximabTrial. We were looking for an infectious agent at the time and did not consider nor investigate any auto or neuro-immune etiology associated with ME in our research. I sincerely hope this research will not become politicized within the scientific community and that for once, this incredible debilitating condition will be investigated thorughly on behalf of all those who continue to suffer with this ravaging illness. The ME community has lost too many patients to this condition especially over the last few year.

    Eco
     
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  8. MeSci

    MeSci ME/CFS since 1995; activity level 6

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  9. lilpink

    lilpink

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    I think huge credit MUST go to Invest in ME who have been exemplary in the way they have proceeded with this . If all charities put the real nub of patient concern at the centre of their work imagine how much more could be achieved? Thank you Invest in ME, and thank you Jonathan Edwards (and your team) for agreeing to take part in these trials.
     
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  10. Legendrew

    Legendrew Content team

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    I couldn't agree more and would also like to extend my thanks! I think the speed of getting things going speaks to the neglect this disease is often given and turning that it positive momentum for what many of us see as one of the best research directions for years. I think most people want to get the trial up and running by early 2014 if not sooner. When you consider many have been ill for 10-20+ years you can understand wanting to get things moving!
     
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  11. Jonathan Edwards

    Jonathan Edwards Board Member

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    Sorry, I realise I never responded to your query on BBB. My understanding is that the blood brain barrier remains stable for most of us for virtually all of our lives and that stress, with its changes in steroid levels and other hypothalamic activities, would not alter it. If the BBB opens up you get water passing into brain substance along with protein. If that is general to the brain you become unconscious quite quickly, as we see in lupus encephalopathy. If it is local you usually find localising neurological signs like changes in reflexes, abnormal movements, loss of sensation etc. These things do not happen when we are stressed.

    That may sound to simplistic, and it is, but I think there may be a useful distinction to make relating to the models we have been discussing. In the PANDAS situation there may well be failure of BBB function in basal ganglia and this can be manifest by things like abnormal movements - what was once called Sydenham's chorea or St Vitus's Dance. On the other hand in the narcolepsy situation we see malfunction of just one tiny subpopulation of cells, probably the ones present in hypothalamus and the effect is much more subtle - maybe just a tendency to fall asleep in the middle of a sentence but then be wide awake to finish it. There are lots of other cells doing other jobs very close to these cells that do not seem to be affected at all. If this was a problem with BBB then one might expect just simple unconsciousness or lots of other problems with basic regulation. I realise that one could argue this various ways but my sense is that ME is probably more like narcolepsy than PANDAS in this respect. I realise that there are more diverse problems but they are still very characteristic to the illness. I doubt that the BBB is compromised. I suspect that signals, maybe autoimmune, are working through interactions that are not truly inflammatory, eve if they involve mediators like TNF that are inflammatory in other contexts. Note that myasthenia gravis is non-inflammatory. Immune processes involving B cells and T cells do not necessarily have anything to do with inflammation, which is a blood vessel response that occurs only in certain contexts.

    I may be wrong about this and I am trying to work through all the evidence I come across but I am impressed by the narcolepsy analogy because in a sense it is so sneaky. Which is why it came as such a surprise that it was related to immune responses. My guess is that nobody has worked out how ME works because it does not follow the textbook story. I think narcolepsy also shows how many different ways there are to mix in all the different causal factors: genes, triggers and antibody loops and ME seems to be able to do that too.
     
  12. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    I agree, Dr/Prof/Jonathan (not sure what to call you!) that the narcolepsy connection is intriguing and may provide useful avenues, and of course about the complexity of ME and probably a wide range of other illnesses too.

    Maybe we are talking about slightly different things when we say 'blood-brain barrier' but I have found numerous scientific papers reporting increased permeability of the BBB due to stress, and not accompanied by any dramatic immediate effects such as unconsciousness.

    This one for example reports such increases in permeability due to exercise-induced oxidative–nitrosative stress. It also suggests a blood biomarker for such a change: the astrocytic protein S100β.

    This one reports increases in BBB permeability due to air pollution. This bit looks particularly interesting and possibly relevant to ME:

     
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  13. user9876

    user9876 Senior Member

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    I came across some work from Roche a while ago where they are designing antibodies to go through the blood brain barrier. I've no idea if it is relavent but could an antibody be created at random that can get through the BBB in a similar way to the ones they are engineering

    http://www.roche.com/investors/ir_update/inv-update-2011-07-14.htm

     
  14. Jonathan Edwards

    Jonathan Edwards Board Member

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    I think there may be several meanings of both BBB and stress to contend with. Both of these papers deal with specific toxic effects, in the first case of molecules released during severe exercise, and in the second case dirt particles from air. I think it may be a mistake to talk of 'stress' at all here because it gets confused with the physiological stress response (adrenaline, steroids) which would be present in a child who hates injections. It is interesting that exercise to exhaustion makes a brain protein appear in the circulation, but maybe not so surprising. When I have exercised to exhaustion I have been pretty nearly unconscious, and on one or two occasions actually passed out, as seems to happen from time to time on the Olympic track! The microvascular structural changes in the second paper are dealing at a rather different level and I am not sure I know enough to interpret them.

    I guess my reservations are partly based on a principle I have found useful. If I come across a possible explanation E for some pathological process I immediately ask what other things would I expect E to predict? If those other things don't seem to be showing up I get sceptical about E. In my experience explanations need to be pinned down very precisely in terms of molecular physiology before they start to predict just the pathology in hand. Generalisation almost always leads into blind alleys. I think stress may be too general a concept to help us here.
     
  15. Jonathan Edwards

    Jonathan Edwards Board Member

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    Yes, Jo Cambridge and I got very interested in something like that idea in the context of multiple sclerosis. It may turn out to be way off target but it seemed an interesting possibility. The Roche antibody cheats because it has two different arms (one to get in to the brain and one to do a job once in there) and as far as we know plasma cells do not make such bi-specific antibodies. But one could imagine an antibody that had a business end that just happened both to flip it in to the brain and cause trouble once in there.

    In fact for MS we wanted to explain something a bit different - how B or plasma cells themselves got in to the brain. In MS clones of plasma cells are found actually in brain tissue and make antibodies there. So the idea we had was that B cells, which carry their own special antibody on their surface, could, with a particularly weird antibody that had been generated at random, flip in to brain and sit there making antibody. It wouldn't even matter whether the antibody reacted with brain. Any antibody in high local concentration irritates brain tissue via microglia. So the antibody would not need to be an 'autoantibody' in the strict sense. We never got any further with testing that idea but the response of relapsing MS to rituximab follows the time course you would predict if it was right (there are lots of other stories that would fit).

    The narcolepsy situation could of course be closer to your original suggestion if it was an antibody that both flipped and bound to hypocretin or its receptors.
     
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  16. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    I agree that there are differences between exercise-induced, pollution-related and psychological stress, but there are also similarities, and there appears to be quite good evidence that psychological stress also increases the permeability of the blood-brain barrier.

    It pains me to cite animal research, as it is commonly irrelevant to humans and I abhor the suffering caused, but this paper refers to an increase in mouse blood−brain barrier permeability resulting from a forced swim protocol (which for the uninitiated means putting animals in water without any means of getting out until they have almost drowned). This is how researchers commonly cause stress in lab animals.

    Whilst there is a multitude of differences between mice and humans, I would expect the effects of stress on the BBB to be similar.

    People may also be interested in the paper as it relates to Gulf War Syndrome, which has many similarities with ME symptom-wise. I don't know whether GWS involves similar abnormalities in B cells.
     
  17. Jonathan Edwards

    Jonathan Edwards Board Member

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    Yes, I am not sure I have much more useful to say on this. The mouse study looks like the effect of maximal exercise on BBB again. I am not sure how the word stress helps the analysis or is justified by the authors in their abstract to be honest. I did a forced swim study 30 years ago and I have not wanted to insult a mouse in this sort of way ever again.
     
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  18. MeSci

    MeSci ME/CFS since 1995; activity level 6

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    Ah, yes - my slow ME brain didn't pick up on the exertion aspect of that stress test.

    May still be relevant to those of us who, like me, developed ME after prolonged over-exertion (among other things).
     
  19. Marco

    Marco Old blackguard

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    Staying on the theme of 'stress' just for a little longer (wasn't Selye's original conception of stress as anything that caused physiological stress which did include psychological stress but in common parlance is now shorthand for psychological stress?) it occurred to me that 'stress' may play a major role in several of the disorders discussed on this thread.

    A key aspect of ME/CFS is the worsening of symptoms in response to physical or cognitive challenge and emotional or psychological stress. Stiff person syndrome and narcloepsy (both proposed to be autoimmune mediated conditions) also show adverse reactions to stressors. In SPS external stimuli (sudden loud noises, light, touch, volitional movement, emotional distress etc) trigger the characteristic painful spasms while narcolpesy seems to be triggered by strong emotions (including surprise, laughter, anger).

    These reactions tend to be very rapid (instantaneous in SPS and narcolepsy and with whatever variant of ME/CFS I have) or within minutes to hours. I may be wrong but the speed of response doesn't seem to me to be likely to reflect disease activity related to autoimmunity which suggests that brain mechanisms (perhaps impaired by an autoimmune insult) relating to arousal and the processing of stimuli may be to blame.

    As I mentioned previously, sensory gating is a neurological measure often used to test deficits in the processing of sensory information. In rodent models (again) isolation rearing (an entirely non- physical stress) has been found to induce sensory gating deficits (isolation results in increased levels of oxidative stress including increased superoxide dismutase activity, decreased oxidized: reduced glutathione ratio and increased lipid peroxidation in brain regions).

    I also wonder whether narcloepsy or stiff person syndrome (or both) might be appropriate analogues for ME/CFS. For those of us who would self-describe as 'wired and tired' the muscle stiffness and spasms of SPS may be familiar while cataplexy (sudden loss of voluntary muscle tone) in narcolepsy may be more appropriate to others.

    I also find it fascinating that two of the key symptoms of narcolepsy are hypnagogic hallucinations (night-time auditory, visual or somatosensory hallucinations) and sleep paralysis. In the early years post 'onset' I experienced both of these on a nightly basis which lasted for hours on end. Thankfully after a year or so they disappeared – not pleasant.

    Intuitively I feel we may be on the right lines here. Unfortunately intuition doesn't cut it so a working model that coherently pulls together all the pieces would be nice to see.
     
  20. Jonathan Edwards

    Jonathan Edwards Board Member

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    I think intuition goes quite a long way if you beat the hell out of it and it still pops up smiling. As you point out, one way to beat the hell out of ideas is to look carefully at time course and anatomical domain. Narcopleptic cataplexy must be a modified neural reflex rather than something to do with blood vessels. My friend Eric would sit down as soon as he saw someone was about to tell a good joke because he wouldn't have time to do so once he started laughing.

    Your experience with hypnagogic states seems to me very telling. This is the sort of detail that a really good model, like Gail Trimble of Corpus Christi, will have an answer to before you have finished the question. And that model is not going to be 'believing you have a disease called ME'. I have a lot to learn but this is a good way to do it. I like to stand my ground a bit but MeSci has put me on the spot today - I'll admit!
     
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