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A neuro-immune model of ME/CFS.

Enid

Senior Member
Messages
3,309
Location
UK
Thanks for the info jace - I well know the effort of wrapping one's brain around anything when really ill. He must be a remarkable person indeed.
 

roxie60

Senior Member
Messages
1,791
Location
Central Illinois, USA
Doesn't sound like anything too new... and doesn't sound good! ;-)

These kinds of immune abnormalities, inflammatory cytokines, T & B cell reactivities, etc. seemingly would be SO easy to test for & differentiate from the normal population. How many years are researchers just going to repeat this stuff over and over without proposing all the immune dysfunction as at least some kind of biomarker?

Well my last metabolic test said I had no issue with my antioxidant levels so I must be the picture of health, nothing wrong here, stop malingering and get productive......whatever. The test they did to determine oxiadative stress / antioxidant levels was one I am not familiar with (well really I'm not familiar with much) - 8-hydroxy-2-deoxyguanosine.
 

jace

Off the fence
Messages
856
Location
England
I've been asked to post this message for Gerwyn. To assist understanding,

PICs - Pro-inflammatory cytokines
RN - reactive nitrogen
OS - oxygen species
I understand that some people are under the impression that the model portrays ME/cfs as an autoimmune disease. The model is best explained by referral to the diagram contained in the paper. Autoimmunity is a very small part of the model. I appreciate that it is difficult for those without a scientific background in this area to understand. I have tried to make it as patient friendly as possible and also attempted to explain the mechanisms to scientists who are not familiar with neuroimmunology.
A cursory examination of the disease model will reveal that an interaction between PICs RN and OS coupled with mitochondrial dysfunction is the cause of the landmark symptom of ME/cfs, namely a global exacerbation of symptoms induced by even trivial increases of cognitive or physical activity. If people do not have this phenotype then the weight of scientific evidence would strongly suggest that they do not have ME/CFS but of course may have idiopathic chronic fatigue and four somatic symptoms and thus fulfill the Fukuda definition of chronic fatigue syndrome.
You may reproduce this e-mail as long as you do so in full.

ETA Well my last metabolic test said I had no issue with my antioxidant levels so I must be the picture of health, nothing wrong here, stop malingering and get productive......whatever. The test they did to determine oxiadative stress / antioxidant levels was one I am not familiar with (well really I'm not familiar with much) - 8-hydroxy-2-deoxyguanosine.

Bear in mind that testing is not always perfect, for instance ranges can be to narrow, they may be testing for the wrong thing... for instance, Thyroid tests in the UK check TSH and T4. The TSH range is considered too narrow by many, and T4 is the precursor to T3. Our illness can mess up conversion, so you may have low TSH, reasonable T4, but a dearth of T3 and therefore exhibit hypothyroid symptoms. To understand your test results, you need the full lab printout and then you need to research. Too much reliance is put on test results, like everything in life they too are fallible.
 

jace

Off the fence
Messages
856
Location
England
I sometimes think that we may get ME as a less deadly option to the disease expressing itself in other ways, cancer for instance. In other words, the body has a fight on it's hands, and is damaged thereby. How it is damaged depends on how/where it fights. I know this is simplistic, and it is just thinking out loud.
 

Chris

Senior Member
Messages
845
Location
Victoria, BC
Thanks, JT--have now read the paper as best I could, though some of it is frankly beyond me. But I do have a couple of comments on it. There is a rather dismaying (to me) repetition of the word "may" that runs right through the argument. There is a need to make it clear that this is a hypothesis, a model, but.. And, to go back to the discussion of definitions, it begins with a very explicit discussion of CFS and ME, which concludes that "ME and CFS are therefore different diagnostic concepts" ( and according to the brief definitions offered here, I am clearly ME and not CFS.) The authors then note that most research has been on ME/CFS, and so use that term for the body of the essay, though I think it is implied (I cannot find an explicit statement) that they are really talking only about what they have just defined as ME.

It does look like an interesting attempt to wrap up the disease processes, including the gradual emergence of autoimmunity as a response to gathering uncleared damage. Nothing here about possible therapies, though--I guess that will have to wait.
Chris
 

jeffrez

Senior Member
Messages
1,112
Location
NY
Just a few observations:

This model provides considerable
evidence that the pathophysiology of ME/CFS is associated
with immuno-inflammatory pathways, which lead to neuro-
logical aberrations, including behavioral responses, and
neuro-endocrine, autonomic and brain dysfunctions.

The model actually doesn't provide evidence. The evidence already perhaps exists, and the model is incorporating that evidence into its schema. But the model itself does not provide new evidence. Just to clarify that point.

Altogether, I have to say that the paper looks kind of like a "kitchen sink" approach, where everything was thrown into the mix, and then random speculations were attached. If I presented this to any of my physicians, they would laugh at me. It might be useful for directing research, but I question even the utility of that - directly, at least.

For example, the authors attribute brain fog to changes in glucose metabolism: "The ensuing lack of glucose would potentially explain the brain fog that so many people with this illness complain of." "Potentially," hmmm. It's just a speculation that, again, my doctors would laugh at.

And specifically, there is really no lack of serum glucose - many ppl w/CFS have increased serum glucose, in fact. As the authors first stated, perhaps there are metabolic changes that reset glucose homeostasis, etc. However, brain fog could just as easily be attributed to: cytokine storms, excitatory neurotoxicity, lowered cortisol or corticosteroid receptor function, impaired alpha-adrenergic or other neurotransmitter/receptor function, NMDA receptor function, thyroid hormone imbalance, disturbances in oxygen uptake patterns and resulting hypoxia, chemical sensitivities, food allergy or autointoxication from dysbiosis, candida toxins, and many other factors that we could go on to list.

A lot of people experience temporary worsenings and then relative improvements in brain fog, in fact. And the brain itself, as we know, is extremely sensitive to changes in blood glucose, and keeps a tight rein on that. So the idea that the brain is "resetting" its glucose metabolism up and down in such short periods seems like one of the least plausible explanations.

Just one example where attempting to force some "theory" onto the phenomenon is not really helpful, imo. Let the researchers find out what exactly is going on, rather than just making up fairly implausible "explanations" that actually don't explain anything. Get the facts, not the fabrications.

Another point unrelated to the paper specifically, but one that I wanted to comment on, regarding the WHO definition of ME mentioned in the paper:

I think the WHO ME definition is flawed, as it refers to a "chronic relapsing-remitting course." But the vast majority of ME/CFS sufferers don't go into remission, from which they then again relapse. The vast majority stay chronically ill, from which there might be small or sometimes even signifcant *improvements,* but they are not "in remission." That's an important distinction, and the language of "remitting" is not accurate, imo.

Stating that there is remission when in the vast majority of cases there is no remission trivializes the disorder. Even if doctors know the WHO ME definition, they are likely to say having ME/CFS is really no big deal since you'll probably go into remission anyway - it's part of the definition! I think that criterion needs to be changed to reflect what is closer to the reality for the vast majority of patients: chronic unwellness, often with worsening symptoms, and occasionally with some minor or relative improvement. Sometimes even major improvement. But almost never remission. If there is remission, in fact, in most cases they DIDN'T have ME, but some other problem (jaw infection, mono, severe allergy, etc.) So imo the definition there is completely erroneous.
 

Mula

Senior Member
Messages
131
Thanks, JT--have now read the paper as best I could, though some of it is frankly beyond me. But I do have a couple of comments on it. There is a rather dismaying (to me) repetition of the word "may" that runs right through the argument. There is a need to make it clear that this is a hypothesis, a model, but.. And, to go back to the discussion of definitions, it begins with a very explicit discussion of CFS and ME, which concludes that "ME and CFS are therefore different diagnostic concepts" ( and according to the brief definitions offered here, I am clearly ME and not CFS.) The authors then note that most research has been on ME/CFS, and so use that term for the body of the essay, though I think it is implied (I cannot find an explicit statement) that they are really talking only about what they have just defined as ME. It does look like an interesting attempt to wrap up the disease processes, including the gradual emergence of autoimmunity as a response to gathering uncleared damage. Nothing here about possible therapies, though--I guess that will have to wait. Chris

Those are good comments. Would you not agree that "may" is the mark of a scientist and that the title "A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome" states it is a model and would so be a hypothesis to explain the complete picture of the disease. Which after examination, it does do.
 

floydguy

Senior Member
Messages
650
I think it's a fairly good stab at a hypothesis. There are parts that are stretches but it resonates pretty well for me. I'd love to see other documents that make such an attempt. Maybe jeffrez could provide some other examples since he seems to think there are many out there that are a lot better.
 

Mula

Senior Member
Messages
131
Just a few observations:



The model actually doesn't provide evidence. The evidence already perhaps exists, and the model is incorporating that evidence into its schema. But the model itself does not provide new evidence. Just to clarify that point.

Altogether, I have to say that the paper looks kind of like a "kitchen sink" approach, where everything was thrown into the mix, and then random speculations were attached. If I presented this to any of my physicians, they would laugh at me. It might be useful for directing research, but I question even the utility of that - directly, at least.

For example, the authors attribute brain fog to changes in glucose metabolism: "The ensuing lack of glucose would potentially explain the brain fog that so many people with this illness complain of." "Potentially," hmmm. It's just a speculation that, again, my doctors would laugh at.

And specifically, there is really no lack of serum glucose - many ppl w/CFS have increased serum glucose, in fact. As the authors first stated, perhaps there are metabolic changes that reset glucose homeostasis, etc. However, brain fog could just as easily be attributed to: cytokine storms, excitatory neurotoxicity, lowered cortisol or corticosteroid receptor function, impaired alpha-adrenergic or other neurotransmitter/receptor function, NMDA receptor function, thyroid hormone imbalance, disturbances in oxygen uptake patterns and resulting hypoxia, chemical sensitivities, food allergy or autointoxication from dysbiosis, candida toxins, and many other factors that we could go on to list.

A lot of people experience temporary worsenings and then relative improvements in brain fog, in fact. And the brain itself, as we know, is extremely sensitive to changes in blood glucose, and keeps a tight rein on that. So the idea that the brain is "resetting" its glucose metabolism up and down in such short periods seems like one of the least plausible explanations.

Just one example where attempting to force some "theory" onto the phenomenon is not really helpful, imo. Let the researchers find out what exactly is going on, rather than just making up fairly implausible "explanations" that actually don't explain anything. Get the facts, not the fabrications.

Another point unrelated to the paper specifically, but one that I wanted to comment on, regarding the WHO definition of ME mentioned in the paper:

I think the WHO ME definition is flawed, as it refers to a "chronic relapsing-remitting course." But the vast majority of ME/CFS sufferers don't go into remission, from which they then again relapse. The vast majority stay chronically ill, from which there might be small or sometimes even signifcant *improvements,* but they are not "in remission." That's an important distinction, and the language of "remitting" is not accurate, imo.

Stating that there is remission when in the vast majority of cases there is no remission trivializes the disorder. Even if doctors know the WHO ME definition, they are likely to say having ME/CFS is really no big deal since you'll probably go into remission anyway - it's part of the definition! I think that criterion needs to be changed to reflect what is closer to the reality for the vast majority of patients: chronic unwellness, often with worsening symptoms, and occasionally with some minor or relative improvement. Sometimes even major improvement. But almost never remission. If there is remission, in fact, in most cases they DIDN'T have ME, but some other problem (jaw infection, mono, severe allergy, etc.) So imo the definition there is completely erroneous.

The model is new evidence. It is constructed on the foundation of all MECFS research and biomedical evidence of how the human body functions. A hypothetical model could not be so if the kitchen sick was not also in there. Patients and clinicians report improvement, remission and relapse. The model must mechanistically explain all.

Speculation is not the right use of terminology.

Jeffrez you are speculating on the model from your simplified understanding of pathophysiology.
 

jeffrez

Senior Member
Messages
1,112
Location
NY
The model is new evidence. It is constructed on the foundation of all MECFS research and biomedical evidence of how the human body functions. A hypothetical model could not be so if the kitchen sick was not also in there. Patients and clinicians report improvement, remission and relapse. The model must mechanistically explain all.

Speculation is not the right use of terminology.

Jeffrez you are speculating on the model from your simplified understanding of pathophysiology.

New evidence would be like someone investigating a murder case finding the gun. Rearranging or presenting what we already know about the case isn't new evidence, only an interpretation of the existing evidence. The latter is what this paper does.

It then goes on to speculate about these things we already know - about the existing evidence - devising a theory to explain it, but there doesn't appear to be a gun anywhere in sight.

Where's the gun? That's what we need to find out.
 

Mula

Senior Member
Messages
131
New evidence would be like someone investigating a murder case finding the gun. Rearranging or presenting what we already know about the case isn't new evidence, only an interpretation of the existing evidence. The latter is what this paper does.

It then goes on to speculate about these things we already know - about the existing evidence - devising a theory to explain it, but there doesn't appear to be a gun anywhere in sight.

Where's the gun? That's what we need to find out.

The model includes the gun, the bullet and the anatomy of impact and subsequent damage. There has never been a paper which achieved a model of MECFS. Please do read the paper and see if you can find the relevant quote.
 

jeffrez

Senior Member
Messages
1,112
Location
NY
The model includes the gun, the bullet and the anatomy of impact and subsequent damage. There has never been a paper which achieved a model of MECFS. Please do read the paper and see if you can find the relevant quote.

No, there's still no gun. Although the analogy might not be exact, and what we really need is a way to extract the bullet. Either way, the paper coalesces some of the existing data in a particular way, but doesn't really provide anything new. We already know everything the paper is stating, and it hasn't led to a treatment. I doubt this paper will lead to that, either, but go on believing it will if it helps you get through your day. I'll go back to waiting for a legitimate breakthrough.
 

Chris

Senior Member
Messages
845
Location
Victoria, BC
Mula, I quite agree that "may" is appropriate for a paper that builds a model--but the accummulation of so many sequential "mays" does begin to produce an unstable structure? Maybe "mays" work better in smaller scale structures, that after validation can begin to build larger structures. But I am not knocking the attempt--just wondering, like others, if it will prove fruitful. Let's hope it does. Chris
 

JT1024

Senior Member
Messages
582
Location
Massachusetts
I suspect there is much more to come. Many of the questions that have been raised in respect to the model proposed by Gerwyn Morris and Michael Maes probably already have an answer. They may just be in various stages of publication.

Many pieces to the puzzle of ME/CFS have been published as well as pieces that have nothing to do with ME. The whole issue of broad diagnostic criteria for cohort selection has served to confuse everyone. Whether this has been intentional on the part of the CDC and others remains to be determined.

Food for thought.. if someone stated "this is" versus "this may", they would open themselves up to denunciation point by point. By proposing something by stating "may" encourages discussion and is more likely to encourage further research.
Don't you think? Perhaps I'm way off base on this but that is my perception at this point.
 

jace

Off the fence
Messages
856
Location
England
The evidence the paper uses is that found in the many references to previous studies. This paper is not recording the findings of a single study, that was never the point. Rather it is taking the broad view, attempting a definition of the big picture, drawing together findings from many many other scientists' works.
 

Enid

Senior Member
Messages
3,309
Location
UK
Drawing together and (sadly) first hand experience couldn't place anyone in a better position.
 

Ecoclimber

Senior Member
Messages
1,011
Who is Gerwyn Morris, never heard of a scientist by the name of Gerwyn Morris? What are his scientific credentials and education? Virology, Retrovirology, Molecular Biology, Pathology, NeuroScience? Any? Medical Degrees?

If people do not have this phenotype then the weight of scientific evidence would strongly suggest that they do not have ME/CFS but of course may have idiopathic chronic fatigue and four somatic symptoms and thus fulfill the Fukuda definition of chronic fatigue syndrome.

Seems to me that whoever Gerwyn Morris happens to be, he is rendering a medical opinion without any scientific methodology, validation, testing or criteria?

Apparently, this would disallow the xmrv, hgrv theories since the models allow for numerous pathogens not in exclusivity of retroviruses. I find it dubious at best, to give any credence or faith to any article that suddenly appears out of the nowhere especially one that seems to be a collection of previous abstract research articles of prior years.

Eco
 

Enid

Senior Member
Messages
3,309
Location
UK
Darwin wasn't strictly a scientist - wasn't it observation on his early travels (and deduction) that allowed him to put together his theory of Evolution.
 

Chris

Senior Member
Messages
845
Location
Victoria, BC
Ecoclimber, I think it is better to respond to an argument than to try to attack the proponent of an argument. If you really think that having a professional degree is any guarantee of being on the right track, I have some reading to suggest to you. You might start with Gary Taubes, "Good calories, bad calories" (yes, he is a journalist, but just read his detailed and very well referenced account); Marcia Angell, "The truth about the drug companies" (she is an M.D. doctor, and was for many years editor of the New England Journal of Medicine--she knows whereof she speaks); and Robert Whitaker, "Anatomy of an epidemic" (yes, another journalist)---and then read David Healy's stuff (and yes, he is a doc researcher with 100s of peer-reviewed articles). Having a graduate degree is no guarantee of being on the right track (I have a non-scientific Ph.D. myself, so can say that with some feeling). Chris