Recent conference in Stockholm. Dr Bansal's talk, youtube Nov 19.

[lansbergen]

so the question might just as likely be why do so few people get ME/cfs?

Infection dose and enough rest?

 

[heapsreal]

Infection dose and enough rest?

Does seem to mention multiple infections or infections close together could play a role. This is what happened in my case. When i first saw my cfs doc he mentioned this being a common cause of cfs/me that he has seen.

Im guessing that if one is in a postviral state from any infection, one could have low enough immune function or even adrenal function which was mentioned in the video, that when the second infection comes along, there isnt alot of defences for it and allows infection to get deeper than a normal one off infection.

I assume this could also mess up B cell function, also now have to defend against more than one pathogen with extra inflammation around which cant be controlled due to the adrenal dysfunction.

 

[Sidereal]

Overall a very good talk. A bit too much emphasis on stress, in my opinion, especially the troubling slide at the very end that he skipped over which had a diagram featuring "worry and stress that something may be wrong" leading to "mild hyperventilation". Pretty much everyone in the modern world is under stress all the time so you still haven't explained why only 0.2-0.4% of the population develop ME and even the people who eventually develop ME don't display these aberrant responses to numerous previous infections they've had in their lives which they were able to get over just fine.

 

[alex3619]

Also about the fact that they have been looking at some autoantibodies I think regarding the hypothalamus? I cant remember now if I am using the correct word.

Yes, that's right. Actually its about autoantibodies to some unspecified regions of the hypothalamus. The hypothalamus is responsible for regulating much of the function of the body.

 

[alex3619]

Very interesting, do you have a link to this work?

The cortisol blinding globulin research is old now. I will try to find a link in a minute, but first I would like to post a bit about it for background. There were whole families who had a very high prevalence of CFS, so they started genetic mapping studies. This was run right here in Queensland, Australia, by a Prof (?) Ian Torpy.

They isolated the gene, then the snp, then discovered a similar defect in the same gene, causing similar symptoms, had been found in a French study. So they published, then called for patients to volunteer so they could figure out the prevalence of these snps in the CFS population. I was one of those, and do not have those snps.

If you look at Torpy's published studies he is a researcher on cortisol and related disorders.

Here are some:

http://www.ncbi.nlm.nih.gov/pubmed/22013108

http://www.ncbi.nlm.nih.gov/pubmed/19643166

http://www.ncbi.nlm.nih.gov/pubmed/17547679

http://www.ncbi.nlm.nih.gov/pubmed/11502797

Research Gate only lists his more recent studies. I will move to PubMed for the older ones. He has published more papers on this than I was aware of, and I did not include links to book chapters.

A loss of CBG function is closely associated with hypotension. Can anyone say OI?

Please note that while CBG is considered by most as a transporter molecule, to a biochemist this view sets up red flags. CBG has the physical structure of a hormone, including the ability to partially bind to a cell membrane and interact like a hormone. I forget the details, I was looking into this around 2000.

This researcher could be valuable to us if we can get him looking at glucocorticoid resistance.

I could not find more on PubMed. I think maybe he really did start publishing around 2001, but I got confused because I was in the study earlier than that. It just took some years to be published.

 

[alex3619]

A bit too much emphasis on stress, in my opinion, especially the troubling slide at the very end that he skipped over which had a diagram featuring "worry and stress that something may be wrong" leading to "mild hyperventilation".

Yes, he shuffled past that really fast, probably knowing it would be controversial, and for good reasons. I didn't agree with much of that slide which I saw by pausing the video.

 

[Helen]

Please note that while CBG is considered by most as a transporter molecule, to a biochemist this view sets up red flags. CBG has the physical structure of a hormone, including the ability to partially bind to a cell membrane and interact like a hormone. I forget the details, I was looking into this around 2000.

This researcher could be valuable to us if we can get him looking at glucocorticoid resistance.

.

Thanks for this post. Another thing. I think it might be worth keeping in mind that the CBG is important concerning serum cortisol testing. If the CBG is affected, the serum cortisol isn´t valid, but a saliva cortisol is, as the saliva cortisol is independent of the CBG level. There are probably lots of "normal" serum cortisol results among PWME due to this. I learnt this from an endocrinologist.

 

[alex3619]

Thanks for this post. Another thing. I think it might be worth keeping in mind that the CBG is important concerning serum cortisol testing. If the CBG is affected, the serum cortisol isn´t valid, but a saliva cortisol is, as the saliva cortisol is independent of the CBG level. There are probably lots of "normal" serum cortisol results among PWME due to this. I learnt this from an endocrinologist.

I agree, but this depends both on how CBG is affected and the kind of assays used. I have not looked into this in enough detail.

 

[alex3619]

Diabetes has two forms, type 1 and 2. Type 1 is about under production of insulin. Type 2 starts as insulin resistance, though can later morph.

So might ME be called Type 2 Addison's Disease? I wonder.

 

[Jonathan Edwards]

auto-immunity to cell nuclei in the hypothalamus;

I had a double take both this time and when Amolak said nuclei to me on Friday. I actually think he is talking of nuclei in the sense of clusters of neurons, not nuclei inside cells. The hypothalamus is divided into several such cluster 'nuclei' which are just groups of closely packed cells with white matter in between. Elsewhere in the brain there are caudate nuclei, nucleus caeruleus, nucleus gracilis, olivary nucleus etc. But I am still not totally sure what he is referring to. I think we need to wait and see because it is clearly very early days yet.

 

[Bob]

I had a double take both this time and when Amolak said nuclei to me on Friday. I actually think he is talking of nuclei in the sense of clusters of neurons, not nuclei inside cells. The hypothalamus is divided into several such cluster 'nuclei' which are just groups of closely packed cells with white matter in between. Elsewhere in the brain there are caudate nuclei, nucleus caeruleus, nucleus gracilis, olivary nucleus etc. But I am still not totally sure what he is referring to. I think we need to wait and see because it is clearly very early days yet.

Ah, thanks Jonathan. I did wonder why he used the specific term 'nuclei'. On reflection, to my recollection, he didn't say "cell nuclei" in the presentation - that was my interpretation.

 

[alex3619]

I actually think he is talking of nuclei in the sense of clusters of neurons, not nuclei inside cells.

That was my understanding too.

This is indeed early days in the research. Sometimes findings like this disappear with larger studies that more aggressively test the hypothesis.

 

[A.B.]

This description of glucocorticoid resistance syndrome doesn't match CFS: http://www.ncbi.nlm.nih.gov/pubmed/17161335 (Note: I have only read the abstract, but HPA axis hyperactivity is not a typical finding in CFS).

What am I missing here?

 

[Jonathan Edwards]

This description of glucocorticoid resistance syndrome doesn't match CFS: http://www.ncbi.nlm.nih.gov/pubmed/17161335 (Note: I have only read the abstract, but HPA axis hyperactivity is not a typical finding in CFS).

What am I missing here?

Interesting to see what Alex thinks. This is of course genetic glucocorticoid resistance in which the receptor is probably defective both in the peripheral tissues and in the feedback loop in the HPA system. Cortisol is made but neither the body not the brainstem notice it. But if there was an antibody to a receptor it might block the receptor ten times more effectively in the body than in the hypothalamus (because of blood brain barrier maybe or a different receptor isoform or accessory proteins bound to it). The rest of the brain would then get the confused signal that there was no cortisol around in the body but the hypothalamus was sure everything was fine. In other situations the brain gets really screwed up by mismatched messages - like in vertigo - so maybe something like that is going on? I am being a bit speculative but maybe it's worth thinking about.

 

[Helen]

@alex3619
Polymorphisms in the glucocorticoid receptor NR3C1 has been shown to be connected to CFS.

http://www.ncbi.nlm.nih.gov/pubmed/16610957

http://www.ncbi.nlm.nih.gov/pubmed/16740143

 

[Jonathan Edwards]

Even more interesting.

And it seems that B lymphocytes express the NR3C1 gene and even more interesting it is this receptor that seems to mediate programmed death of B lymphocytes in the presence of glucocorticoid. This is the 'perfect storm' scenario for an autoimmune disease, where a receptor on a B cell that controls proliferation or death is a potential target for autoantibody. If a B cell makes antibody that blocks a receptor on itself that would be used to signal death as part of the 'no-anti-self' veto then it can escape veto.

Pure speculation but it would be in line with a whole string of autoimmune disease against B cell surface receptors or their ligands - IgG in rheumatoid, C1q in lupus, AChR (on thymic stromal cells) in myasthenia, Toll-like receptors that bind DNA and nucleoproteins in lupus, scleroderma etc, TRIM21 in Sjogren's, peanut agglutinin receptor in sarcoid, Con A receptor in some Crohn's, possibly thyroxine receptors in thyroid diseases and even insulin receptors in diabetes maybe.

 

[Snow Leopard]

Glucocorticoid resistance does not explain most of the evidence gathered so far. In fact major reviews and models have been written trying to explain findings of enhanced GCr sensitivity, which makes the most sense given all of the neuroendocrine studies so far in CFS.

The best (in my opinion) review of the neuroendocrine findings, despite being out of date and written by a protege of an unpopular psychiatrist is still this one:

http://www.ncbi.nlm.nih.gov/pubmed/12700181 (Cleare 2003)

There was a more recent attempt, but I was not as impressed:
http://www.hindawi.com/journals/isrn/2013/784520/ (Tomas, Julia Newton, Watson 2013)

(Anyone who is seriously interested in this stuff needs to read the above two articles).

The SNPs found by the CDC group, in the papers mentioned by @Helen have been suggest as a possible cause for this increased sensitivity (note again: opposite of resistance). And indeed this assumption is specifically mentioned in these papers (which does have some author continuity)

http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000273
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084839

Glucocorticoid resistance might be a problem in a few people, but it does not fit with the rest of the evidence gathered in CFS so far.


If there is a central problem here, then I am willing to bet that it will be something other than GCr SNPs, or alpha/beta ratios.

 

[Jonathan Edwards]

Glucocorticoid resistance does not explain most of the evidence gathered so far. In fact major reviews and models have been written trying to explain findings of enhanced GCr sensitivity, which makes the most sense given all of the neuroendocrine studies so far in CFS.

The best (in my opinion) review of the neuroendocrine findings, despite being out of date and written by a protege of an unpopular psychiatrist is still this one:

http://www.ncbi.nlm.nih.gov/pubmed/1270018 (Cleare 2003)

There was a more recent attempt, but I was not as impressed:
http://www.hindawi.com/journals/isrn/2013/784520/ (Tomas, Julia Newton, Watson 2013)

(Anyone who is seriously interested in this stuff needs to read the above two articles).

The SNPs found by the CDC group, in the papers mentioned by @Helen have been suggest as a possible cause for this increased sensitivity (note again: opposite of resistance). And indeed this assumption is specifically mentioned in these papers (which does have some author continuity)

http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000273
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0084839

Glucocorticoid resistance might be a problem in a few people, but it does not fit with the rest of the evidence gathered in CFS so far.


If there is a central problem here, then I am willing to bet that it will be something other than GCr SNPs, or alpha/beta ratios.

Thanks Snow Leopard. I need to study these papers in detail. But if, as I am suggesting, peripheral receptors are blocked but hypothalamic receptors are not, then could one have sensitivity to steroid in a suppression test but resistance in terms of peripheral physiology? Autoantibodies often produce paradoxical effects on function.

 

[Marco]

@alex3619
Polymorphisms in the glucocorticoid receptor NR3C1 has been shown to be connected to CFS.

http://www.ncbi.nlm.nih.gov/pubmed/16610957

http://www.ncbi.nlm.nih.gov/pubmed/16740143

Two things.

These papers originate from the CDC Wichita studies - who'd have thunk it!

Secondly the seond of the 'top three' genes identified was COMT. I've looked into this gene previously in the context of sensory gating and concluded that :

Although it now appears that attempts to link a single genetic polymorphism to a particular disease were overoptimistic, it does appear that individuals who carry the COMT val to met mutation and in particular the low COMT activity met/met genotype may be predisposed to greater pain sensitivity and a loss of higher cognitive function when put under stress. It may be that ME/CFS patients carrying the met allele (particularly met/met) are more likely to experience higher levels of pain and/or cognitive fatiguability and may represent a sub-set with greater overlap with Fibromyalgia symptomology. The same genotype also appears to represent a risk factor for developing ADHD in males only.

 

[A.B.]

The best (in my opinion) review of the neuroendocrine findings, despite being out of date and written by a protege of an unpopular psychiatrist is still this one:

http://www.ncbi.nlm.nih.gov/pubmed/1270018 (Cleare 2003)

The link doesn't point to a paper by Cleare. Anyway, I know that Cleare argued that the HPA axis abnormalities are reversible by behavioural changes, which makes me doubt that his or her conclusions actually apply to CFS.