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

Snow Leopard

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South Australia
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.

It is possible, but unlikely, given that similar findings have been found from in-vitro testing of blood cells.

Cleare 2003 said:
In vitro studies of feedback provide further support for enhanced GR sensitivity. Visser et al. (69) looked at CD4-positive T cells from a small group of subjects with CFS. They found that a lower concentration of dexamethasone was needed to inhibit CD4 function, suggesting increased sensitivity to dexamethasone. Visser et al. (70) followed up this study by measuring GR function directly on the peripheral blood mononuclear cells of 10 subjects with CFS and 14 controls. Although there was no difference in GR affinity or number, or of GR mRNA expression, the peripheral blood mononuclear cells from patients with CFS were again more sensitive to dexamethasone, suggesting an abnormality in signal transduction beyond the level of receptor binding.
 
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Marco

Grrrrrrr!
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2,386
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Near Cognac, France
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

Interesting discussion but I'm not quite sure I follow this line of reasoning. Why would the BBB protect the hypothalamus (letting it carry on going 'la, la, la' while the rest of the brain os goin berserk? Is it the case that a specific function of the hypothalamus is to monitor and respond to glucocorticoid levels via feedback loops while other parts of the brain are 'passive consumers'? Wouldn't signals of peripheral 'stress' due to cortisol resistance be fed back to the brain via the hypothalamus?
 

Snow Leopard

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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.

It seems I misplaced a 1 at the end of the link, but I've fixed the link, and posted it again here:
http://www.ncbi.nlm.nih.gov/pubmed/12700181

I don't see what is so radical about suggesting that CBT can change cortisol or GCr expression levels, because it is certainly true in other illnesses. In that review, it was not suggested that this would somehow cure CFS.

Although I should also state that I personally I don't believe these findings are central to CFS, so I don't believe that reversing these findings will reverse the underlying disease.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
These papers originate from the CDC Wichita studies - who'd have thunk it!

What is the significance of that Marco - I am new to this.

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)

The first URL seems broken Snow Leopard. I have not yet got this full text. I agree that the second one is a little woolly, although I was impressed by Watson at Bristol. I cannot get my head around the idea that childhood trauma would lead to methylation of genes in lymphocytes derived de novo years later from bone marrow stem cells. Especially as in the vast majority of children with childhood trauma it seems to have no clinical effect whatever.

I still like the idea that the paradoxical findings might be due to auotimmunity - like the Grand Old Duke of York, neither up nor down (or maybe both at once).
 

Snow Leopard

Hibernating
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Location
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What is the significance of that Marco - I am new to this.

It is the old debate about the (less specific) CDC 'empirical criteria' (which was based on questionnaire scores). Of course this criteria was primarily used for the Georgia population based studies, not the Witchita population based studies (which used the Fukuda criteria). Although I believe the empirical criteria was originally developed on the Witchita set. http://www.biomedcentral.com/1741-7015/3/19

Confused yet? Maybe I am at this point.

So anyway, the point is that we'd have to double check the criteria used for those particular studies.

Edit:yes, they relied on the CDC 'empirical criteria' in those particular CDC gene studies.
(Saying they were based on the Witchita sample leads to confusion as both criteria have been used for Witchita based studies).
 
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Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
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

Interesting discussion but I'm not quite sure I follow this line of reasoning. Why would the BBB protect the hypothalamus (letting it carry on going 'la, la, la' while the rest of the brain os goin berserk? Is it the case that a specific function of the hypothalamus is to monitor and respond to glucocorticoid levels via feedback loops while other parts of the brain are 'passive consumers'? Wouldn't signals of peripheral 'stress' due to cortisol resistance be fed back to the brain via the hypothalamus?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Interesting discussion but I'm not quite sure I follow this line of reasoning. Why would the BBB protect the hypothalamus (letting it carry on going 'la, la, la' while the rest of the brain os goin berserk? Is it the case that a specific function of the hypothalamus is to monitor and respond to glucocorticoid levels via feedback loops while other parts of the brain are 'passive consumers'? Wouldn't signals of peripheral 'stress' due to cortisol resistance be fed back to the brain via the hypothalamus?

I don't think signals of peripheral response failure (like OI) would feed back to the brain through glucocorticoid receptors even if the feedback was through the hypothalamus - it would be through baroreceptors. And the rest of the brain might feel uncomfortable too. The nausea of vertigo may be mediated by hypothalamus in the final stage but the disparity is between inputs to vestibular and optic pathways around the pons, I think. Still trying to sort this all out!
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
It is the old debate about the (less specific) CDC 'empirical criteria' (which was based on questionnaire scores). Of course this criteria was primarily used for the Georgia population based studies, not the Witchita population based studies (which used the Fukuda criteria). Although I believe the empirical criteria was originally developed on the Witchita set. http://www.biomedcentral.com/1741-7015/3/19

My mistake. Thanks for the correction. But contrary to popular opinion I've been quite impressed with some of the CDC work.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
'In vitro studies of feedback provide further support for enhanced GR sensitivity. Visser et al. (69) looked at CD4-positive T cells from a small group of subjects with CFS. They found that a lower concentration of dexamethasone was needed to inhibit CD4 function, suggesting increased sensitivity to dexamethasone. Visser et al. (70) followed up this study by measuring GR function directly on the peripheral blood mononuclear cells of 10 subjects with CFS and 14 controls. Although there was no difference in GR affinity or number, or of GR mRNA expression, the peripheral blood mononuclear cells from patients with CFS were again more sensitive to dexamethasone, suggesting an abnormality in signal transduction beyond the level of receptor binding.'

I am not too impressed by those data. If autoantibodies are involved it could be anywhere along a path from cell membrane to nucleus. And if the interaction is an antibody based steric one it may be sensitive to the context of other accessory molecules around the receptor. This sort of thing is all over the place in autoimmune mechanisms. On the other hand it does allow one to turn almost any prediction though 180 degrees when convenient and that is of course a sign of a weak hypothesis generating system!!
 

Snow Leopard

Hibernating
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5,902
Location
South Australia
I was making my own speculations a while back, with the following assumptions:

Cortisol levels are lower than normal in CFS patients
GCr activity is higher than normal in CFS patients.
Leading to similar function being maintained overall.

But an increase in GCr activity would also result in a subtle shift in the cortisol-complexed functions of the GCr vs the direct actions such as transactivation/transrepression. The question is why, or more specifically, what downstream differences would this lead to?

Some time passed and then I started to become more interested in the various cellular stress signalling mechanisms...
 
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alex3619

Senior Member
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13,810
Location
Logan, Queensland, Australia
@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

I prefer to call it a CFS-like syndrome at this point. It may or may not correspond with ME. However its easy to see this could be a major risk factor. Cortisol is critical at handling major stressors including exercise, and keeps inflammatory processes suppressed. A lack of response would allow increased inflammation and decrease energy, and that is only the beginning.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC295915/pdf/jcinvest00027-0017.pdf

Glucocorticoid receptor beta inhibits the cortisol response. Whether this effects the hypothalmic function would depend on the expression in the specific regions. Peripheral increases in beta glucocorticoid receptors may or may not equate with central expression.

So its entirely possible that issues with the HPA may be irrelevant, or peripheral, or a complicating factor, or very important but we are missing something.

Increased expression of the beta isoform looks like being tissue dependent. The tissue distribution might be very important.

We really need to know the details of the finding.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
So its entirely possible that issues with the HPA may be irrelevant, or peripheral, or a complicating factor, or very important but we are missing something.

Increased expression of the beta isoform looks like being tissue dependent. The tissue distribution might be very important.

We really need to know the details of the finding.

This is where I find the PR discussion so helpful. At least I am pretty clear that this is worth further inspection and replication. Even if it is all secondary, which it could well be, if one could understand these detailed issues one might be able to see what it is secondary too I guess.
 

lansbergen

Senior Member
Messages
2,512
If autoantibodies are involved it could be anywhere along a path from cell membrane to nucleus. And if the interaction is an antibody based steric one it may be sensitive to the context of other accessory molecules around the receptor

Does any known autoimmune disease improve from top to bottom and from central to perifere?

Are flare ups needed for improvement?
 

Kati

Patient in training
Messages
5,497
Yes, I looked at this over the weekend, after IiME had flagged it up for me. I think it was a European ME meeting in Stockholm, just recently. I had also talked with Amolak about some of these things on Friday.

I thought this was a very impressive and balanced overview. I agree that the emphasis on the need for repeatable results was good. He is talking about autoantibodies to brain stem/hypothalamic structures. I don't think he would want people to read too much into that yet but it sounds very interesting - and clearly they have started work. The collaborative B cell work is still blinded so there is nothing that can actually be reported yet.

I think the cortisol resistance idea is fascinating and well worth further exploration - I very much agree with Alex here. And Alex's mention of a genetic resistance giving a CFS-like syndrome is also very interesting. My devil's advocate self says 'But how could this explain poor Justy's experience at St Pancras (so sorry to hear about that). Just having cortisol resistance shouldn't make sensory stimuli intolerable should it?' But maybe it can. Maybe if one part of the brain thinks there is enough cortisol and another part is getting messages saying there is none it flags up some sort of automatic danger message. An autoantibody to some link in the HPA axis would be such a simple explanation.

There is also this hint that low affinity/specificity antibodies and maybe IgM persisting might be involved - which might explain the paradoxical results with EBV responses Dr Scheibenbogen finds.

And @wdb and @Bob, I finally figured out what I was doing wrong on the tagging - thanks.

For me the really positive thing about this presentation is that I think it is a manifestation of a growing European collaborative effort to get everyone on the same page and interacting. And this sort of broad balanced view is exactly what is needed.


i have an experience with cortisol from a couple years back. It was in December, after a prolonged period of stress.I felt just retched. i went to my Dr and told her somethng was wrong (more than usual) and asked for testing. We did a 3hours glucose tolerance test which was normal. My TSH was newly high àt 7.22 (never had a proble with that) and on a return visit, right before the Christmas break, my AM cortisol was at a critical low, it was 44 when the normal is between 180 and 850. Since it was last minute, my dr asked an endocrine dr's advice and started me on Cortef, 20 mg in the morning and 10 mg at night. That did not do anything to me. It did nothing to my feeling lousy and in fact 6 weeks after starting this therapy my AM cortisol was still only 72. With the endocrine dr's advice i started the slow and painful process of weaning off that and after 2-3 months we did an ACTH challenge test which proved normal and my cortisol was then normal. My thyroid remained abnormal and I was started on replacement therapy. The endocrinologist was happy to discharge me from his care and in his view, there was no explanations and nor did he want to expore anything.

i also have a problem with epinephrine in dental freezing. i had a reaction at the dentist about 3years ago. i know it's the epinephrine because 1 month later i needed more freezing and we used plain lidocaine and there was no crash. The initial reaction i got, on top of having my heart racing and wanted to get out of my chest is I had a horrible crash that lasted 2-3 weeks. It was retched.

Just recently my dentist, after many, many procedures that he did with plain lidocaine, decided that the reaction i had was not likely to be epinephrine, because he could not explain it, so he injeted me with a small amount of epinephrine/ lido telling me seconds after the facts. i was very upset that he did without my consent, but my point is I had migraine headache for 2-3 days following that, and I am still in relapse from 2weeks ago from 'just a little bit of epinephrine'.

Coincidence? i don't think so,
 
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Jonathan Edwards

"Gibberish"
Messages
5,256
Does any known autoimmune disease improve from top to bottom and from central to perifere?

Are flare ups needed for improvement?

Not sure what top and bottom and centre and periphery mean here.
Some autoimmune diseases peter out - that's about all we know.
 

Kati

Patient in training
Messages
5,497
This is common. I have a similar issue. Even adrenaline from playing fast paced computer games can crash me.
In case some people missed it, I have a poll question over here in regards to epinephrine sensitivity at the dentist. I agree with you, I think it is very common in our patient population but it is often disregarded as unimportant. The answers of this poll will be shared/have been shared with a researcher.