A defect in cortisol production in rheumatoid arthritis: why are we still looking?

[beaverfury]

I guess this would be a good starting point:

Mathematical Modeling of the Hypothalamic-Pituitary-Adrenal Axis

Holy crap, that is complex! I cant believe people do that stuff. I will stick to making sandwhiches.

Wake me when its all over.

 

[natasa778]

If the HPA axis is in dynamic equilibrium with the immune system and a strong stress response suppresses the immune system, then the opposite effect would be that an activated immune system would suppress the HPA axis. This may explain the findings in RA, CFS patients as well as other groups.

Absolutely, I have always felt that to be the case... in terms of 'evidence' for this I feel we can only push it as far as taking it from animal studies, like the one that currer posted.

I don't see how we could ever prove that beyond doubt in humans (short of unethical experimenting on healthy people, to see what happens because in real humans with developed/established health conditions we would get forever entangled in chicken-or-egg situation and 'NEVER COME TO ANY REAL CONCLUSIONS'.

 

[Snow Leopard]

bla bla.. you could by the trial and error of punching in millions of bits of information, come up with some model?
Hell, the antivirus system on my computer juggles thousands of bits of information every second.
It must be susceptible to analysis this way?

Just wonderin. I cant do it. Im battling to make a sandwhich

Here is one prepared earlier (by Broderick and colleagues):
http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000273

The problem is that the assumption of increased GC receptor expression or activity has not shown to be the case when CFS patients have been tested. So the statements in the Seckl/Yahuda about increased GC receptor density paper don't actually apply to CFS cases.

The model does not consider suppression due to the effect of the immune system (which is a logical consequence of the feedback systems, but wasn't actually mentioned in the previous articles I cited - I apologise to currer if there was any misunderstanding)

 

[beaverfury]

Here is one prepared earlier (by Broderick and colleagues):
http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000273

The problem is that the assumption of increased GC receptor expression or activity has not shown to be the case when CFS patients have been tested. So the statements in the Seckl/Yahuda about increased GC receptor density paper don't actually apply to CFS cases.

The model does not consider suppression due to the effect of the immune system (which is a logical consequence of the feedback systems, but wasn't actually mentioned in the previous articles I cited - I apologise to currer if there was any misunderstanding)

Ok. Phew! I can comprehend 50% of the text, none of the math. Ive got some learning to do.

Interesting that they propose a treatment plan of lowering cortisol levels rather than raising as you would expect.
Wonder how that goes??

Now i have to read about HPA axis stable steady states and GC receptors.

 

[Snow Leopard]

Interesting that they propose a treatment plan of lowering cortisol levels rather than raising as you would expect.
Wonder how that goes??

I bet it doesn't work.

 

[caledonia]

According to Rich Vank, the HPA axis problem is caused by lack of glutathione in the hypothalmus and pituitary. This results in them no longer being able to make the proper signals to the adrenals and thyroid, so they lose functioning. The treatment would be to do a methylation protocol to raise glutathione, thus restoring function.

 

[jimells]

they seem to do experiment after experiment, for years WITHOUT COMING TO ANY FREAKIN CONCLUSIONS!!

Well, actually the studies do come to conclusions: "We conclude we need more grant money to keep publishing useless papers"

 

[beaverfury]

Well, actually the studies do come to conclusions: "We conclude we need more grant money to keep publishing useless papers"

"We conclude that....OH, MY GOD!.. WHAT'S THAT?.........We've never even seen ONE of those before!!!!!"

"Thats my lunch, Dr Bob. Youre looking through the wrong end of the microscope!"

 

[beaverfury]

Here is one prepared earlier (by Broderick and colleagues):
http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000273
)

'A number of chronic diseases have been characterized by abnormalities in HPA axis regulation. These include major depression and its subtypes, anxiety disorders such as post-traumatic stress disorder, panic disorder and cognitive disorders such as Alzheimer's disease and minimal cognitive impairment of aging [3]. Dysregulation of the HPA axis has also been linked to the pathophysiology of Gulf War illness [4], post-infective fatigue [5], and chronic fatigue syndrome (CFS) [6],[7]. It is not clear what causes this dysregulation, but it is manifested in many HPA axis disorders as a hypercortisol or hypocortisol state. The existence of these separate and stable states is not surprising when one considers the multiple feedforward and feedback mechanisms that regulate the HPA axis. Systems such as this often display complex dynamics that readily accommodate multiple stable steady states which are known as attractors because the system is naturally drawn back to these resting states after perturbation. However, if the perturbation is of sufficient strength and duration, the system can be pushed away from a given resting state and into the basin of new attractor.'

I like this bit
'We propose that a well-directed push given at the right moment may encourage the axis to reset under its own volition.'

Yeah, just give it a shove! Thats my sort of science.

They propose this
'A candidate treatment that displays robust properties in the face of significant biological variability and measurement uncertainty requires that cortisol be further suppressed for a short period until adrenocorticotropic hormone levels exceed 30% of baseline. Treatment may then be discontinued, and the HPA axis will naturally progress to a stable attractor defined by normal hormone levels.'

Theres a discussion on this at http://forums.phoenixrising.me/index.php?threads/hpa-axis-reboot.17879/
But be sure and come back here

 

[Snow Leopard]

Here is an interesting one for you guys, a paper that turns things on its head. I am surprised it took me this long to find this paper as I have been hinting towards results like this.


Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome
http://cfids-cab.org/cfs-inform/Cytokines/gaab.etal04.pdf

Results. CFS patients showed an inverse stress-induced response pattern of LPS stimulated cytokines responses in comparison to healthy controls, i.e. stimulated cytokine production decreased shortly after stress in CFS patients, while it increased in controls. Fatigue scores and basal LPS-induced cytokine levels were significantly
associated for TNF-a in controls and for both cytokines in CFS patients. Stress induced changes in stimulated cytokine production were not associated with general
fatigue scores in the control group, whereas in the CFS group, fatigue scores were significantly correlated with integrated levels of LPS-induced cytokines.

In conclusion, CFS patients did not show exaggerated pro-inflammatory cytokine responses during stress, but rather the opposite was the case. An enhanced sensitivity to the suppressive effects of glucocorticoids could serve as a possible physiological explanation for this finding. LPS induced cytokine levels were strongly correlated with general fatigue levels in CFS patients, although cytokine levels were comparable to those of controls. An enhanced perception of cytokine induced
symptoms, possibly due to sensitization processes, could serve as an explanatory model to account for these findings.

The authors also discuss the previous studies which did not find increased Glucocorticoid receptor density or activity. (therefore the typical explanation is likely false and something more interesting is at play)

Actually, I feel the sensitization could be on a cellular level rather than a brain level, mediated by other biochemical deficiencies.

In conclusion, you should try increasing your psychosocial stress levels.

 

[beaverfury]

'Actually, I feel the sensitization could be on a cellular level rather than a brain level, mediated by other biochemical deficiencies.' snowleopard


The plot thickens, as my brain dissolves.
Ive just been reading cort's article on cellular ion channel malfunctionshttp://phoenixrising.me/research-2/...chronic-fatigue-syndrome-mecfs/comment-page-1.

Potential causes of channel dysfunction – The natural history of CFS suggests that an early pathogenic or toxic insult often occurs. Several viruses, including HIV and the picornaviruses are able to alter ion channel flow. Toxins can be key ion channels disrupters because they often attack the membrane surrounding the cell. Some toxins can even create new channels that cause severe ionic imbalances through the leakage of ions out of the cell.

Is this the sort of thing you might be alluding to? (fishing). I guess theres a thousand things can go wrong in a cell.
I wonder how this ties in with varying cortisol levels? Beyond me.

 

[lansbergen]

http://www.me-cvs.nl/index.php?pageid=4817&printlink=true&highlight=ebv

LPS-induced IL-10 production in whole blood cultures from chronic fatigue syndrome
patients is increased but supersensitive to inhibition by dexamethasone

Abstract

Several causes have been held responsible for the chronic fatigue syndrome
(CFS), including an altered hypothalamus-pituitary-adrenal gland (HPA)-axis
activity, viral infections and a reduced Th1 activity. Therefore, it was
investigated whether the regulation of IL-10 is different in CFS. LPS-induced
cytokine secretion in whole blood cultures showed a significant increase in
IL-10 and a trend towards a decrease in IL-12 as compared with healthy
controls. In patients and controls, IL-12 secretion was equally sensitive to
suppression by dexamethasone, whereas IL-10 secretion appeared more sensitive
in CFS-patients. In controls, IL-10 and IL-12 secretion were inversely
correlated with free serum cortisol (r=-0.492, p<0.02 and r=-0.434, p<0.05,
respectively). In CFS, such an inverse correlation was found for IL-12
(r=-0.611, p<0.02) but not for IL-10 (r=-0.341, ns). These data are
suggestive for a disturbed glucocorticoid regulation of IL-10 in CFS.

 

[Snow Leopard]

One more.

http://www.ncbi.nlm.nih.gov/pubmed/10690878

J Clin Endocrinol Metab. 2000 Feb;85(2):692-6.
Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome.

Kavelaars A, Kuis W, Knook L, Sinnema G, Heijnen CJ.
Source

Department of Pediatric Immunology, Wilhelmina Children's Hospital of the University Medical Center Utrecht, The Netherlands. a.kavelaars@wkz.azu.nl
Abstract

The present study was designed to investigate the interaction between neuroendocrine mediators and the immune system in chronic fatigue syndrome (CFS). We examined the sensitivity of the immune system to the glucocorticoid agonist dexamethasone and the beta2-adrenergic agonist terbutaline in 15 adolescent girls with CFS and 14 age- and sex-matched controls. Dexamethasone inhibits T-cell proliferation in healthy controls and in CFS patients. However, the maximal effect of dexamethasone on T-cell proliferation is significantly reduced in CFS patients as compared with controls. The beta2-adrenergic receptor agonist terbutaline inhibits tumor necrosis factor-alpha production and enhances interleukin-10 production by monocytes. Our data demonstrate that the capacity of a beta2-adrenergic agonist to regulate the production of these two cytokines is also reduced in CFS patients. We did not observe differences in baseline or CRH-induced cortisol and ACTH between CFS patients and controls. Baseline noradrenaline was similar in CFS and controls, whereas baseline adrenaline levels were significantly higher in CFS patients. We conclude that CFS is accompanied by a relative resistance of the immune system to regulation by the neuroendocrine system. Based on these data, we suggest CFS should be viewed as a disease of deficient neuroendocrine-immune communication.

 

[August59]

One more.

http://www.ncbi.nlm.nih.gov/pubmed/10690878

J Clin Endocrinol Metab. 2000 Feb;85(2):692-6.
Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome.

Kavelaars A, Kuis W, Knook L, Sinnema G, Heijnen CJ.
Source

Department of Pediatric Immunology, Wilhelmina Children's Hospital of the University Medical Center Utrecht, The Netherlands. a.kavelaars@wkz.azu.nl
Abstract

The present study was designed to investigate the interaction between neuroendocrine mediators and the immune system in chronic fatigue syndrome (CFS). We examined the sensitivity of the immune system to the glucocorticoid agonist dexamethasone and the beta2-adrenergic agonist terbutaline in 15 adolescent girls with CFS and 14 age- and sex-matched controls. Dexamethasone inhibits T-cell proliferation in healthy controls and in CFS patients. However, the maximal effect of dexamethasone on T-cell proliferation is significantly reduced in CFS patients as compared with controls. The beta2-adrenergic receptor agonist terbutaline inhibits tumor necrosis factor-alpha production and enhances interleukin-10 production by monocytes. Our data demonstrate that the capacity of a beta2-adrenergic agonist to regulate the production of these two cytokines is also reduced in CFS patients. We did not observe differences in baseline or CRH-induced cortisol and ACTH between CFS patients and controls. Baseline noradrenaline was similar in CFS and controls, whereas baseline adrenaline levels were significantly higher in CFS patients. We conclude that CFS is accompanied by a relative resistance of the immune system to regulation by the neuroendocrine system. Based on these data, we suggest CFS should be viewed as a disease of deficient neuroendocrine-immune communication.

This sure would make a good new name for us to use in association with our disease:

Neuroendocrine-Immune Encephalomyelitis or NIE or NIEM, we could drop the Encephalo and then it would be Neuroendocrine-Immune Myelitis or NIM for short. Nah, we better leave the Encephalo in it.

I'm just playing around with names as the sooner CFS is gone the happier I will be!

Thanks Snow Leopard for a great thread. It is sort of interesting that there were several threads starting with somewhat similar subjects at he same time. So, it must be on peoples minds and I think it is a very plausible subject for discussion and research if it can start where they left off and move on. I don't care to see some of this research repeated as it is just wasting funding.

 

[Hip]

This is a very astute observation and one with which I agree. Physics has "theoretical physicists" trying to make sense of experiments. I don't think medicine has the same well organized gang of people. On top of that, most people that pursue the medical field aren't that good at Mathematics which hinders their ability to create and test models.

This is a good point, Nanonug, and one which I have often pondered on myself.

To restate your point: there is a distinct division in physics: there are the experimental physicists, who set up laboratory experiments (sometimes with billion dollar budgets) in order to make specific observations, measurements and tests on the laws of nature, and on the behaviors of physical world; and then there are the theoretical physicists who, with nothing more costly than a pencil and paper, sit down at their desks trying to develop theories that explain how the physical world actually works (with of course the help of the data derived from experimental physics).

The experimentalists are doers that are at home in the lab. The theoreticians are the thinkers that are at home in a library or any place they are left alone to engage in deep thinking. These are quite different personalty types, and each prefers their own domain.

In the medical, biochemical and microbiology fields, there does not seem to be this distinction between the doers and the thinkers, as far as I am aware. I personally don't have any direct experience of this academic area, but from what I can work out, in the biological sciences, most people are primarily experimentalists that work in labs, with some of these guys moonlighting as theoreticians.

Because there seem to be few dedicated theoreticians in the biological sciences, this means there are not enough people sitting down with pencil and paper, devising new theoretical models that explain biochemical mechanisms and disease etiologies.

Though it has to be said that biology is a different beast to physics. In the history physics, time and time again, very complex looking phenomena are often eventually boiled down to a startlingly simple and beautiful mathematical equation that, remarkably, captures all the facets of the phenomenon. In physics, complex phenomena arise out of a underlying substrate of beautifully simple laws.

However, in the biological sciences, even the underlying substrate itself seems complex. You don't seem to get many occasions in the history biology where a complex phenomenon is boiled down to a simple equation or law that you can print on a T-shirt. In fact, often the reverse: when you try to understand a simple concept in biology, like say that of heredity, instead of boiling down to a simple equation, it explodes into something extremely detailed and convoluted, like the complex science of genetics.

 

[beaverfury]

However, in the biological sciences, even the underlying substrate itself seems complex. You don't seem to get many occasions in the history biology where a complex phenomenon is boiled down to a simple equation or law that you can print on a T-shirt. In fact, often the reverse: when you try to understand a simple concept in biology, like say that of heredity, instead of boiling down to a simple equation, it explodes into something extremely detailed and convoluted, like the complex science of genetics.

Since getting cfs i have found the, 'shit happens' T-shirt has a new resonance for me.

I dont like Freud's 'anatomy is destiny'.

 

[beaverfury]

Neuroendocrine-Immune Encephalomyelitis or NIE or NIEM, we could drop the Encephalo and then it would be Neuroendocrine-Immune Myelitis or NIM for short. Nah, we better leave the Encephalo in it.

Those are hell better names than what we've got. Cant wait till they finally pull the trigger on this name change.
If something generalised like 'Neuroendocrine immune dysfunction' doesnt serve in the long term, it is still a more workable solution than 'chronic fatigue syndrome' in the medium term, and would give us some breathing space.
I know science has to tread lightly for fear of mistep, but politically.....

 

[beaverfury]

In the medical, biochemical and microbiology fields, there does not seem to be this distinction between the doers and the thinkers, as far as I am aware. I personally don't have any direct experience of this academic area, but from what I can work out, in the biological sciences, most people are primarily experimentalists that work in labs, with some of these guys moonlighting as theoreticians.

Because there seem to be few dedicated theoreticians in the biological sciences, this means there are not enough people sitting down with pencil and paper, devising new theoretical models that explain biochemical mechanisms and disease etiologies.

Theres not enough philosophical debunking of mainstream beliefs concerning current scientific research either.
The conflation of 'in vitro' theory with 'in vivo' effectiveness is an example.(Mea culpa. Maybe i am only thinking of my own idealistic gullibilty).
The latest antioxidant, the great new supplement, anti-aging strategies, brain enhancing nootropics, medications can all be rendered worthless if the right person doesnt take the right chemical- at the right dose- at the right time.
Drinking enough water, getting enough sleep, getting maximum nutrition and enough aerobic exersise(we're screwed there) could be by far more effective than any particular chemical i'm putting into my recalcitrant system.

The explosion of new research, its desemination in fitness magazines, forums, soundbites in the media are not offset
by cold reality. This is not the fault of scientists themselves, who by profession are the most cautious of creatures.

I'm guilty of swallowing all these idealistic narratives, along with a ton of supplements. I keep searching for a dopaminergic holy grail, hoping for inreased energy, motivation, libido! Confusing these with success in career, enhanced sexual relationships and freedom from illness. So far, i'm alone, ill, sleep deprived... and i've got a headache.

The results that these industrious lab moles put down on paper are grasped by people of divergent motivations.
Mainly, healthy people that have commercial interests, and commercially vulnerable folk who have health interests!

I'm going off subject probably. Suffice to say there are a few gaps in the market.