Re: Esther Sternberg's talk at the NIH Workshop

July 2, 2003

-Great Post Rich! I believe this is a theory that many researchers

have.. Broken or dysfunctional HPA (feedback stress loop).. Possible,

Probable Cause?? Damage to Hypothalamus? .. This would also explain

the growth hormone problems...With over an active sympathetic nervous

system,also too much CRF, causes elevations in Somatostatin which

inhibits growth hormone release... So.. the real question is how do

we normalize the HPA? Many pharmaceutical co. are currently working

on CRF agonist, however last I checked they're having many problem

with it.. could be many yrs. before this arrives on the market..If in

fact it is proven that people with CFS have damage/lesion on the

hypothalamus the big question is can this be repaired??? Thanks..

-- In , " rvankonynen "

<richvank@a...> wrote:

> Esther Sternberg gave a talk at the NIH CFS workshop on June 12,

> 2003 in Bethesda, MD on the subject of " Health Consequences of a

> Dysregulated Stress Response. " Esther is the Director of the

> Integrative Neural Immune Program and Chief of the Section on

> Neuroendocrine Immunology & Behavior of the National Institute for

> Mental Health of the NIH. She is an expert on the interaction

> between the brain, the endocrine system and the immune system.

>

> Before discussing her talk, I want to give some background that I

> hope will set the scene. First, I think there is quite a bit of

> evidence in the literature and in the personal experience of many

> individual PWCs that prior to the onset of CFS (especially for

those

> with rapid or sudden onset) there is often found a history of a

> combination of various kinds of stress that is experienced as long-

> term and severe. But since not everyone who experiences such

stress

> develops CFS, it seems likely that the genetic makeup of PWCs is

> also an important factor determining whether they will develop

CFS.

> There seems to be a growing consensus developing about disease in

> general these days that it results from an interaction between a

> person's genetic makeup and some external influence, be it a toxin,

> a pathogen, emotional stress, or some other factor, including

> lifestyle factors such as nutrition. So the important points here

> are that stress appears to be an significant factor in the onset of

> many cases of CFS, and genetic makeup is probably also important.

>

> The next point I want to make is that it is known that the main

> system by which the body responds to stress is the hypothalamus-

> pituitary-adrenal (HPA) axis. Various inputs to the hypothalamus

> from different parts of the brain convey information to it about

> stresses of various types that are being experienced by the body.

> In response to these signals the hypothalamus secretes CRH

> (corticotrophin releasing hormone). This hormone causes the

> pituitary gland to secrete ACTH (adrenocorticotropin hormone),

which

> in turn causes the cortices of the adrenal glands to secrete

> glucocorticoids, the principal one being cortisol (also called

> hydrocortisone). In a normal, healthy person, there is a negative

> feedback operating that communicates between the adrenals, the

> pituitary and the hypothalamus and keeps the cortisol level

properly

> controlled.

>

> In addition to the action of the HPA axis, stress also causes the

> sympathetic nervous system to be activated. The sympathetic

nervous

> system signals the medullas of the adrenal glands to secrete

> adrenalin and noradrenalin.

>

> The next important point is that it is known that the HPA axis and

> the sympathetic nervous system affect the operation of the immune

> system. Since we know that the immune system is dysregulated in

> CFS, it is thus not a big stretch of the imagination to suspect

that

> at least some of this immune dysregulation might be caused by

action

> of the HPA axis and the sympathetic nervous system in response to

> stress. I think this is the reason Esther was invited to speak on

> neuroendocrine aspects of the stress response and how they

influence

> the immune system.

>

> One of the main points Esther made is that if the HPA axis is

> upregulated, so that the glucocorticoid secretion is elevated, the

> effect on the immune system is to suppress it. This includes

> suppressing inflammation, but also suppressing the Th1 immune

> response, which defends against viral and intracellular bacterial

> infections in particular, and shifting the immune response to Th2.

> It also causes prolonged wound healing and a decreased production

of

> antibodies when a vaccine is given. On the other hand, if the HPA

> axis is blunted or downregulated, the effect on the immune system

is

> to promote inflammation. This includes autoimmune inflammatory

> diseases.

>

> In her handout, Esther noted that the noradrenalin and adrenalin

> produced in response to the sympathetic nervous system also induce

a

> Th1 to Th2 immune response shift.

>

> Esther discussed the different immune responses of and

Fischer

> rats, which are inbred types of rats that have somewhat opposite

HPA

> axis behaviors because of genetic mutations. They serve as models

> for people who have either up- or down-regulated HPA axes. By

> manipulating these rats surgically or pharmacologically,

researchers

> have been able to change their response to inflammatory stimuli.

> Esther emphasized that the rats that were genetically prone to

> inflammation did not actually develop it unless they were exposed

to

> appropriate stimuli, such as pieces of bacteria.

>

> She also discussed the observed higher prevalences of inflammatory

> autoimmune diseases in women. The prevalences are two to tenfold

> higher in women than in men. Higher prevalences are also found in

> female rats than in male rats. She noted that estrogen plays a

> major role in modulating the immune system, and suggested that this

> is particularly important during pregnancy, when the balance

between

> the glucocorticoid and estrogen regulation of the mother's immune

> system probably is what prevents rejection of the fetus. (It may

be

> that this feature of the control of the female immune system is

> involved in the observed higher prevalence of CFS in women than in

> men.)

>

> Esther suggested that there may be genetic factors, developmental

> factors and environmental factors involved in CFS, based on

> experience with rat models and with inflammatory diseases in humans.

>

> Here's my view of the significance of what Esther discussed for CFS:

>

> It looks to me as though CFS onset occurs when a person with a

> certain genetic makeup is subjected to a long-term combination of

> various types of stress. The result is that the HPA axis and the

> sympathetic nervous system respond to the stress by becoming

> upregulated for a long time, raising the secretion of

> glucocorticoids, adrenalin and noradrenalin, and that these cause a

> strong Th1-to-Th2 immune response shift. (Something Esther didn't

> discuss, but which I think also comes into the picture here is that

> there is a depletion of glutathione, partly as a result of the

> oxidation of some of the adrenalin and noradrenalin to form o-

> quinones, which are detoxed in phase-2 detox using glutathione.

> Glutathione depletion is also known to promote the Th1-to-Th2

> shift.)

>

> As a result of the shift to Th2, the body does not have an

effective

> defense against viral or intracellular bacterial infections.

> Several types of viruses (such as Epstein—Barr) are already present

> in the cells of the body of most people in the latent state. They

> become activated and produce infections. The immune system

attempts

> to respond, but is not able to do so effectively because of its

> suppression by the HPA axis and the sympathetic nervous system. In

> its attempt, it further drains the body's supply of cysteine to

make

> glutathione, robbing the skeletal muscles of their supply, as

> Bounous and Molson hypothesized. The muscles thus go low in

> glutathione, and the oxidizing free radicals there (including

> peroxynitrite) rise in concentration, blocking their metabolism and

> producing the fatigue.

>

> Later on in the pathogenesis, the HPA axis becomes blunted or

> downregulated. I think this occurs because of a direct attack on

> the hypothalamus. I don't know whether this is due to toxins,

> pathogens or oxidizing free radicals, or some combination, but

> elevations in all of these are known to result from glutathione

> depletion, and the hypothalamus is not protected by the blood-brain

> barrier. Even though the HPA axis becomes downregulated, there is

> still not an effective Th1 response to attack the viral infections,

> because of the glutathione depletion at this point. However, the

> downregulated HPA axis now opens the PWC up to inflammation, and

> this explains things such as the high prevalence of Hashimoto's

> thyroiditis and elevated antinuclear antibody. The PWC thus ends

up

> with the worst of both worlds, with no effective protection from

> either the viruses and the intracellular bacteria or from

> inflammation.

>

> I think this makes a very believable front end to the story of how

> CFS gets going in at least the sudden or rapid onset cohort. It

> remains to identify the genetic polymorphisms that predispose some

> people to CFS when subjected to the appropriate long-term stress

> combination. I suspect that the relevant polymorphisms will be

> found in some part or parts of the operation of the HPA axis or the

> immune system or both. It makes sense to me that they would have

to

> be located in systems involved in the early part of the

pathogenesis

> of CFS in order to be accessed, and thus to be relevant to

> increasing the probability of going on to onset of CFS.

>

> Rich Van Konynenburg

July 2, 2003

,

Yes, I think that hypothalamus repair is a very big question in

CFS. Once the damage mechanisms have been stopped, assuming that we

can stop them (infections, if present in the brain, are not easy to

stop), then the next problem is fixing the damage that has already

been done. I think that things like nerve growth factor and growth

hormone are possibilities for study, and I think that's why Dr.

Cheney is trying them.

Rich

> -Great Post Rich! I believe this is a theory that many

researchers

> have.. Broken or dysfunctional HPA (feedback stress loop)..

Possible,

> Probable Cause?? Damage to Hypothalamus? .. This would also

explain

> the growth hormone problems...With over an active sympathetic

nervous

> system,also too much CRF, causes elevations in Somatostatin which

> inhibits growth hormone release... So.. the real question is how

do

> we normalize the HPA? Many pharmaceutical co. are currently

working

> on CRF agonist, however last I checked they're having many problem

> with it.. could be many yrs. before this arrives on the market..If

in

> fact it is proven that people with CFS have damage/lesion on the

> hypothalamus the big question is can this be repaired??? Thanks..

> --

July 3, 2003

Hi, .

> Thanks, Rich, for posting this.

You're welcome.

> My question: If there are so many predisposing factors necessary

to cause CFIDS in a person, how does this correlate with outbreaks

of the illness such as those described by Cheney and ?

I'm not sure how many predisposing factors are necessary. There does

appear to be a genetic component in some cases, though, based on

twin studies and family studies.

In the clusters such as the one at Incline Village, it seems likely

that there was a strong infectious component or environmental

component, even though it was never elucidated. argues for

mold toxins there. If there is a strong enough infectious or

environmental component, genetic predisposition may not be very

influential or may not even be necessary. As an example, Borrellia

seems to be powerful enough that people with perfectly healthy

immune systems can get Lyme disease, and Lyme disease has almost

identical symptoms as CFS. I'm not saying that it was Lyme disease

at Incline Village, just that a powerful enough pathogen can make

people ill, whether they have unusual genetic characteristics or

not.

Why are there so many more people with CFIDS-like illness now than

there were in the past, when it was also described?

I think that you're right in saying that there is a higher

prevalence of CFS now, though that's difficult to prove because of

the lack of good numbers historically and the lack of a longstanding

and precise definition of the illness and a straightforward

diagnostic test.

My guess is that it's due to a higher load of combined stress

carried by people now, because of things like lifestyle choices and

environmental toxins, perhaps combined with poorer nutrition as a

result of depletion of nutrients in the soils on which crops are

grown, together with more extensive consumption of processed and

fast foods, which have many of the nutrients removed from them by

refining. Fad diets may be a factor also. It may also not be an

accident that the incidence is higher in women, and the clusters

started appearing at a time when societal changes and expectations

were placing many conflicting demands on women, which no doubt

raised their overall levels of stress.

Of course, you understand that I am only speculating about these

things!

>

> Bond

Rich

>

July 3, 2003

,

Yes, I think genetics probably plays an important part in CFS, and

it seems to be the combination of having a particular genetic

makeup, and then being exposed to a certain stressor or stressors

from the environment that leads to the illness.

Concerning your uncles who have Crohn's disease, how are they

doing? If they are looking for a better solution than they

currently have, I would suggest that they take a look at Dr.

Gregg's Crohn's remedies. They don't require prescription drugs,

and they have worked in a dramatic way for many people, including my

father-in-law. Dave's Crohn's disease website is

http://www.krysalis-sparx.com/crohn.htm

Rich

> In a message dated 7/3/03 4:47:51 AM Eastern Daylight Time,

> writes:

>

> > In the clusters such as the one at Incline Village, it seems

likely

> > that there was a strong infectious component or environmental

> > component, even though it was never elucidated. argues for

> > mold toxins there. If there is a strong enough infectious or

> > environmental component, genetic predisposition may not be very

> > influential or may not even be necessary. As an example,

Borrellia

> > seems to be powerful enough that people with perfectly healthy

> > immune systems can get Lyme disease, and Lyme disease has almost

> > identical symptoms as CFS. I'm not saying that it was Lyme

disease

> > at Incline Village, just that a powerful enough pathogen can

make

> > people ill, whether they have unusual genetic characteristics or

> > not.

> >

>

> Hi Rich, I was thinking about this a lot lately. I recently read

the book

> Biography of a Germ which is the story of Borrellia. In it it

talks about how

> some people have lyme in them and it does not cause any major

problems at all.

> It seems to me if that is correct then some of us are set up for

CFS due to

> genetics (even if I have lyme as my cause of CFS for instance, two

of the 4

> sibblings on my dad's side have crohns) and stress factors and

maybe then an

> outside component like 's mold hypothesis or lyme comes into

play for being

> the straw that breaks the camel's back?

>

July 3, 2003

Thought you'd get away from me by taking the discussion over here?

HAH! I really do appreciate your work Rich. You're doing a hell of a

job.

I just think it's a waste of time to implicate stressors that have

never demonstrated capacity to initiate this kind of immune

dysfunction.

We can immediately exclude diet, pollution, lifestyle and attitude.

Which for some reason are factors that many researchers just don't

want to let go of.

I've actually heard people protesting to an " emotionally induced

immune suppression theorist " that they had sudden onset during one of

the happiest times in their lives, only to hear the unbelievable

stretch of the imagination " Well there is your stress. Extreme

happiness is a form of stress to the immune system " .

I would be surprised if there weren't genetic variants that

influence susceptibility, but how relevant is that in the face of a

phenomenon that has demonstrated a capacity to move through the

population in such a dramatic manner?

People who have managed to make it through 70 years of life without

CFS suddenly find their genetic makeup insufficient to ward off this

illness at approximately the same time as a few hundred thousand other

people of all ages.

Wouldn't it be more productive to find what changed during this time

period?

People were certain that CFS only struck down the weak until they saw

that the support groups were full of marathon runners, tennis pro's,

champion swimmers, hang glider instructors, health food store

owners... Then all of a sudden it was a " burnout syndrome " of

yuppies. Type A personalities that overstressed themselves by working

too hard or having too much fun.

Researchers just love this theory too much to let it go even though it

doesn't remotely fit the facts.

The CFS phenomenon seems to consist of a reduction in a persons

ability to withstand stressors that are inconsequential to a normal

person.

We need to find something that can do that and not waste time

overstressing the importance of the stressors unless some of them

turn out to be precipitators common to a large number of illness

onsets.

I believe that the association of emotional stress with onset is an

important clue, but not as an initiator of illness, but rather as a

consequence of it.

I believe that the emotional state corresponds to the inflammatory

process which is a direct physiological response to the infection.

(Didn't we just go through this with H Pylori)

-

July 3, 2003

,

Thanks for your thoughts. I really wasn't trying to hide from you.

I just try to respond to comments from whichever direction they

come. I posted the Esther Sternberg summary on several lists. I

guess my summaries of that meeting are the only ones out there right

now, so the market is hot! Hopefully the NIH will put out their own

version soon. They audio recorded the whole workshop. They aren't

selling tapes, but I was told that they do plan to put out a report

on the workshop.

I think there is room for lots of views on what causes CFS. I

really do believe that we are dealing with quite a few subsets, and

the answer will not be the same for everyone.

Rich

> Thought you'd get away from me by taking the discussion over here?

> HAH! I really do appreciate your work Rich. You're doing a hell

of a

> job.

> I just think it's a waste of time to implicate stressors that have

> never demonstrated capacity to initiate this kind of immune

> dysfunction.

> We can immediately exclude diet, pollution, lifestyle and attitude.

> Which for some reason are factors that many researchers just don't

> want to let go of.

> I've actually heard people protesting to an " emotionally induced

> immune suppression theorist " that they had sudden onset during one

of

> the happiest times in their lives, only to hear the unbelievable

> stretch of the imagination " Well there is your stress. Extreme

> happiness is a form of stress to the immune system " .

> I would be surprised if there weren't genetic variants that

> influence susceptibility, but how relevant is that in the face of

a

> phenomenon that has demonstrated a capacity to move through the

> population in such a dramatic manner?

> People who have managed to make it through 70 years of life

without

> CFS suddenly find their genetic makeup insufficient to ward off

this

> illness at approximately the same time as a few hundred thousand

other

> people of all ages.

> Wouldn't it be more productive to find what changed during this

time

> period?

> People were certain that CFS only struck down the weak until they

saw

> that the support groups were full of marathon runners, tennis

pro's,

> champion swimmers, hang glider instructors, health food store

> owners... Then all of a sudden it was a " burnout syndrome " of

> yuppies. Type A personalities that overstressed themselves by

working

> too hard or having too much fun.

> Researchers just love this theory too much to let it go even

though it

> doesn't remotely fit the facts.

> The CFS phenomenon seems to consist of a reduction in a persons

> ability to withstand stressors that are inconsequential to a

normal

> person.

> We need to find something that can do that and not waste time

> overstressing the importance of the stressors unless some of them

> turn out to be precipitators common to a large number of illness

> onsets.

> I believe that the association of emotional stress with onset is

an

> important clue, but not as an initiator of illness, but rather as

a

> consequence of it.

> I believe that the emotional state corresponds to the inflammatory

> process which is a direct physiological response to the infection.

> (Didn't we just go through this with H Pylori)

> -

July 4, 2003

I don't mean to be obstreperous. If I'm not making any sense, feel

free to tell me to shut up.

I am sure there are as many CFS subsets as there are secondary

pathogens and the limitless number of different combinations of these

secondary pathogens that come together in different ways to create

symptoms.

Add variables of individual susceptibility, environmental exposures,

and all the varying degrees of each, not to mention the changes that

everybody experiences during the course of illness progression and I'm

certain that the number of subgroups has the capacity to be just

slightly less than infinite.

Breaking this illness down into subgroups eventually leads to the

uniqueness of each individual case.

We are bound together as a syndrome by our concurrencies, not defined

by our differences.

I think that it is an endless task to concentrate on all the variables

that separate CFS into subsets.

I'm not suggesting that I know all the answers, but I'd like to see

attention focused only on abnormalities that are truly abnormal and

not on stressors that within the range of normal experience.

-

July 4, 2003

They don't require prescription drugs,

> and they have worked in a dramatic way for many people, including

my

> father-in-law. Dave's Crohn's disease website is

>

> http://www.krysalis-sparx.com/crohn.htm

>

> Rich

Rich, did you happen to use Dave's protocol to kill your cancer

cells? I do want to speak for Jim Clements but I am pretty sure that

what he and Dave are saying about CFS is the same. PWC's have

anaerobic metabolism and healthy people have aerobic metabolism. The

anaerobic metabolism only producing two counts of ATP versus the 36

by areobic metabolism. Also the increase in lactic acid created from

the anaerobic metabolism causes such muscles faigue and pain. Jim has

a different approach to change a person from anaerobic to aerobic

metabolism but the results should be the same. I am starting on his

program next week.

Bob

July 4, 2003

,

I think I get your drift. Obviously, there is value in raising our

efficiency by grouping cases together that really are similar in

terms of the disease mechanism or pathogenesis, and not treating

each case as an individual subset. And obviously, the " front end "

is going to be unique to every case if we cut it finely enough.

However, on the issue of talking about stressors that are within the

range of normal experience, I do think this is important, because

some people become ill when subjected to stressors that could be

considered to be within the normal range. We aren't all equally

able to cope with such normal stressors. I think that's a big

reason why some people become ill and some don't. There's also a

range in what would be considered normal stressors. One person's

normal is another person's stressed-out. It gets particularly

tricky when several stressors are combined at the same time. Each

one may be a " normal " stressor, but if they happen to hit a person

all at once, they add up, because the body deals with different

kinds of stressors using many of the same few general mechanisms,

the HPA axis in particular. A recent paper on trigger factors in

CFS found that about half the PWCs reported combined stressors prior

to onset. In reviewing individual cases, I often find incredible

loads of a variety of stressors all hitting at once prior to onset.

Rich

> I don't mean to be obstreperous. If I'm not making any sense, feel

> free to tell me to shut up.

> I am sure there are as many CFS subsets as there are secondary

> pathogens and the limitless number of different combinations of

these

> secondary pathogens that come together in different ways to create

> symptoms.

> Add variables of individual susceptibility, environmental

exposures,

> and all the varying degrees of each, not to mention the changes

that

> everybody experiences during the course of illness progression and

I'm

> certain that the number of subgroups has the capacity to be just

> slightly less than infinite.

> Breaking this illness down into subgroups eventually leads to the

> uniqueness of each individual case.

> We are bound together as a syndrome by our concurrencies, not

defined

> by our differences.

> I think that it is an endless task to concentrate on all the

variables

> that separate CFS into subsets.

> I'm not suggesting that I know all the answers, but I'd like to

see

> attention focused only on abnormalities that are truly abnormal

and

> not on stressors that within the range of normal experience.

> -

July 4, 2003

Bob,

When I had cancer, Dave had not yet come up with his treatments for

it, but I did take Immunopower (not the same as ImmunePro) which has

many of the things Dave advocates. Of course, I also had surgery,

chemo, radiation and a lot of prayer, so it's difficult to separate

out what did what. I can say that the combination did work, though,

and I'm very happy about that.

Yes, there are some similarities between Dave's and Jim's ideas

about CFS. And for that matter, I agree that there is a metabolic

problem in CFS, too. Where we all differ somewhat is in how to fix

that, although we aren't really so far apart there, either. What

works best may vary from case to case, too.

I wish you success with Jim's program, and hope you will keep us

posted.

Rich

>

> They don't require prescription drugs,

> > and they have worked in a dramatic way for many people,

including

> my

> > father-in-law. Dave's Crohn's disease website is

> >

> > http://www.krysalis-sparx.com/crohn.htm

> >

> > Rich

> Rich, did you happen to use Dave's protocol to kill your cancer

> cells? I do want to speak for Jim Clements but I am pretty sure

that

> what he and Dave are saying about CFS is the same. PWC's have

> anaerobic metabolism and healthy people have aerobic metabolism.

The

> anaerobic metabolism only producing two counts of ATP versus the

36

> by areobic metabolism. Also the increase in lactic acid created

from

> the anaerobic metabolism causes such muscles faigue and pain. Jim

has

> a different approach to change a person from anaerobic to aerobic

> metabolism but the results should be the same. I am starting on

his

> program next week.

>

> Bob

July 4, 2003

> In reviewing individual cases, I often find incredible

> loads of a variety of stressors all hitting at once prior to onset.

>

> Rich

you can count me in that category!

marcia

July 20, 2003

Thanks,

I am also trying to find an answer for that. I could not find an answer. I

am lately using Rhodiola Rosea. It is of some help to regulate the HPA axis

dysfunction but I could not find the right dosage yet.So far I am happy with

the result.

Thanks.

Nil