Re: RNase-L activation and cleavage in CFS

November 15, 2005

Hi Rich,

My question is, how do we know that it's not the glutathione depletion

that's a downstream effect, rather than the RNaseL cleavage? I tend to

believe the top of the chain will be the genetic abnormalities or an

infection. So say this is the way it happens (forgive my

simplification, this is just an example of a possibility): Infection->

increased elastase -> RNaseL cleavage -> Inability to fight infections

+ harm LMW RNaseL does -> CFIDS.

You talked about the fact that stressors deplete glutathione. So

couldn't something like the above chain, for example, explain why our

bodies are under constant 'stress', and wouldn't low glutathione be

expected, as well as other things that are downregulated?

All due respect intended - it just seems to me it's possible the low

glutathione is a symptom and not the root cause.

Is it also not a bit misleading and reductive to suggest LMW RNaseL

has only received attention due to being discovered early on, and its

potential for profit?

>

> Hi, Cort, , and the group.

>

> I'd like to review how I believe RNase-L activation and cleavage

> occur in CFS, and what their role is in the pathogenesis.

>

> First, the RNase-L response is normally a temporary holding action

> in the body to prevent the spread of a viral infection until the

> cell-mediated immunity can ramp up (it takes a few days) and kill

> the virus-infected cells. The abnormalities in the RNase-L system

> in CFS are two: first, that it stays activated for a much longer

> time than it should, rather than deactivating, and second, that the

> RNase-L is cleaved and reforms in a lower-molecular weight form that

> is unregulated.

>

> Why does the first abnormality occur? I think the most obvious

> explanation is the one that Dr. Cheney offered some years ago--the

> cavalry never arrives. That is, there is a reactivated endogenous

> viral infection, the immune system detects it, it activates the

> RNase-L system by means of producing interferon to slow the

> infection down, and it tries to bring on the cell-mediated immunity

> to knock it out. But the cell-mediated immune response does not

> ramp up, and the RNase-L is left holding the bag.

>

> Why doesn't the cell-mediated immunity ramp up? Well, we know it is

> activated, but it doesn't seem to be able to complete its response,

> which involves proliferating the particular T cells that are set up

> to go after that particular virus. So it is just " stuck " in the

> activated state, but not able to mobilize the forces needed to kill

> the virally-infected cells.

>

> Why can't the T cells proliferate like they're supposed to? I've

> suggested it's because of glutathione depletion. There's plenty of

> evidence in the literature (much of it reviewed by Wulf Droege) that

> glutathione depletion in the T cells will cause this exact

> behavior. What's more, glutathione depletion is also responsible

> for the reactivation of the latent endogenous virus itself, and

> there is evidence in the literature for that as well.

>

> Is glutathione depleted in CFS? It certainly is in many PWCs. I've

> reviewed the published evidence for this. We also hear it

> repeatedly from PWCs on this list who have had their glutathione

> measured. Dr. Cheney found that glutathione depletion was almost

> universal in his patients, and reported this back in 1999. Dr.

> Holtorf has been quoted on this list as saying that he no longer

> measures glutathione in his CFS patients, because he had found in

> the past that they were all low. I don't think this is a

> controversial point any more. True, there are some PWCs with normal

> or high glutathione levels, and I have suggested that this may

> result from genetic variations in the enzymes that use glutathione,

> causing them to be less able to use it for the appropriate purposes.

> The results would be similar to not having enough glutathione.

>

> How does glutathione become depleted? It looks to me as though it's

> caused by a combination of genetic predisposition and some

> combination of long-term physical, chemical, biological and/or

> psychological stressors. Based on what I have learned recently

> about autism and the similarities between many of the features of

> autism and CFS, I now suspect that the genetic predisposition

> involves genetic variations in the genes that code for enzymes and

> other proteins involved in the sulfur metabolism, particularly in

> the methionine (methylation) cycle, the transsulfuration pathway,

> and/or the glutathione system.

>

> Running the above sequence backward, one has the basic etiology and

> early pathogenesis of CFS.

>

> Now, why does the RNase-L become cleaved, to form the low molecular

> weight version? It is known that the enzymes elastase and calpain

> are able to accomplish this. of these, calpain is normally

> inhibited by intracellular thiols, of which glutathione is normally

> the most abundant. It seems likely to me, then, that depletion of

> glutathione would remove the inhibition from calpain, and it would

> be able to cleave RNase-L, which is observed.

>

> Does the activated and cleaved RNase-L have deleterious effects in

> CFS? No doubt it does. It is able to attack messenger RNA

> representing the expression of normal genes in the cells, and the

> result of this has to be that there is less production of new

> enzymes and proteins needed by the cells, and therefore their normal

> metabolism can be expected to be suppressed.

>

> There have been various studies showing correlations between RNase-L

> levels and other features of CFS. Do these correlations mean that

> RNase-L caused these other features? Not necessarily, and in most

> cases I suspect that it did not. The correlations could be the

> result of glutathione depletion causing both the activated and

> cleaved RNase-L and the other feature studied.

>

> Bounous and Molson hypothesized several years ago that there is a

> competition between the immune system and the skeletal muscles for

> the raw materials to make glutathione at the onset of symptoms of

> CFS. I think they were right about this. In the presence of

> glutathione depletion, these two do compete, and neither one

> actually wins, because there simply isn't enough cysteine available

> to make all the glutathione that is needed. The result is that the

> skeletal muscles experience partial blockades of their oxidative

> metabolism due to the elevation of superoxide and peroxynitrite in

> the absence of enought glutathione to keep them under control. The

> mitochondria of the muscles are not able to produce ATP fast enough

> to keep up with the demand from normal muscle operation, and the PWC

> experiences physical fatigue. If they overdo, they dig themselves

> into a hole because of damage by reactive oxygen species, which rise

> because of the depletion of glutathione, and because of the

> depletion of adenosine from the cells, which is difficult to replace.

>

> At the same time, the PWC cannot mount an effective cell-mediated

> defense against the viruses, also because of glutathione depletion.

> I think that this mechanism explains the initial phase of the

> pathogenesis of CFS for many PWCs. It agrees with known

> biochemistry and physiology, and it explains the observations.

>

> Why has RNase-L activation received so much attention in CFS, if it

> is actually a downstream effect? I think there are several

> reasons. First, it was one of the earliest biochemical phenomena

> discovered in CFS, because Bob Suhadolnik decided to look for it

> early on, because of the seeming involvement of viruses in CFS, and

> the known action of RNase-L in viral infections. Second, because

> the development of Ampligen, which acts on RNase-L, showed the

> potential for making a profit on CFS treatment. The order in which

> things are discovered is not related to the actual order of the

> cause-effect sequence in a disease, however. In fact, the late

> manifestations of the pathogenesis are often the most visible. To

> get at root causes, you have to track these manifestations back to

> their source, and not assume that they are the root cause of the

> disease.

>

> Rich

>

November 15, 2005

Hi, .

Thanks very much for your comments. I'll insert mine below, with

asterisks.

> >

> > Hi, Cort, , and the group.

> >

> > I'd like to review how I believe RNase-L activation and cleavage

> > occur in CFS, and what their role is in the pathogenesis.

> >

> > First, the RNase-L response is normally a temporary holding

action

> > in the body to prevent the spread of a viral infection until the

> > cell-mediated immunity can ramp up (it takes a few days) and

kill

> > the virus-infected cells. The abnormalities in the RNase-L

system

> > in CFS are two: first, that it stays activated for a much

longer

> > time than it should, rather than deactivating, and second, that

the

> > RNase-L is cleaved and reforms in a lower-molecular weight form

that

> > is unregulated.

> >

> > Why does the first abnormality occur? I think the most obvious

> > explanation is the one that Dr. Cheney offered some years ago--

the

> > cavalry never arrives. That is, there is a reactivated

endogenous

> > viral infection, the immune system detects it, it activates the

> > RNase-L system by means of producing interferon to slow the

> > infection down, and it tries to bring on the cell-mediated

immunity

> > to knock it out. But the cell-mediated immune response does not

> > ramp up, and the RNase-L is left holding the bag.

> >

> > Why doesn't the cell-mediated immunity ramp up? Well, we know

it is

> > activated, but it doesn't seem to be able to complete its

response,

> > which involves proliferating the particular T cells that are set

up

> > to go after that particular virus. So it is just " stuck " in the

> > activated state, but not able to mobilize the forces needed to

kill

> > the virally-infected cells.

> >

> > Why can't the T cells proliferate like they're supposed to?

I've

> > suggested it's because of glutathione depletion. There's plenty

of

> > evidence in the literature (much of it reviewed by Wulf Droege)

that

> > glutathione depletion in the T cells will cause this exact

> > behavior. What's more, glutathione depletion is also

responsible

> > for the reactivation of the latent endogenous virus itself, and

> > there is evidence in the literature for that as well.

> >

> > Is glutathione depleted in CFS? It certainly is in many PWCs.

I've

> > reviewed the published evidence for this. We also hear it

> > repeatedly from PWCs on this list who have had their glutathione

> > measured. Dr. Cheney found that glutathione depletion was

almost

> > universal in his patients, and reported this back in 1999. Dr.

> > Holtorf has been quoted on this list as saying that he no longer

> > measures glutathione in his CFS patients, because he had found

in

> > the past that they were all low. I don't think this is a

> > controversial point any more. True, there are some PWCs with

normal

> > or high glutathione levels, and I have suggested that this may

> > result from genetic variations in the enzymes that use

glutathione,

> > causing them to be less able to use it for the appropriate

purposes.

> > The results would be similar to not having enough glutathione.

> >

> > How does glutathione become depleted? It looks to me as though

it's

> > caused by a combination of genetic predisposition and some

> > combination of long-term physical, chemical, biological and/or

> > psychological stressors. Based on what I have learned recently

> > about autism and the similarities between many of the features

of

> > autism and CFS, I now suspect that the genetic predisposition

> > involves genetic variations in the genes that code for enzymes

and

> > other proteins involved in the sulfur metabolism, particularly

in

> > the methionine (methylation) cycle, the transsulfuration

pathway,

> > and/or the glutathione system.

> >

> > Running the above sequence backward, one has the basic etiology

and

> > early pathogenesis of CFS.

> >

> > Now, why does the RNase-L become cleaved, to form the low

molecular

> > weight version? It is known that the enzymes elastase and

calpain

> > are able to accomplish this. of these, calpain is normally

> > inhibited by intracellular thiols, of which glutathione is

normally

> > the most abundant. It seems likely to me, then, that depletion

of

> > glutathione would remove the inhibition from calpain, and it

would

> > be able to cleave RNase-L, which is observed.

> >

> > Does the activated and cleaved RNase-L have deleterious effects

in

> > CFS? No doubt it does. It is able to attack messenger RNA

> > representing the expression of normal genes in the cells, and

the

> > result of this has to be that there is less production of new

> > enzymes and proteins needed by the cells, and therefore their

normal

> > metabolism can be expected to be suppressed.

> >

> > There have been various studies showing correlations between

RNase-L

> > levels and other features of CFS. Do these correlations mean

that

> > RNase-L caused these other features? Not necessarily, and in

most

> > cases I suspect that it did not. The correlations could be the

> > result of glutathione depletion causing both the activated and

> > cleaved RNase-L and the other feature studied.

> >

> > Bounous and Molson hypothesized several years ago that there is

a

> > competition between the immune system and the skeletal muscles

for

> > the raw materials to make glutathione at the onset of symptoms

of

> > CFS. I think they were right about this. In the presence of

> > glutathione depletion, these two do compete, and neither one

> > actually wins, because there simply isn't enough cysteine

available

> > to make all the glutathione that is needed. The result is that

the

> > skeletal muscles experience partial blockades of their oxidative

> > metabolism due to the elevation of superoxide and peroxynitrite

in

> > the absence of enought glutathione to keep them under control.

The

> > mitochondria of the muscles are not able to produce ATP fast

enough

> > to keep up with the demand from normal muscle operation, and the

PWC

> > experiences physical fatigue. If they overdo, they dig

themselves

> > into a hole because of damage by reactive oxygen species, which

rise

> > because of the depletion of glutathione, and because of the

> > depletion of adenosine from the cells, which is difficult to

replace.

> >

> > At the same time, the PWC cannot mount an effective cell-

mediated

> > defense against the viruses, also because of glutathione

depletion.

> > I think that this mechanism explains the initial phase of the

> > pathogenesis of CFS for many PWCs. It agrees with known

> > biochemistry and physiology, and it explains the observations.

> >

> > Why has RNase-L activation received so much attention in CFS, if

it

> > is actually a downstream effect? I think there are several

> > reasons. First, it was one of the earliest biochemical

phenomena

> > discovered in CFS, because Bob Suhadolnik decided to look for it

> > early on, because of the seeming involvement of viruses in CFS,

and

> > the known action of RNase-L in viral infections. Second,

because

> > the development of Ampligen, which acts on RNase-L, showed the

> > potential for making a profit on CFS treatment. The order in

which

> > things are discovered is not related to the actual order of the

> > cause-effect sequence in a disease, however. In fact, the late

> > manifestations of the pathogenesis are often the most visible.

To

> > get at root causes, you have to track these manifestations back

to

> > their source, and not assume that they are the root cause of the

> > disease.

> >

> > Rich

> >

>

November 15, 2005

I agree with Rich.I think GSH depletion is more upstream than

RnaseL. It just makes much more sense. GSH depletion automatically

(there is many studies supporting this btw) induces a TH2 dominant

immune system and subsequent TH1 downregulation. Cell mediated is

automatically impaired when GSH is gone.

What impairs GSH is unknown but, again I agree with Rich with the

causes and the sulfer metabolism problems in CFS due to all of this.

Dont know if its gene related, or rather so many stressors that

cause this massive loss of GSH.

I mean a diet defcient in phase II detox mechs, GSH under

production, and then life stress can to me easily equal loss of cell

mediated immunity which will start probably with the reactivated

herepes type viruses which is usually the first thing we notice

(like EVB) . Without GSH/cell immunity these guys get loose, and the

subsequent and eventual RnaseL problem occurs. The protease

imbalance with elastase etc can be explained due to oxidative stress

and such. It is complicated with RnaseL, but i do think it is more

downstream.

You guys really need to read sci.life.extension, they have some

wonderful insights into GSH and phase II detox.

For example, Rich or anyone may be interested in :

New clues about vitamin D functions in the nervous system and

glutathione synthesis

http://groups.google.com/group/sci.life-

extension/browse_thread/thread/be2bac1804291183/dea72ffbf469dec3?

hl=en#dea72ffbf469dec3

Effect of antioxidant-enriched diets on glutathione redox status in

tissue homogenates and mitochondria of the senescence-accelerated

mouse

http://groups.google.com/group/sci.life-

extension/browse_thread/thread/025d54ba845af02f/b3dd27f2ae177cb9?

hl=en#b3dd27f2ae177cb9

and much more if you search

I also read some interesting things about thyroid function,

riboflavin and glutathione. I was not aware of *** item below :

Thyroid function is dependent on iodine, zinc, copper, boron,

manganese.

**Thyroid hormone is needed to activate riboflavin which reduces

glutahione, activates folic acid, and activates B6.

B6 is needed to make glutathione.

Folic Acid is needed with B12 to turn over homocysteine to SAMe.

They are also both used to make DNA and RNA, and those are needed to

make proteins.

Activated riboflavin is necessary in the Kreb's cylce, as is B5

JL

November 16, 2005

Thanks Rich . I appreciate you pointing out it's a hypothesis, I

think it's important to make sure we are reminded that a lot of stuff

we're taking in is theoretical. I know most people know, but

sometimes, with a few different theories discussed on CFS lists, it

seems they're taken as fact. Especially those theories that fit the

model of us being overburdened, our immune systems being down, and

latent infections become active - a model itself that I think is taken

with too much certitude. Among the only research/information I'm

interested in anymore are the gene studies and the stuff the NCF

funds, because these think outside this box, which to me has become a

bit tired. (And though they think outside the box, the principles

about it that make sense to us remain).

I'm not convinced gluthathione will be THE key, but I'm not

unconvinced it won't help a lot of people or be maybe the key in one

type of CFS.

***I think any model for the pathogenesis of CFS has to be able to

account for why some people get CFS but most don't, why PWCs seem to

have a high load of longterm stress prior to their onset,

why the latent viruses reactivate, why the immune system is unable

to defeat them, and why profound physical fatigue develops.***

I think this is well understood by now, and it's not that I don't get

that this is a reason for looking to the role of glutathione, it's

just that I believe there are or will be better explanations. I do

take issue with this idea that we have a " high load of longterm

stress " . It seems extremely doubtful that we have more mental or

physical stressors than anyone else, as others have pointed out

before. I think this thinking leads to a mischaracterisation of our

illness, and I also feel any approaches to treatment developed from

this will be intrinsically limited.

***Again, thank you for your comments, . The best way to

make progress is to propose alternative hypotheses and shoot at all

of them to see what survives, in terms of accounting for all the

observations.***

That is well said, I agree with this wholeheartedly.

And I just want to make sure it's understood that when I wrote above

about people taking things as fact, I don't think it's a problem to

believe in something without entirely being able to substantiate it. I

don't mind if someone says 'I'm sure it's (this or that cause)!'. But

I've often noticed on various patient lists that many PWCs write 'we

*know* this and this about our illness' and their language implies

it's factual, when really it comes from various theoretical strands.

Much of it comes from a naturopathic model of what fatigue is, rather

than necessarily a characterisation of CFS ... and this is the sort of

stuff I hope people start looking at more critically.

Right, I'm so tired, I can't tell if I've made sense... here's hoping so!

Warm regards,

November 16, 2005

From the e-mail to

***I think the answer is that we don't know. What I have offered is

a hypothesis, which I believe has considerable support, but which

cannot be regarded as scientifically proven. The purpose of

developing hypotheses in the scientific process, it to have

something to shoot at, to see if it can be falsified. If it can,

then it has to be changed. What I have presented is what has

survived so far, after being shot at for quite a while, by myself

and others.

CORT - well Rich, I'm shooting at your theory. I actually think its been

injured - certainly not on life support - but in need of some assistance.

***The other thing I would say about that is that CFS is such a

heterogeneous disorder as currently defined, that I expect that it

will take more than one final theory to explain all the subsets.

I tend to

> believe the top of the chain will be the genetic abnormalities or

an

> infection.

***I think that you are right about the genetic abnormalities being

at the top. There has to be a reason why some people develop CFS,

while most don't, even though the things found to happen to PWCs

prior to their onset probably happen to many other people as well,

but they don't develop CFS. Genetics is probably the reason. Also,

there are studies showing familial association of CFS cases as well

as twin studies that indicate that there is a genetic component. So

I'm with you on the genetic abnormalities.

CORT - Except that that recently published twin study showing only a modest

genetic component - about 30% in women and really nothing in men with CFS. So

yes you can say there is a genetic but you cannot say there is a signficant one.

These qualifiers seem to missing in much on what you write. I think this is what

is so frustrating to me - I give you evidence that I think should lead you to

qualify your statements - yet it fails to do so.

***Concerning the infection, I also agree that this occurs at the

onset for many cases of CFS. However, one interesting thing is that

almost without expception, as far as I have seen,the viral

infections that are found in early CFS are by viruses that are known

to cause inactive, latent infections in humans, including the whole

herpes family of viruses (EBV, CMV, HHV-6 and the rest) as well as

sackie B3 and others.

CORT: I just have to say this is a very controversial and difficult of

research. The consensus now is that EBV is not reactivated to an increased

degree in CFS. If CMV is, it is reactivated in only a small group of patients.

The story with regards to HHV-6 is very complex; it does appear CFS patients

have a greater tendency towards HHV-6 reactivation than healthy controls but

what that means is anyones guess. HHV-6 reactivation in many cases of healthy

controls is entirely benign, in others it may have pathologic effects. While

some studies have shown evidence of increased viral reactivation others have

not. It doesnt seem that a) one can say alot about this with any authority or

that it plays a big role in CFS. Given the differing findings by some many

studies regarding viral reactivation in CFS, this is a pretty weak plank to rest

an argument on.

It is also true that prospective studies have shown that a certain percentage

of people (@10%) who come down with primary EBV infection, ROss River virus and

Q fever come down with CFS. Thus in at least some cases there is no need to

make the case for viral reactivation and the case isnt that strong anyway.

*****If this is true, then something else must have happened

behind the scenes to allow this reactivation. Since it is known

that glutathione depletion both suppresses the type of immune

response needed to defeat viral infections, and also triggers the

proliferation of latent herpes viruses, it seems very llkely to me

that glutathione depletion is what is behind these viral

reactivations.

CORT: THIS IS CERTAINLY POSSIBLE.

When one also looks at the studies of triggering

events and factors in CFS, which I reviewed in my poster paper, one

finds that all of these are known to place demands on glutathione.

It therefore seems to me that this picture fits together rather

well: Genetic predisposition-->A combination of stressors that

lower glutathione-->suppression of cell-mediated immunity--

>reactivation of latent viruses-->onset of infection-->further

depletion of glutathione by immune system demands-->depletion of

glutathione in skeletal muscle becuase immune system has depleted

cysteine-->physical fatigue.

CORT: THIS IS POSSIBLE, I certainly dont deny its possible. Its an nice

theory, it makes sense but the nub of it is is that but studies done so far on

glutathione status in CFS do not support the contention that it plays a CENTRAL

role in CFS. More on that in another e-mail.

***I think this is an interesting sequence. Concerning the

infection, please note my comments above. The infection doesn't

seem to be the first thing that happens in CFS, at least in the

histories I have received from so many PWCs. They usually report a

difficult period in their lives, in which it seems to them that

their " resistance " went down, and then they became ill. I think the

" resistance " is a manifestation of glutathione supplies.

CORT: In your poster you suggest a hypercortisolic state (high stress)

probably precedes the 'mild' hypocortisolic state found in CFS. THere is not

evidence for that yet - we should know, however, with the Dubbo study. Since in

that poster you assert that the hypercortisolic state results in TH1 suppression

and increased norepinephrine activity in CFS results in decreased GSH status it

would seem that these are central facets of CFS and that changing them not our

GSH status is the key to resolving CFS.

I would note that trials of whey protein in AIDS, which does have low GSH

levels show that whey protein rather quickly returns GSH status to normal. Based

on that evidence I would suggest that many CFS patients have indeed returned

their GSH levels to normal, that it has proved beneficial in some degree to many

of them but it has in no resolved their CFS. This suggests GSH is either

depleted or not high enough in CFS patients, probably due to high levels of

oxidative stress but it does not suggest GSH plays a central role.

I know you have made a case for the complex nature of CFS, of the need to

resolve later infections, etc. that occurred as a result of the GSH depletion,

that explains the why glutathione enhancement does not present a cure but it

precisely the need for such convoluted explanations that worry. The more

convoluted an argument has to get to make a theory stretch to fit the facts the

more one thinks the theory simply doesnt fit the fact. The most parsimonious

explanation for GSH's inability to help all CFS patients and its inability to

cure any of them is that it is a by-product of CFS not a central cause of it.

In some ways this would not be surprising. Oxidative stress, after all, in

found in an huge range of diseases (cancer, diabetes, asthma, Alzhiemers, heart

disease,etc.). While it undoubtedly plays a role in the pathology of those

diseases it is entirely possibly that it is simply an common accompanient to

chronic diseases. Since infection can result in increased oxidative stress it

would probably, I would guess, be increased in any infectious disease in which

it occurs. Does this mean it causes it? Of course not.

Does it mean low GSH levels could accentuate disease and that increasing GSH

levels would be helpful? OF course it does.

***Concerning elastase, it is my understanding that it is found in

neutrophils. The types of infections found at the onset of CFS,

however, are viral in nature, and neutrophils are not part of the

immune response that is normally mobilized to fight viral

infections.

CORT - I dont know how you came with the idea that we know what types of

infection occur at the ONSET of the disease. As I said before Ross RIver, EBV

primary infection and Q fever have been shown to be associated with CFS but they

probably make up only a small set of triggering agents. Q-fever is a bacteria

as is lyme. The most common pathogen, mycoplasm, found in CFS is also a

bacteria.

*****Furthermore, RNase-L is an intracellular substance, and

the low molecular weight version in CFS has been found in

monocytes. I don't understand how elastase would gain access to the

RNase-L. Maybe I don't understand this well enough.

CORT - I think you dont but then again neither do I! I do know though that

elastase is produced in the granules inside monoctyes. HOw it gets to RNase L

is a very good question. We're probably just missing something.

***I also don't understand how RNase-L cleavage in the monocytes

would interfere with the ability to fight viral infections, which

involves T cells.

CORT: We could be dealing with viruses or other pathogens that attack

monocytes. Several pathogens - are actually adapted to live in the phagosomes

in which they are supposed to be digested. Monocytes are one of the key

carriers of HIV. MOnocytes are also important antigen presenting cells to T and

B cells. They are also involved in ingesting microorganisms that have been

targeted by B-cells with antibodies and in complement activation.

>

> You talked about the fact that stressors deplete glutathione. So

> couldn't something like the above chain, for example, explain why

our

> bodies are under constant 'stress', and wouldn't low glutathione be

> expected, as well as other things that are downregulated?

CORT - This is another question I have. Since just about anything stressful

can deplete GSH one would think the body is always dealing with trials of

short-term GSH depletion and - that the GSH system is pretty robust.

THis everything under the sun effect is one of the joys and problems with any

GSH depletion theory; since it is a master antioxidant then depletion of it in a

cell of your choice will result in problems. I imagine you could make a case

for GSH depletion in a large number of diseases. Thats not necessarily a good

thing! THe proof, of course, lies in the pudding, is GSH actually depleted in

those diseases? and does reversing the course of GSH depletion reverse the

course of the disease

The question is - if profound GSH depletion occurs then why does it occur in

CFS patients? WHat is the matter with the production, transport, etc of GSH in

CFS patients?

***Thank you. I intend all due respect to you, also. I haven't

actually suggested that low glutathione is the root cause. I think

that the root causes are a combination of a genetic predisposition

and some combination of a variety of factors (physical, chemical,

biological and/or psychological) that produce a condition of long-

term stress, which lead to the depletion of glutathione.

CORT - with all due respect Rich, except for these rare proviso's, one really

gets the impression you think GSH depletion is it. Just about every time a

dysregulation in CFS turns up, from the heart, to the immune system to whatever,

you attempt to, and often can theoretically, in terms of GSH depletion. If its

not the primary cause for CFS in your scenario its must be right below.

If its really secondary and in fact only improves but does not make well CFS

patients then I think would be great if you would turn your considerable

brainpower and creativity towards the primary factors in CFS; those which are

upstream of GSH. Does your above statement means you believe GSH depletion is

secondary in CFS and primary in autism?

To say the cause of CFS is a combination of factors, all of which almost every

one faces with some regularity (infections, stress full events, too much work)

but which END UP in a state of long term stress that causes CFS is to say that

long term stress CAUSES CFS. Since I would imagine long term stress enhances the

risk for many diseases it comes close to saying nothing at all.

We know long term doesnt CAUSE CFS, we do know it is a risk factor for CFS.

Lots of people - most people -who have long term stress do not get CFS. Some

people with CFS, such as myself, were not under any discernable long-term

stress. The question then is why at least some (certainly not all) CFS patients

had sufficient phsyiological problems dealing with long-term stressors that they

came down with CFS.

In your poster you suggested norepinephrine activation preceded GSH depletion

in CFS. (I accept that is probably happening in CFS). So what causes that? That

would seem to be a good avenue of research. YOu also suggested hypercortisolism;

we'll see how that turns out but why would CFS patients be more subject to

hypercortisolism or perhaps more importantly, have a more negative effect from

it?

Given that the hypocortisolism in CFS is characterized as 'mild' does this

suggest that the hypercortisolism was mild as well?

>

> Is it also not a bit misleading and reductive to suggest LMW RNaseL

> has only received attention due to being discovered early on, and

its

> potential for profit?

***And I think there are people who believe that it may have a

fundamental role in the pathogenesis. Many of them don't seem to

want to look at what happens earlier in CFS, though. Why doesn't

the RNase-L activation turn off, like it's supposed to?

CORT - I dont think they dont want to look at it. FIrst of all, as I noted

before, RNase L activation is not always increased in CFS and studies no longer

use it as a marker - they use RNase L fragmentation.

When they

have turned it off, in some PWCs, using Ampligen, why did it pop

back up after the Ampligen was stopped, in at least some of them?

There has to be more going on than this, it seems to me.

CORT - this could be because AMPLIGEN is actually composed, so far as I

understand it, of bit of RNA that the 2-5OAS enzyme responds to. (IFN activates

the 2-5OAS enzyme which produces dimers that activate RNase L). THe problem in

CFS appears to be the oligonucleotides (bits of RNA) that trigger 2-5OAS to

produce dimers that inactivate RNase L and leave it vulnerable to proteolytic

attack instead of the trimers that activate RNase L but leave it protected. IF

you flood the system with 'good' RNA it will respond correctly. (This is why De

Meirleir et. al. believe the system is working correctly - it is the inputs to

the system that are off). If you stop flooding the system with RNA and you still

have what is producing the aberrant RNA then the system goes back to its former

state; ie dimer production, RNase L vulnerability and fragmentation. That is

how I understand Ampligen. I could be wrong.

***Again, thank you for your comments, . The best way to

make progress is to propose alternative hypotheses and shoot at all

of them to see what survives, in terms of accounting for all the

observations.

>

Rich

>

> >

> > Hi, Cort, , and the group.

> >

> > I'd like to review how I believe RNase-L activation and cleavage

> > occur in CFS, and what their role is in the pathogenesis.

> >

> > First, the RNase-L response is normally a temporary holding

action

> > in the body to prevent the spread of a viral infection until the

> > cell-mediated immunity can ramp up (it takes a few days) and

kill

> > the virus-infected cells. The abnormalities in the RNase-L

system

> > in CFS are two: first, that it stays activated for a much

longer

> > time than it should, rather than deactivating, and second, that

the

> > RNase-L is cleaved and reforms in a lower-molecular weight form

that

> > is unregulated.

> >

> > Why does the first abnormality occur? I think the most obvious

> > explanation is the one that Dr. Cheney offered some years ago--

the

> > cavalry never arrives. That is, there is a reactivated

endogenous

> > viral infection, the immune system detects it, it activates the

> > RNase-L system by means of producing interferon to slow the

> > infection down, and it tries to bring on the cell-mediated

immunity

> > to knock it out. But the cell-mediated immune response does not

> > ramp up, and the RNase-L is left holding the bag.

> >

> > Why doesn't the cell-mediated immunity ramp up? Well, we know

it is

> > activated, but it doesn't seem to be able to complete its

response,

> > which involves proliferating the particular T cells that are set

up

> > to go after that particular virus. So it is just " stuck " in the

> > activated state, but not able to mobilize the forces needed to

kill

> > the virally-infected cells.

> >

> > Why can't the T cells proliferate like they're supposed to?

I've

> > suggested it's because of glutathione depletion. There's plenty

of

> > evidence in the literature (much of it reviewed by Wulf Droege)

that

> > glutathione depletion in the T cells will cause this exact

> > behavior. What's more, glutathione depletion is also

responsible

> > for the reactivation of the latent endogenous virus itself, and

> > there is evidence in the literature for that as well.

> >

> > Is glutathione depleted in CFS? It certainly is in many PWCs.

I've

> > reviewed the published evidence for this. We also hear it

> > repeatedly from PWCs on this list who have had their glutathione

> > measured. Dr. Cheney found that glutathione depletion was

almost

> > universal in his patients, and reported this back in 1999. Dr.

> > Holtorf has been quoted on this list as saying that he no longer

> > measures glutathione in his CFS patients, because he had found

in

> > the past that they were all low. I don't think this is a

> > controversial point any more. True, there are some PWCs with

normal

> > or high glutathione levels, and I have suggested that this may

> > result from genetic variations in the enzymes that use

glutathione,

> > causing them to be less able to use it for the appropriate

purposes.

> > The results would be similar to not having enough glutathione.

> >

> > How does glutathione become depleted? It looks to me as though

it's

> > caused by a combination of genetic predisposition and some

> > combination of long-term physical, chemical, biological and/or

> > psychological stressors. Based on what I have learned recently

> > about autism and the similarities between many of the features

of

> > autism and CFS, I now suspect that the genetic predisposition

> > involves genetic variations in the genes that code for enzymes

and

> > other proteins involved in the sulfur metabolism, particularly

in

> > the methionine (methylation) cycle, the transsulfuration

pathway,

> > and/or the glutathione system.

> >

> > Running the above sequence backward, one has the basic etiology

and

> > early pathogenesis of CFS.

> >

> > Now, why does the RNase-L become cleaved, to form the low

molecular

> > weight version? It is known that the enzymes elastase and

calpain

> > are able to accomplish this. of these, calpain is normally

> > inhibited by intracellular thiols, of which glutathione is

normally

> > the most abundant. It seems likely to me, then, that depletion

of

> > glutathione would remove the inhibition from calpain, and it

would

> > be able to cleave RNase-L, which is observed.

> >

> > Does the activated and cleaved RNase-L have deleterious effects

in

> > CFS? No doubt it does. It is able to attack messenger RNA

> > representing the expression of normal genes in the cells, and

the

> > result of this has to be that there is less production of new

> > enzymes and proteins needed by the cells, and therefore their

normal

> > metabolism can be expected to be suppressed.

> >

> > There have been various studies showing correlations between

RNase-L

> > levels and other features of CFS. Do these correlations mean

that

> > RNase-L caused these other features? Not necessarily, and in

most

> > cases I suspect that it did not. The correlations could be the

> > result of glutathione depletion causing both the activated and

> > cleaved RNase-L and the other feature studied.

> >

> > Bounous and Molson hypothesized several years ago that there is

a

> > competition between the immune system and the skeletal muscles

for

> > the raw materials to make glutathione at the onset of symptoms

of

> > CFS. I think they were right about this. In the presence of

> > glutathione depletion, these two do compete, and neither one

> > actually wins, because there simply isn't enough cysteine

available

> > to make all the glutathione that is needed. The result is that

the

> > skeletal muscles experience partial blockades of their oxidative

> > metabolism due to the elevation of superoxide and peroxynitrite

in

> > the absence of enought glutathione to keep them under control.

The

> > mitochondria of the muscles are not able to produce ATP fast

enough

> > to keep up with the demand from normal muscle operation, and the

PWC

> > experiences physical fatigue. If they overdo, they dig

themselves

> > into a hole because of damage by reactive oxygen species, which

rise

> > because of the depletion of glutathione, and because of the

> > depletion of adenosine from the cells, which is difficult to

replace.

> >

> > At the same time, the PWC cannot mount an effective cell-

mediated

> > defense against the viruses, also because of glutathione

depletion.

> > I think that this mechanism explains the initial phase of the

> > pathogenesis of CFS for many PWCs. It agrees with known

> > biochemistry and physiology, and it explains the observations.

> >

> > Why has RNase-L activation received so much attention in CFS, if

it

> > is actually a downstream effect? I think there are several

> > reasons. First, it was one of the earliest biochemical

phenomena

> > discovered in CFS, because Bob Suhadolnik decided to look for it

> > early on, because of the seeming involvement of viruses in CFS,

and

> > the known action of RNase-L in viral infections. Second,

because

> > the development of Ampligen, which acts on RNase-L, showed the

> > potential for making a profit on CFS treatment. The order in

which

> > things are discovered is not related to the actual order of the

> > cause-effect sequence in a disease, however. In fact, the late

> > manifestations of the pathogenesis are often the most visible.

To

> > get at root causes, you have to track these manifestations back

to

> > their source, and not assume that they are the root cause of the

> > disease.

> >

> > Rich

> >

>

This list is intended for patients to share personal experiences with each

other, not to give medical advice. If you are interested in any treatment

discussed here, please consult your doctor.

November 16, 2005

I would note that trials of whey protein in AIDS, which does have low GSH

levels show that whey protein rather quickly returns GSH status to normal. Based

on that evidence I would suggest that many CFS patients have indeed returned

their GSH levels to normal, that it has proved beneficial in some degree to many

of them but it has in no resolved their CFS. This suggests GSH is either

depleted or not high enough in CFS patients, probably due to high levels of

oxidative stress but it does not suggest GSH plays a central role.

I think in cases where mercury has been allowed to accumulate because of having

low gsh for some time, the mercury creates 'blocks' in our systems that along

with the other buildup of bacterial and viral infections will keep the gsh from

being brought back to normal.

The most parsimonious explanation for GSH's inability to help all CFS patients

and its inability to cure any of them is that it is a by-product of CFS not a

central cause of it.

I don't recall Rich ever saying it 'was' the cause of it. What he's always said

is there were 'triggers' (virus/bacterial infections, toxic exposure, other

stess/stressors) that cause the gsh to go low and then when toxins (like

mercury) accumulate with the infections it makes it hard to restore the gsh and

all the other downstream things that happen. Now with the findings of the

importance of methylation and those 'loops' maybe the rest of the answers will

be unraveled. Rich has never said 'he knows it all' about CFS but that he's

working on his hypothesis as it evolves. I for one am thankful for the work that

he's doing and his willingness to share it all along the way.

Does it mean low GSH levels could accentuate disease and that increasing GSH

levels would be helpful? OF course it does.

I guess I dont' see why the argument with this?

As I said before Ross RIver, EBV primary infection and Q fever have been shown

to be associated with CFS but they probably make up only a small set of

triggering agents. Q-fever is a bacteria as is lyme. The most common pathogen,

mycoplasm, found in CFS is also a bacteria.

But how do we know that mcyo is not an 'opportunistic infection (as well as

Q-fever, lyme and the others) that comes AFTER the immune system is compromised

and glutathione is low?

CORT - This is another question I have. Since just about anything stressful

can deplete GSH one would think the body is always dealing with trials of

short-term GSH depletion and - that the GSH system is pretty robust.

that may be true in 'normal' people without the genetic predisposition that cfs

patients may have.

The question is - if profound GSH depletion occurs then why does it occur in

CFS patients? WHat is the matter with the production, transport, etc of GSH in

CFS patients?

well, obviously not all the facts are known, thats whats being worked on now :-)

Personally my tests show very low glutathione and all other testing has

correlated with Rich's theories so far, so maybe in your case you have a lot of

arguments against it, but for me, it seems to fit. Rich (and I as well) have

always said there are subsets, not all of us are going to find the same

cause/cure. Maybe it won't fit your case.

To say the cause of CFS is a combination of factors, all of which almost every

one faces with some regularity (infections, stress full events, too much work)

but which END UP in a state of long term stress that causes CFS is to say that

long term stress CAUSES CFS. Since I would imagine long term stress enhances the

risk for many diseases it comes close to saying nothing at all.

Cort, you leave out the fact that he has said 'genetics' are a part of this!

We know long term doesnt CAUSE CFS, we do know it is a risk factor for CFS.

Lots of people - most people -who have long term stress do not get CFS. Some

people with CFS, such as myself, were not under any discernable long-term

stress. The question then is why at least some (certainly not all) CFS patients

had sufficient phsyiological problems dealing with long-term stressors that they

came down with CFS.

genetics, genetics, genetics.....

In your poster you suggested norepinephrine activation preceded GSH depletion

in CFS. (I accept that is probably happening in CFS). So what causes that?

wouldn't that be caused by the 'stressors' mentioned? Stimulating the adrenals

to 'fight'?

Marcia

November 16, 2005

rvankonynen <richvank@...> wrote:

exact

> > Is glutathione depleted in CFS? It certainly is in many PWCs.

I've

> > reviewed the published evidence for this.

CORT - I know its on the web but I dont actually remember you reviewing so I

will. THis is from your poster

Cheney [7,8] reported that his CFS clinical patients were

almost universally low in GSH.

• s et al. [9] found that patients could be divided

statistically into two distinct groups, one having significantly

elevated erythrocyte GSH relative to a healthy control group, and

the other having significantly lower values.

CORT - approximately 1/4 of the CFS patients had lower GSH; this means the

majority of CFS patients actually had higher than normal GSH levels. This

suggests that GSH production was probably going gangbusters in most CFS patients

- probably in response to increased levels of oxidative stress.

• Fulle et al. [10] found elevated total (reduced plus

oxidized) glutathione in muscle biopsy specimens from PWCs relative

to healthy controls, but they did not report values for reduced

glutathione alone.

CORT - once again elevated GSH; I know you put a proviso in there but it makes

your case more difficult.

• y Keenoy et al. [11] found that a subgroup of

fatigued patients with low magnesium, whose body stores of Mg did

not improve with supplementation, had significantly lower GSH.

CORT - this was actually a subgroup of a subgroup. Patients with low and

normal magnesium levels actually had nearly identical GSH levels. It was a

subgroup of those with low mg. levels who had low GSH. I dont know how many

there were but it couldnt have been too many.

• y Keenoy et al. [12] did not find a significant

difference between CFS patients and fatigued controls in terms of

whole-blood GSH, but they did not compare with a healthy control

group.

CORT - another BUT - but still no evidence of decreased GSH in CFS.

• Kennedy et al. [13] found significantly lower red blood cell

GSH in PWCs compared to healthy controls (p=0.05).

CORT - Kennedy et. al. only found evidence of decreaesd GSH in about 1/3rd of

CFS patients who were obese and hypertensive. Because these conditions

predispose them for diseases with high oxidative stress and because most CFS

patients, those who were not obese and hypertensive had normal GSH levels,

Kennedy et. al. suggested CFS was not a disease of decreased antioxidant levels

but of increased oxidative stress.

• Kurup and Kurup [14] found significantly lower red blood

cell GSH in myalgic encephalomyelitis patients compared to healthy

controls (p<0.01).

We're also missing the recent Jammes study, I think it was, that did not show

reduced GSH levels.

CORT - havent been able to get the Krurup study but it fits your theory. So we

have one that found GSH depletion in CFS patients, three which found small

subgroups of CFS patients had low GSH (one of which may have been confounded by

their medical condition) and three that did not. Thats not much evidence for a

proposed central facet of CFS. . It suggests to me that GSH depletion can be a

consequence of CFS probably due to increased oxidative stress ( as it is in

other diseases). GSH supplementation can and as we know from reports from this

group and others is a helpful therapy in CFS patients with low antioxidant

levels as it is in other diseases.

I'm sure there will be more studies of oxidative stress in CFS, it is an area

of real interest, and we will learn more about GSH levels in CFS. It would be

great if a study looked at the full course - GSH in different cell types, levels

of the different enzymes, etc. - but there is no evidence this is going to

happen. GSH research in CFS, such as it is, takes place in the midst of studies

not specifically designed to examine it.

I dont think the story is done on GSH - who knows, maybe further studies

will back up Cheney's and Holtorf's claims. I think the qualifications

regarding the GSH theory are not presented in this group - you certainly dont

allude to them and your sometimes selective citing of the evidence - on your

poster, and in the group - does not, I think give the full picture. This is of

course commonly done in medical research - it is refreshing to come across

papers that cite both sides of the argument - but its doesnt happen that often.

Generally one has to dig to uncover any fault-lines if they are present.

We also hear it

> > repeatedly from PWCs on this list who have had their glutathione

> > measured. Dr. Cheney found that glutathione depletion was

almost

> > universal in his patients, and reported this back in 1999. Dr.

> > Holtorf has been quoted on this list as saying that he no longer

> > measures glutathione in his CFS patients, because he had found

in

> > the past that they were all low. I don't think this is a

> > controversial point any more. True, there are some PWCs with

normal

> > or high glutathione levels, and I have suggested that this may

> > result from genetic variations in the enzymes that use

glutathione,

> > causing them to be less able to use it for the appropriate

purposes.

> > The results would be similar to not having enough glutathione.

> >

> > How does glutathione become depleted? It looks to me as though

it's

> > caused by a combination of genetic predisposition and some

> > combination of long-term physical, chemical, biological and/or

> > psychological stressors. Based on what I have learned recently

> > about autism and the similarities between many of the features

of

> > autism and CFS, I now suspect that the genetic predisposition

> > involves genetic variations in the genes that code for enzymes

and

> > other proteins involved in the sulfur metabolism, particularly

in

> > the methionine (methylation) cycle, the transsulfuration

pathway,

> > and/or the glutathione system.

> >

> > Running the above sequence backward, one has the basic etiology

and

> > early pathogenesis of CFS.

> >

> > Now, why does the RNase-L become cleaved, to form the low

molecular

> > weight version? It is known that the enzymes elastase and

calpain

> > are able to accomplish this. of these, calpain is normally

> > inhibited by intracellular thiols, of which glutathione is

normally

> > the most abundant. It seems likely to me, then, that depletion

of

> > glutathione would remove the inhibition from calpain, and it

would

> > be able to cleave RNase-L, which is observed.

> >

> > Does the activated and cleaved RNase-L have deleterious effects

in

> > CFS? No doubt it does. It is able to attack messenger RNA

> > representing the expression of normal genes in the cells, and

the

> > result of this has to be that there is less production of new

> > enzymes and proteins needed by the cells, and therefore their

normal

> > metabolism can be expected to be suppressed.

> >

> > There have been various studies showing correlations between

RNase-L

> > levels and other features of CFS. Do these correlations mean

that

> > RNase-L caused these other features? Not necessarily, and in

most

> > cases I suspect that it did not. The correlations could be the

> > result of glutathione depletion causing both the activated and

> > cleaved RNase-L and the other feature studied.

> >

> > Bounous and Molson hypothesized several years ago that there is

a

> > competition between the immune system and the skeletal muscles

for

> > the raw materials to make glutathione at the onset of symptoms

of

> > CFS. I think they were right about this. In the presence of

> > glutathione depletion, these two do compete, and neither one

> > actually wins, because there simply isn't enough cysteine

available

> > to make all the glutathione that is needed. The result is that

the

> > skeletal muscles experience partial blockades of their oxidative

> > metabolism due to the elevation of superoxide and peroxynitrite

in

> > the absence of enought glutathione to keep them under control.

The

> > mitochondria of the muscles are not able to produce ATP fast

enough

> > to keep up with the demand from normal muscle operation, and the

PWC

> > experiences physical fatigue. If they overdo, they dig

themselves

> > into a hole because of damage by reactive oxygen species, which

rise

> > because of the depletion of glutathione, and because of the

> > depletion of adenosine from the cells, which is difficult to

replace.

> >

> > At the same time, the PWC cannot mount an effective cell-

mediated

> > defense against the viruses, also because of glutathione

depletion.

> > I think that this mechanism explains the initial phase of the

> > pathogenesis of CFS for many PWCs. It agrees with known

> > biochemistry and physiology, and it explains the observations.

> >

> > Why has RNase-L activation received so much attention in CFS, if

it

> > is actually a downstream effect? I think there are several

> > reasons. First, it was one of the earliest biochemical

phenomena

> > discovered in CFS, because Bob Suhadolnik decided to look for it

> > early on, because of the seeming involvement of viruses in CFS,

and

> > the known action of RNase-L in viral infections. Second,

because

> > the development of Ampligen, which acts on RNase-L, showed the

> > potential for making a profit on CFS treatment. The order in

which

> > things are discovered is not related to the actual order of the

> > cause-effect sequence in a disease, however. In fact, the late

> > manifestations of the pathogenesis are often the most visible.

To

> > get at root causes, you have to track these manifestations back

to

> > their source, and not assume that they are the root cause of the

> > disease.

> >

> > Rich

> >

>

This list is intended for patients to share personal experiences with each

other, not to give medical advice. If you are interested in any treatment

discussed here, please consult your doctor.

November 16, 2005

" >

> CORT: In your poster you suggest a hypercortisolic state (high stress)

> probably precedes the 'mild' hypocortisolic state found in CFS. THere is

> not evidence for that yet - we should know, however, with the Dubbo study.

> "

Cort,

That is what I have great difficulty to understand.Alternative medicine has

known this for long time and treating their patients accordingly. It could

be that they do not give complete cure but at least,I believe they are on

the right track and they do not use sick patients as guinea pigs for their

high profit meds. For some reason mainstream medicine never concentrates on

cortisol and HPA axis subject. (ASI test,etc..) This really really drives me

crazy. Sorry for being emotional but I have suffered for so long that I just

can find any excuses for the mainstream medicine not to include this

cortisol studies in their researches.I can not find any explanation. I do

not know if you have read book of Dr. Poesnecker Chronic fatigue unmasked.

If you have not you might wish to give a look or you might wish to check

their website www.chronicfatigue,org . You will see that those alternative

practitioners have found out that cortisol is high at first than gets less.

They even have a saliva testing for that but unfortunately mainstream

medicine do not even accept this test.Mainstream medicine should first

accept and prove this and than should move into more complex subjects like

why HPA axis goes wild in the first place,why adrenals do not respond at

later stages,which brain parts are involved in continuous stress

trigger,etc.. But they have not even yet worked on this cortisol issue. How

long will it take them to go into other more important subjects and find out

the root cause. I don't know how many years of life I have left but I am not

sure I will be able to see the results of this slow going study.

" The question then is why at least some (certainly not all) CFS patients had

sufficient phsyiological problems dealing with long-term stressors that they

came down with CFS. "

That is exactly what the question is.That is what mainstream medicine should

concentrate on.

>

" > In your poster you suggested norepinephrine activation preceded GSH

depletion in CFS. (I accept that is probably happening in CFS). So what

causes that?

That would seem to be a good avenue of research. You also suggested

hypercortisolism; we'll see how that turns out but why would CFS patients be

more subject to hypercortisolism or perhaps more importantly, have a more

negative effect from it? "

Yes,Exactly?

>

Rich,

please do not think that my words are directly to you. I know that you have

done a lot of work on this illness and it could be that some day you may

also be one of the first ones who finds the root cause as I know you have

devoted yourself to this subject.

My words are in general to mainstream medicine and, sorry all,if I have gone

emotional. Cort's questions touched to a very sensitive point in me.

best wishes to all,

Nil

November 17, 2005

Marcia <mgrahn@...> wrote: I would note that trials of whey

protein in AIDS, which does have low GSH levels show that whey protein rather

quickly returns GSH status to normal. Based on that evidence I would suggest

that many CFS patients have indeed returned their GSH levels to normal, that it

has proved beneficial in some degree to many of them but it has in no resolved

their CFS. This suggests GSH is either depleted or not high enough in CFS

patients, probably due to high levels of oxidative stress but it does not

suggest GSH plays a central role.

I think in cases where mercury has been allowed to accumulate because of having

low gsh for some time, the mercury creates 'blocks' in our systems that along

with the other buildup of bacterial and viral infections will keep the gsh from

being brought back to normal.

CORT - that is an idea, another of the great untested ideas in CFS. I would

think since GSH is the master antioxidant increasing GSH levels would put one

back on the road toward mercury detoxification.