Jim Clements' Hypothesis

[Guest guest]

Jim,

Welcome to the list! I listened to your presentation, and I would say

that in my opinion you are basically on the right track and have a

good understanding of the biochemistry of intermediary metabolism and

an ability to explain things well. I, too, have some background in

engineering (and also some in the physical sciences) and have been

trying to piece together what's going on in CFIDS and FMS, in my case

for about three and a half years. I can identify with your systems

approach, and I think that this is just the kind of approach that's

needed. My impression of the professional researchers in CFS is that

they confine themselves pretty much to their own specialties, and

don't venture out of their boxes very far to try to tie the whole

disease process together. I can understand why they do this, in view

of their funding mechanism, but I think it delays progress in

understanding these disorders quite a bit. I posted my " metabolic

pathogenesis hypothesis " to this list and several others last spring.

You can find it by looking me up in the archives. It was one of my

first messages to this list. It's good to know another person in what

I call the " metabolic camp " of CFS researchers.

I am in agreement with you on quite a few things, but also differ with

you in several ways. First, I don't believe that it is valid to lump

together all the observations that have been made in these disorders

and say that they all apply to a single population of PWCs. I did

this at first, also, because it is the Occam's Razor approach. My

Ph.D. research training was in the physical sciences, and that's the

approach commonly used there. However, as I took a careful look at a

larger number of individual cases using detailed questionnaires, I

concluded that we are really dealing with at least several subsets

in the total population of PWCs, and that they have different

histories, different biochemical parameter values, and

different outcomes with various treatments. They are not all the

same. Furthermore, I see big differences between the " pure " FM people

and the " pure " CFS people in terms of their histories, their symptoms,

their biochemical parameters, and their results with various

treatments. I don't think it's valid to lump them all together,

although it may well be that inside the cells involved, the same

things might be going on. It may be that different cell types are

involved in pure FM and pure CFS, such as nerve cells for the former

and muscles cells for the latter.

I might add that the professional researchers are now trending toward

this same non-lumping point of view, as evidenced by recent papers and

by the talks at the State of the Science meeting. One speaker noted

that in the original Fukuda paper on the definition of CFS, it was

already stated that the population so defined was not homogeneous.

The current definition of CFS takes in all the subsets of PWCs,

because they have essentially the same set of symptoms, but they

didn't all get there in the same way, in my opinion.

I agree with you that the crux of the pathogenesis of these disorders

is in the intermediary metabolism, and I gather that Dr. Cheney agrees

also, as he talks about mitochondrial dysfunction that is not genetic.

I believe that all the PWCs have partial blockades in their

intermediary metabolism (this is the same concept as Dr.

Conley's " functional blocks " in his book America Exhausted), which

decrease the production of ATP, and that explains why they have

essentially the same symptoms, but I don't believe they all have the

same route toward getting the partial blockades, nor do I believe that

they have the same partial blockades.

I agree that a problem in oxygen supply probably accounts for one or

more subsets, but the oxygen supply problem does not result from B12

deficiency for all the cases, even in this general category. Other

possibilities are (1)hypercoagulation, a la Berg, which leads to

fibrin in the capillaries, which impedes the diffusion of oxygen into

the tissues, (2) carbon monoxide poisoning, a la Albert Donnay, which

blocks uptake of oxygen by hemoglobin, and also blocks transfer to

cytochrome oxidase, and (3)lung insufficiency, due to past pneumonia

or histoplasmosis or other serious lung disease that damaged the

lungs.

Furthermore, I don't believe that deficient oxygen supply is actually

the root cause for the main subset of PWCs. Rather, it looks as

though the main subset suffered a combination of stressors (emotional,

mental, chemical, biological, and physical) which resulted in

depletion of their glutathione and increased secretion of cortisol. A

wide range of stressors has been found to cause these " common

denominator " effects. This combination led to suppression of Th1

(cell-mediated) immunity, and the glutathione depletion itself led to

a degradation of Phase II detoxication in the liver and partial

blockades in the Krebs cycles of the muscle (and in cases of FM, the

nerve) cells because of the rise in peroxynitrite concentration

allowed in the absence of glutathione.

The suppression of Th1 immunity made the PWCs vulnerable to viruses,

yeast, and intracellular bacteria, which established infections. The

degradation in Phase II detoxication led to buildup of toxins, which

produced direct cytotoxic effects and also produced chemical

sensitivities, when the immune system responded to the elevated

concentrations. The partial blockade in the Krebs cycles of the

muscle cells produced the fatigue and muscle weakness because of the

ATP shortage. The partial blockades in the Krebs cycles of the nerve

cells also produced an ATP shortage, which led to problems in powering

the Na-K ATPase ion pumps, and thus lowered the membrane potentials

and thus the threshold for firing. This shortage also perturbed the

osmotic potential because of lack of the normal 3 for 2 Na to K ion

exchange, leading to imbibition of water by the cells and swelling,

producing pressure headaches, and in some, the use of Chiari surgery.

The partial blockades in the Krebs cycles led to the rise in pyruvate,

and in some cases lactate, because the pyruvate flow into the Krebs

cycles is reduced, as you noted. Fat cannot be metabolized at a

normal rate because this requires a complete Krebs cycle.

Carbohydrates cannot be used at normal rates in many PWCs because the

partial blockade at aconitase in the Krebs cycles causes a rise in

citrate, which downregulates phosphofructokinase in the glycolysis

chains. This leads to the stubborn weight gains in many PWCs. The

pain comes from the lowered firing thresholds in the cells of the

nervous system. Because the muscle cells cannot burn carbohydrates

and fats at normal rates, they turn to amino acids, by anaplerosis,

which does not require a complete Krebs cycle. This lowers the amino

acid concentrations in the blood, which robs other cells of the

substrates needed to make neurotransmitters, hormones, and other

substances. This also accounts for the problems with fingernails,

which are made of alpha keratin, which must be synthesized from amino

acids. The magnesium depletion is caused by chelation in the blood by

the elevated citrate, and loss in the urine. The misshapen red blood

cells may result from depletion of glutathione in these cells, so that

they cannot protect against oxidative stress. I agree with your

analysis of the breathing problems. I wonder if the low total RBC

numbers are caused by premature death of the RBCs because of

glutathione depletion.

I'm not sure you're right about the cause of reflux. Dr. Cheney says

it's a result of low stomach acid, but that the problem is that the

pyloric sphincter doesn't open when the pH in the stomach is not

sufficiently acid. Normally, the pancreas doesn't put out sodium

bicarbonate to neutralize the HCl until some acidic chyme enters the

duodenum and triggers the secretion of secretin by cells there, which

signals the pancreas to put out pancreatic juice, including sodium

bicarbonate.

Concerning Dilnaz Panjwani's work, I'm told by Young in Australia

that when she looked into it further, she found that the 2,3 BPG (DPG)

was actually elevated in PWCs. This makes more sense, because the pH

of the blood is more alkaline than normal, as you noted, and this

tends to cause the 2,3 BPG to rise in an effort to displace the oxygen

from the hemoglobin, as you noted.

You alluded to Dr. R. St. Amand's hypothesis about excess

phosphate reabsorption. My opinion about this at present is that it

applies to a subset closer to the " pure FM " category than the " pure

CFS " category. I think the mechanism here is that the excess

phosphate ties up magnesium inside the mitochondria, and this

downregulates the pyruvate decarboxylase and/or the isocitrate

dehydrogenase, thus introducing partial blockades before and within

the Krebs cycles. I might add that Dr. St. Amand does not agree with

me on the mechanism, at least not at this point!

I think those are my main comments. I hope this is helpful, and I

hope you are able to help many more people with your approach. I

would suggest that you develop some criteria for PWCs to use up front,

though, to determine whether they are in the subset or subsets that

will be helped by your approach, since I fear that there will be quite

a few who will not be. When I first started looking into these

disorders, I thought that there would be one answer for all, but I no

longer believe this. I don't like the term " garbage can diagnosis, "

but I have been forced by the data that I have seen to recognize that

doctors have placed many miscellaneous cases into the CFS bin, and in

many cases, legitimately so, because they satisfy the broad definition

of Fukuda et al. for CFS. But they do not look at all homogeneous

when you start taking a close and detailed look at their stories.

Best regards,

Rich Van Konynenburg

>

> Hello cfsfmexperimetal egroup members,

>

> My name is Jim Clements. I do not have CFIDS/FMS but have helped

> some people with the condition to reverse their symptoms. My long

> range intention is to bring the products that I have used to the

> market at an affordable price but that is down the road. I will not

> be trying to market anything on the list but would like to share the

> results that people have found. And, also learn from those on the

> list that are actively searching and proving things from themselves.

>

> If you would be interested in reading/studying my theory on the

cause

> of FMS I have put the presentation online at the following URL

>

> http://www.xmission.com/~total/temple/index.html

>

> enter the site, click PROGRAM, click " FMS:A Hypothesis of Etiology "

>

> If you see any glaring flaws in the hypothesis I would appreciate

your

> input.

>

>

> All the best,

> Jim

> clements@x...

[Guest guest]

Rich,

Thank you for the excellent post. I will have to print it out and

go over it more thoroughly. You have brought up some very good points

that I need to investigate further. I would like to comment on just a

couple of things that you mention.

> >

> > Hello cfsfmexperimetal egroup members,

> >

> > My name is Jim Clements. I do not have CFIDS/FMS but have

helped

> > some people with the condition to reverse their symptoms. My long

> > range intention is to bring the products that I have used to the

> > market at an affordable price but that is down the road. I will

not

> > be trying to market anything on the list but would like to share

the

> > results that people have found. And, also learn from those on the

> > list that are actively searching and proving things from

themselves.

> >

> > If you would be interested in reading/studying my theory on the

> cause

> > of FMS I have put the presentation online at the following URL

> >

> > http://www.xmission.com/~total/temple/index.html

> >

> > enter the site, click PROGRAM, click " FMS:A Hypothesis of

Etiology "

> >

> > If you see any glaring flaws in the hypothesis I would appreciate

> your

> > input.

> >

> >

> > All the best,

> > Jim

> > clements@x

[Guest guest]

Jim,

Here are some comments on your post.

Rich

>

> One key difference reported in different research results was that

in

> the case of FM, there is a decrease in lactic acid production, and

in

> CFIDS there is an increase in lactic acid. This difference is no

> doubt going to spawn all kinds of different responses in other body

> systems.

Jim,

Which references are you using on lactic acid in FM and CFIDS? I

wasn't able to figure it out from your webpage.

> I've lately been pondering in this area. With a bottleneck in the

> processing of glucose at the mitochondria it could back up glucose

and

> fats in the bloodstream. The pancreas, sensing the increase in

> glucose, secretes more insulin, which is responsible for helping the

> glucose into the cell. Sounds like the makings for type II

diabetes.

Jim,

This is what I think goes on, also. Many PWCs have been found to have

elevated basal insulin levels in their blood. The insulin pushes the

glucose into the liver and fat cells and converts it to stored fat.

If the pancreas can produce enough insulin, and the liver and fat

cells continue to be responsive, the fat storage and weight gain will

continue. If the pancreas can't produce enough insulin, or if the

liver and fat cells become insulin resistant, then Type II diabetes

will ensue. Some PWCs do have Type II diabetes, but most don't.

Another thing that elevated insulin does is to prevent the muscle

cells from releasing amino acids to the blood from the breakdown of

nonmyofibrillar protein. This may contribute to the low blood amino

acid levels in some PWCs.

>

> I was not aware of the triggering effect that pH had on the pyloric

> valve. I think that if there are insufficient alkalizing agents to

> neutralize the acid produced in the stomach that in time the

quantity

> and acidity of the stomach acid will be reduced because the

digestive

> system knows not to produce more than it can neutralize.

Jim,

I have not yet verified Dr. Cheney's claim that the pyloric sphincter

is sensitive to stomach acid. My physiology book (Guyton & Hall,

ninth edition) doesn't say that. It does say that it is sensitive to

gastrin, and that gastrin also stimulates acid secretion, so maybe

it's really sensitive to the acid that the gastrin stimulates. But I

don't have that nailed down yet.

> > Concerning Dilnaz Panjwani's work, I'm told by Young in

> Australia

> > that when she looked into it further, she found that the 2,3 BPG

> (DPG)

> > was actually elevated in PWCs. This makes more sense, because the

> pH

> > of the blood is more alkaline than normal, as you noted, and this

> > tends to cause the 2,3 BPG to rise in an effort to displace the

> oxygen

> > from the hemoglobin, as you noted.

>

> Do you have a reference for this.

Jim,

Sorry, I don't have a reference for this, but I will ask if he

does. I do think we have to be careful about accepting research

results at face value. People do make mistakes, sample populations

are often small, and the current definition of CFS is pretty broad.

>

> From what I have read the tranfer of O2 into the cell relies more

upon

> osmotic forces and 2,3 DPG only comes into play to temporarily

> compensate in potentially hypoxic creating conditions.

Jim,

A comprehensive computer model that incorporates 2,3 BPG (DPG) was

published recently (P.J. Mulquiney, W.A. Bubb, and P.W. Kuchel,

Biochem. J. (1999) 342, 567-604 (three papers printed back to back)).

I think this model supports what you are saying. The pH effect (Bohr

effect) that results from the lower than normal CO2 concentration

appears to be a bigger factor in determining the release of oxygen

from hemoglobin in CFS than does the 2,3 BPG. It would really be nice

to have some hard, published data on venous CO2 pressure and venous

pH in PWCs. Dr. Cheney reportedly says he nearly always sees high pH

and low CO2, and I think that makes sense, but it would be nice to see

the data.

Rich

[Guest guest]

Rich,

Here are the two pages that I have used to support that FMS is low

in lactic acid production and CFIDS is high in lactic acid production.

Glycolysis abnormalities in fibromyalgia.

http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?uid=8006296 & form=6 & db=m & Dopt\

=b

RES: New CFS Evidence Emerges in Australia

http://listserv.nodak.edu/scripts/wa.exe?A2=ind9905C & L=co-cure & P=R1203 & m=2102

So in the case of FMS there is a buildup of pyruvate and in the case

of CFS the pyruvate seems to be processed into lactic acid. I agree

that you have to be careful what you take as being accurate

information. Prove everything.

Jim

clements@...

> > One key difference reported in different research results was that

> in

> > the case of FM, there is a decrease in lactic acid production, and

> in

> > CFIDS there is an increase in lactic acid. This difference is no

> > doubt going to spawn all kinds of different responses in other body

> > systems.

>

>

> Jim,

>

> Which references are you using on lactic acid in FM and CFIDS? I

> wasn't able to figure it out from your webpage.

>

>