The Third International Congress of Bioenergetic Medicine,
Sponsored by the Institute of Quantum and Molecular Medicine,
National College of Oriental Medicine and
The Florida School of Acupuncture and Oriental Medicine,
Clarion Plaza Hotel, Orlando, Florida
February 5-7, 1999
 

This lecture precedes a workshop that was given by Dr. Cheney on the same day.
These are notes, and are not word for word. Dr. Cheney refers to slides.
(The transcript of the workshop is also available.) 

INCIDENCE

.....There's a 4-city study in the United States conducted by the CDC--about 10 per 100,000; another study in Australia, 40 per 100,000. It seemed like every study around the world began to see larger and larger numbers. [There's] a question of whether the disease was more prevalent, or more physician diagnosis. The incidence is now thought to lie between 200 and 600 per 100,000, approaching almost 1% of the population. It is very common and extremely disabling. 

The disability in this syndrome is truly impressive. The largest insurance carrier in the U.S. reported huge increases from 1989 to 1993--in the case of men a 365% increase, and for women a 557% increase. This is the highest increase of any disease covered by this major disability carrier. 

There seems to be [an increase] with each passing year, beginning in the late 70s but especially in the 1980s. The data base in 1990 asked the date patients became ill. It stopped in 1990 because that's when I asked the computer [......?]. It peaked in 1987, and after a couple of years there was a slow decline and then a rapid dropoff. It's probably fictitious. They usually come after they've been sick 4 or 5 or 6 years down the road. And then in 1994, I hit the button again and in each instance, the peak production remained fixed. In 1987, suggesting that there might be a point epidemic, peaking in 1987. Again the total number of cases continues to rise. There are still new cases being produced all the time. 

A group in England, Ramsay's group, saw a similar peak, again 1987. In Minneapolis a group headed by Paul Peterson, again 1987. 

There may be something that began, almost at the same time HIV began. There may be a link between this syndrome and HIV disease. 

PHYSICAL FINDINGS

Physical findings are readily seen, and are a sort of basis for the belief that it's a real disease in my mind. In the case control study that we did, there's frequently lymphatic tenderness, not lymphatic enlargement. By placing your hands on the posterior cervical chain and the supraclavicular node chain compressing these areas left to right, patients will commonly complain that they are tender, left side more than right. The reason it may be left-sided is the anatomy of the thoracic duct, the left is the main terminal vessel, eventually emptying into the left jugular. Immune activation states would be expected to back up and fill these vessels. 

If you just ask if it's tender they frequently produce tenderness. Tender swollen areas can go up and down very rapidly. Another physical finding--the crimson crescent, sort of purple, found in about 80%. 

When you use a reflex hammer out, move away from these people as you tap. About 80% are hyperflexive. Balance is always aberrant. Patients almost always fall over. Test the Romberg, tandem stance and ? with eyes closed. This particular one is so frequent, it was published in a Harvard journal--a defect in vestibular apparatus. 

About 10% progressively lose their fingerprints. There's disruption. This generates interest with the FBI. People can't teach if they can't furnish fingerprints. The pathophysiology--lymphocytic ..it is that penetrates the vessels that engorge the areas around these vessels and may impair nutritional flow. Also they have punched-out lesions within the fibroblasts themselves. Fibroblasts make collagen, and it's necessary for the ground substance. 

IMMUNE ACTIVATION

What does it all mean? One category is something is wrong with the brain. The hypereflexia, these 2 particular findings are easiest to access in the clinic. Second, they're immune activated. Even the loss of fingerprints is immune activated. 

I'll describe a particular case control study in the workshop this afternoon. With regard to immune activation there is a great bulk of published literature, all kinds of studies showing this. Here's a little study we did on the interleukin receptor. It's just one measure of immune activation. These people are without a doubt immune activated. 

RNASE-L

This paper by Suhadolnik is important. It's the most important conceptual idea in the field, interferon in a cytokine activated by a white cell, typically in response to a viral infection, or perhaps an intracellular pathogen. Interferon sits down on its receptor and on the cell membrane around the body and ultimately activates the enzyme system within the cell. That system's called the 2-5A synthetase pathway. It consumes a great deal of ATP and it ultimately activates this enzyme called RNaseL . This enzyme is present in essentially every cell in the body and has a very interesting purpose. Under normal circumstances this enzyme regulates protein synthesis so that when you're a little bit under a certain set point for protein synthesis--we're talking about hormone or other enzymes that operate the cell--if you're a little bit under this, the system down regulates and you come back up. And if you're a little bit over this, the system ramps up and you come back down. So it has a kind of regulatory function for protein synthesis. It also has a supra-physiologic function--namely when infected with a virus this system activates significantly and tends to chew up messenger RNA encoded by viruses, and that RNaseL then becomes a potent anti-viral weapon as it sits there and chomps messenger RNA from the virus and that virus is decoupled from its
DNA or RNA and can no longer replicate. So it has a physiologic function of regulating human protein synthesis and a supra-physiologic function when ramped up of destroying RNA encoded by viruses. 

The way you measure this is you take the patient's blood and you extract the cytosalic (....?) of the lymphocytes and you put it in a test tube and a target ribosomal RNA is used, and they'll measure how long it takes for the RNA cell in that white cell cytosalt (?) to digest the ribosomal RNA target. And typically human beings will digest some of this target in about 20 minutes and leave certain residual products that then migrate on these gels. In the case of chronic fatigue syndrome, the rate of digestion is so great that they will digest in 20 seconds ribosomal RNA target that a normal human being cannot digest in 20 minutes. And when you digest frequently or quickly these target molecules you end up with very digested components that migrate off the gel and you end up with these blank strips. And so in the Lake Tahoe region about two years ago, where we first saw this disease, you would run this assay and all you would see would be blank strips because they had huge activation of this enzyme system. 

This is a quantitation of the RNaseL activity in the patient population compared to the normal population. Interestingly, though, some CFIDS patients have normal values. Perhaps in the workshop we'll go into them. They're really quite interesting. They represent a different stage in the illness. 

A particular drug called Ampligen, which a piece of genetic material, actually it's a piece of double-stranded RNA which regulates this RnaseL pathway, was applied to patients in a double-blinded placebo-controlled trial in the early 90s, of which I was a party. And this is the structure of Ampligen, and it's mismatched in a couple of regions or RNA to make it ephemeral. It only lasts about 8 minutes before it's destroyed by the body, It's not very stable, but it has a biological life of much greater... 

Since it regulates the RNaseL pathway, the thought was that if you could regulate that back down to normal, the patients would... and indeed that's essentially what we saw. This is the placebo, this is the treatment limb, and in about 24 weeks they were clearly separated. They tend to get better and better as time goes on and it appears now that treatment may have to extend to even 18 months to get these patients to where they can return to work. 

HHV-6

Also, in addition to activation of the immune system, particularly this RNaseL pathway, evidence of common and ubiquitous human herpes viruses, ranging from EBV to CMV to HHV-6 and to other viruses were frequent. This is a study out of the NIH showing white cells in culture. These are normal white cells, the small ones. These are large giant cells infected with HHV6. The HHV6 strain A is a lytic virus. It replicates rapidly within the white cell. The white cell expands and then it explodes, releasing thousands of virions into the blood that then move out and infect other cells. This is basically a fluorescent microscopy stain using antibody tags to identify them. In fact these large cells are infected with HHV6. 

HHV6 was first discovered in HIV disease. In fact HIV and HHV-6a seem to be an important dual combo in generating the disease we now know as AIDS. If there is any relationship between HIV disease and chronic fatigue syndrome it's most acutely HHV6. This is a virus they share in common, with a frequent culture positivity rate of about 70% in these cases. 

BRAIN DISORDER

In addition to immune activation, particularly this RNaseL pathway, and also evidence of activation of common human herpes viruses, brain disorder is impressive in this disease, and it comes in different forms in terms of clinical presentation. They say, "I've lost my mind, I can't think very well, I can't process information, my memory is shot, I can't think very quickly, I'm overwhelmed." It may come emotionally as molehills become mountains. "I'm depressed, I'm irritated, I don't know what's wrong with me, I'm not myself." And it comes in other soft neurologic findings of balance disturbances, and hyperreflexia and disorders of locomotion and it's really quite an impressive disease from the brain standpoint. 

This is a nice study out of Harvard which looked at functional scans of the brain using a SPECT scan that measures blood flow and they compared chronic fatigue syndrome with AIDS dementia complex and with depression. They wanted to see if the disorder of brain dysfunction was more like AIDS dementia complex or if it was more like depression or maybe it wasn't even there at all. 
 

They took scans of the deep brain that sliced through the thalamus, as against scans to the cerebellum, and they took these ratios of one cut to another cut to factor out natural variations in blood flow, which occur in all of us from moment to moment and from time to time. By taking a ratio they factored out these natural variations in blood flow and got lower variances. What they found essentially was that CFIDS and AIDS dementia complex cannot be distinguished. They look identical by this cut analysis, as opposed to depression and normal people, which look identical by this particular analysis. 

What's interesting about this of course is that HHV-6, which is a virus shared in common, attacks the brain, and specifically likes the central brain region. Also seen are MRI (?) scan lesions, most commonly these punctate lesions. I guess you can see them here. In the high cerebral convexity they are seen in about 80% of cases, also seen in older people so they're not necessarily abnormal except by age. But in some cases there are far more significant types of lesions really more reminiscent of multiple sclerosis. There's a lot of relationship clinically in some cases between MS and chronic fatigue syndrome, although they're differentiated clinically as well. 

You can examine the brain more carefully using a dual chromatography technique on cerebral spinal fluid, which we did some years ago in Boston, and you can separate out the chronic fatigue syndrome patients due to metabolic aberrations in the cerebral spinal fluid quite readily from the normal population, suggesting that this is severe metabolic disturbance in the brains of these patients. 

Perhaps one of the more important publications out of the National Institutes of Health in this disease has to do with aberration of the hypothalamic-pituitary-adrenal axis. This particular study was launched initially to prove that this was depression because the HPA axis is deranged in a certain way in depressed people. Instead what they found was that the axis was in fact deranged, but was the opposite of depression. Rather than activated, which it is in depression, these patients had a suppression of this axis, indeed a suppression of the adrenal axis, localized to an injury to the hypothalamus, as proven by this paper. 

We've extended this study a little bit by looking at cortisol response to stress. It is known that the stress hormone system responds significantly to a defined stressor, in this case, exercise. In the case of CFIDS versus control groups where the cortisol typically doubles, depending how sick they are--the walking wounded, or can't work but can take care of themselves--versus having trouble taking care of themselves--these are different functional categorizations kps (Karnofsky?) scores. The cortisol level dropped and dropped and actually reversed in the more significantly ill, meaning that rather than having an augmented adrenal response to stress they actually had a reversed adrenal response to stress, which is the fundamental reason they cannot work, because you cannot work if your cortisol axis goes south instead of north in response to a stress situation, you simply can't function in the workplace. 

NARCOTIC ANTAGONISTS AND AGONISTS

This slide is a pathophysiologic summary of all that I've said before. This disease begins as an immune activation state--could be a toxin, a viral trigger or some other process, initiating alpha interferon, which then activates the 2-5a RNaseL pathway. This RNaseL pathway really disrupts cell metabolism. It can affect every single enzyme system and every single hormone and every single structure in the cell. It has a devastating effect. I think the center of focus for this metabolic derangement is in the area of detoxification defects. The alpha interferon can also injure the central nervous system directly through the opium receptor, because in rat studies it's been observed that alpha interferon's injury to the deep brain can be blocked by narcotics or narcotic antagonists. 

Let me explain why some of the patients respond well to narcotic antagonists and agonists. The neurotoxicity seems to be centered at the hypothalamus, which can downregulate the cortisol access, and if that happens you're in a positive feedback loop. As you downregulate the HPA axis you upregulate the immune system and you're kind of in a vicious cycle and it can go on and on and on for years.

ENERGY PRODUCTION

To look specifically at energy production, since this is a fatiguing illness, we elicited the support of a group at U.N.C. Chapel Hill to look at mitochondria, using a very interesting laser scanning microscopy that allows you to look at a single mitochondria in a living cell, and measure its energy production. 

This is actually what it looks like under fluorescent (fluorescence?) conditions and in a computer-generated coloremetry (?) and essentially the reddish areas are hot energy generation of a single mitochondria in a single white cell--see this round structure here?--it's a lymphocyte stuck on a glass, and the little dots of light that you see are the actual mitochondria, making energy, making ATP, and the intensity of this fluorescense (?) light is proportional to the inner membrane mitochondrial potential, which is proportional to ATP generation. So you're actually looking, in this coloremetry model, at the actual energy production of the cell. 

If you plot the different mitochondrial distributions of energy production, this is a normal map--most of the mitochondria operate at a very high energetic level with inner membrane potentials of 180 to 240 milligalls (?), but a subset of mitochondria operate somewhat lower. I don't have the slide to show this, but chronic fatigue syndrome patients are the exact opposite of this, they're the mirror image. Most of their mitochondria are operating down here; very few are operating up here. Indeed there is a significant derangement in mitochondrial function. They're essentially browned out--almost like a rheostat (?) tuning down their mitochondrial energy production. And it's quite generalized, suggesting a metabolic origin as opposed to a point mitochondrial problem or a cell-specific mitochondrial problem. 

Which brings me to a generalized concept, and we'll conclude here in just a few minutes, and that is what about chronic fatigue syndrome as a xenobiotic toxicity disorder. As I said before, the RNase activity significantly disrupts cell enzyme function, and if you were to disrupt cell enzyme function across all organ systems you might ask the question, what would make you feel the worst? if your brain was down regulated energetically, functionally. How would you feel? If your heart was down regulated energetically or functionally how would you feel? 

LIVER

It turns out that the organ system most responsible for how you feel, or whether you feel bad, is your liver. If your liver doesn't work you are rapidly poisoned by the lowest common denominator of the body, and the lowest common denominator of the environment. Indeed, the poor circulation is so toxic that if you were to remove the liver you would probably start seizing from toxic encephalopathy in a matter of minutes. The poor circulation in extremities is an extremely toxic place, only modulated by the toxicity of the bowel. There are other obvious external toxicity factors and other internal toxicity factors, but we believe that the toxicity of this disease is centrally bound up with this disorder of detox functionality brought on by this heavy RNaseL activity. 

The first people to actually measure this were these patients being poisoned by their own bodies. This is a group out of Newcastle near Sydney Australia, headed by Dunstan and McGregor. Dunstan's a brilliant biochemist, and they would do lipid?/liquid? Hypersomething chromatography (?) on urine and measure essentially metabolites coming from microorganisms in the g.i. tract. 

And they found, this is my attempt to freehand draw a urine chromatograph (?) and I'm sorry about it, but, at any rate each of these spikes represents a metabolic waste product--could be human waste or non-human waste. Many of these are toxic although not all of them are toxic. But they found in position 12, which they labeled chronic fatigue syndrome urinary marker 1, this particular toxin correlated very well with their measure of symptomology of this disease. So they called it CF (?) Sum (?) 1. They would subsequently find others in these chromatographic technologies that also related to subsets of symptoms.
This is the correlation co-efficients for CFS Sum 1, against all the major symptoms of chronic fatigue syndrome. Also another one-- CFS 2 (?)--you can see it doesn't quite span as many symptoms as CFS Sum 1 and beta alanine, which is a bacterial xenobiotic. 

With regard to xenobiotics, the g.i. tract is of course a significant source of xenobiotic toxicity, but a major source of xenobiotic toxicity are root canal teeth. Root canal teeth can be easily infected with microorganisms about 60% of the time, anaerobes (?) about 40% of the time, candida species. And these species sit in the labrynth of the teethÛthe so-called dentin, which is like a piece of dead coral in a root canal tooth. And these things can elaborate huge xenobiotic toxicities, molecules, that in the absence of effective detox, can really lay you low. 

These are actually some of the important enzymes of energy production inhibited to the tune of 90% by these toxins, done by the toxicology lab at the University of Kentucky. These are three patients whose root canal teeth were extracted and sent to the University of Kentucky and measured for this toxicological feature. This is normal, and this is the level of inhibition of phosphoglycerine (?) kinase, an important enzyme in energy production. And so the point is, again, in the absence of effective detoxification, you become sick to the lowest common denominator of toxicity in your body, and that may be your gut--in most people--root canal teeth in some people, cavitations in some people, and environmental toxins can be the tip of the iceberg for this. 

So this little diagram sort of demonstrates this. The bowel is a source of toxins, the toxins are the little green balls, the root canal and cavitation are a source of toxins, the liver sits here, and by phase 1, phase 2 detoxification can convert or transform these toxins into water soluble forms, which are then excreted in the kidney. If that doesn't happen, these fat soluble, often fat soluble, toxins get loaded into fat structures of the body, particularly the central nervous system, and in particular the deep structures of the brain surrounding the hypothalamus, which is very leaky from a blood/brain perspective. And so these things can load into the brain and cause significant neurotoxicity. Obviously root canal cavitation production of these has a direct access to the brain because they can actually bypass portal circulation. 

GLUTATHIONE

So we began to focus more and more on glutathione deficiency, because it was the one feature of detoxification failure that was being seen over and over and over again, and if you look at this particular molecule I think you begin to appreciate as you read about it that the glutathione molecule is the central detox molecule for the cell. 

And we found evidence of whole blood glutathione depletion compared to normal population and evidence of functional impairment by urinary lipid peroxide elevation, which would be expected in a setting of whole blood glutathione depletion. 

In addition we found a peculiar deficiency of selenium within the white cell compartment, not so much other places, as more severely expressed in the white cell. Selenium deficiency would profoundly affect glutathione functionality. Also, if you found glutathione deficiency, you would expect to see significant problems with Vitamin E and if you want to measure a vitamin deficiency in this disease, the most severe one is Vitamin E. Glutathione and Vitamin E are important (...?), they sort of couple to each other, and they recycle each other, so deficiencies in glutathione will lead to excessive consumption of Vitamin E. You see this severe depression of Vitamin E here. 

With regard to glutathione, a fact that's little known and little recognized, is that glutathione is an important and very powerful anti-microbial. This is a study published out of PNAS (?) BY Anthony Falci, no less, of the NIAID, which showed that in HIV culture systems within four days of culture you can get logarhythmic growth of HIV by injecting a chemical known as 4-ball (?) ester. It's a very powerful inducer of viral replication. But if you raise the glutathione level to just 15 millisomething (?) in the same culture disc, and reapply the 4-ball (?) ester, you get absolutely no response from the HIV. 

In other words, glutathione is probably one of the best anti-virals there is. And the converse is true. In glutathione deficiency you become susceptible to whatever is in you, and it can then activate. 

With regard to the selenium issue, there are viral genes expressed in HIV. These genes are also found in other lytic types of viruses such as hepatitis B and hepatitis C; they are also suspected in HHV6, strain A, which is a lytic virus. These genes can encode selenium proteins, which consume large numbers of selenium atoms, which results in selenium depletion at the cell level, glutathione deficiency and ultimately apoptotic cell death. So the presence of these viruses that carry this gene can preferentially knock out glutathione systems. 

So to conclude, glutathione has potent anti-viral properties; CFS patients are glutathione-deficient; glutathione deficiency has potent pro-viral effects; selenium protein (?) in cutting (?) genes could provide a significant survival advantage (something?) to the viruses. 

I'll present this at the workshop this afternoon--ways, in this case nutritional ways, to support and build up this glutathione system, which if you don't do, it's very difficult to help these patients to detoxify from whatever. In fact, their primary detoxification system is impaired. 

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