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A talk given by Assoc. Professor Tim K. Roberts of the Collaborative Pain Research Unit at the University of Newcastle, to the Hobart ME/CFS Support Group at the ME Awareness Week Public Meeting in Hobart, Tasmania, on 13th May 2000.
This is a transcript of the first part of the meeting, prepared directly from an audio recording by Kit Murdoch. Edited for accuracy etc. by Professor Tim Roberts and Dr Dougald McLean.
Contents
Introduction
Research testing
Chronic Fatigue Syndrome
Symptoms
Secondary Symptoms
Energy Pathway Dysfunction in CFS
The Proteolytic Response
Distinct Amino Acid Profiles
Urine Testing and Research
Urine Metabolites
Amino Acids
Ornithine and Ammonia Toxicity
Citric Acid
Underlying Infections
Flinders Island Rickettsia
Chlamydiae
PCR Testing
Gastrointestinal and Digestive Disorders
Neurally Mediated Hypotension
I represent a group of researchers in the University of Newcastle who have been looking at chronic pain and chronic fatigue for the last nine years. We have a group that I think works very together, and we've found some very interesting results.
We have also done studies on Fibromyalgia (FM), Irritable Bowel Syndrome (IBS), Temperomandibular Joint Dysfunction (TMJ), Scotoma and Scotopic vision (which is a problem some children have, where they have a difficulty in reading). We have also recently done some work on Autism and three sub-groups of Autism - Attention Deficit Disorder (ADD) , Attention Deficit Hyperactivity Disorder (ADHD), and Aspergers Syndrome. I'll be talking about those a little bit later.
The underlying situation, from the biochemistry that we've done, is that we feel that there is an indication of a change to the body's homoeostatis. What we have done is to try and develop that, to work out why it has occurred.
Very briefly today I'll show you some of the research that we've done. But most often I'll skip over that and try and get to what might be useful to you - that is, our indications of where your doctor could take you in treatment. I emphasise right from the start that our group is a group of biologists, a group of research scientists, so we are not clinicians in the sense of being able to deal directly with patients. But at the end of the day, I hope that I can say something useful.
What we've done, in our Collaborative Pain Research Unit (CPRU), is set up a series of tests on urine, on blood lipids, on faeces (where we measure the bacteria and look at the faecal lipids to see about uptake of fats from the diet into the body). We're also doing some bacterial work on detecting hidden infections and staphylococcal toxins.
When we did our first work, many CFS patients were very keen just to have the tests done. To see if, through our testing, they could see that there was a change in their normal body function, and thus get an indication that they had something organically wrong, rather than some psychiatric disease.
We were overwhelmed in the number of tests we had and eventually set up a company called Bioscreen. It is not my intention today to suggest that you should all race out and have our tests done. I don't think that's what I'm here for. What I'm here for is to try and tell you where research is at present into chronic fatigue, and what might be useful ways to go. So you'll see things about Bioscreen around the place. That is a company that we've set up to generate funds to do our research, and so far that part of it has worked well. Although I think, in a commercial sense, the company, outside the University, wouldn't be a viable organisation. But one day, perhaps!
So, what I'll do very briefly is to have a look at Chronic Fatigue Syndrome. I want to just bring to your attention that indeed we may be talking about individuals who are very, very sick; individuals who fit the clinical definition. That's only about 0.2% to 0.5% of the population. But there is probably 40% to 50% of the population with chronic pain or chronic fatigue. That represents a lot of you who are carers; people who are working, but are tired ... and so on. And we believe the same underlying basis is there.
The model that I'd like to give you is that there is some central phenomenon, which is some sort of underlying infection - most likely a bacterium or a number of bacteria - and that the infection there gives a set of symptoms. That infection then causes a whole lot of systems to "go down". I'll try to put those on the board as I go, so that eventually I can come up with what might be a list here of ways to go forward.
This study was done in the United States (34,000 households):
So that's what we're looking at. We're looking at a gradation of symptoms.
In terms of the principle symptoms of Chronic Fatigue Syndrome we're looking at fatigue for more than 6 months and then all of these other things that are there [22]. I'll let you have a look at those.
[A diagram was presented to the audience]
This central circle encloses those diseases that have this symptom set. Already we know that things like Typhus (Flinders Island Typhus) would have that symptom set. We know that Rheumatoid Arthritis would have that symptom set.
So what we can do is to consider that set of symptoms as a sponge cake and we can take out slices. We already know that this slice is called Rheumatoid Arthritis, we know that this slice is called Typhus, and we know that this slice is called Brucellosis and so on.
When we've excluded all those other illnesses (as your doctor has), we're left with this [ME, CFS, FMS, GWS etc]. My hypothesis is - there are a whole lot of other organisms that will eventually be new slices. So this number left here [ME, CFS, FMS, GWS etc] - that's you lot here - will diminish.
What that does though, is then give us a whole lot of secondary symptoms. Those secondary symptoms are:
Each time we treat one of these, we're dealing with what I call a secondary problem, which we believe is initiated by this primary problem.
So that's the hypothesis that we're looking at. What I'd like to do in the next twenty minutes (which is impossible!) is to give you a "flavour" of where we've been in our research.
Our first research was in looking at Chronic Fatigue Syndrome patients and normal subjects (controls) and running urine samples through the gas chromatograph and mass spectrometer - looking for molecules that might be different.
And we found differences between CFS and controls. We found differences in the normal energy pathways - the amino acids and the organic acids of the citric acid cycle and so on - and we investigated those. We also found new molecules, which we think are produced by these organisms we're looking for.
For those of you who may know about energy - we get our energy from our mitochondria, which are little organelles within cells that generate energy. We found the citric acid cycle, the urea cycle, the utilisation of amino acids for energy, was not occurring properly. And hence, we then have gone on to work with clinicians to show that indeed if you supplement individuals with amino acids then you have the chance of alleviating some of the symptoms.
What we've found in CFS (and in chronic pain, Irritable Bowel Syndrome, Autism, and scotopic sensitivity or dyslexia) is that there is a proteolytic response occurring. In other words, the body has gone away from using sugars for energy and fats for energy, and has started to break down "host" proteins [the body's own proteins] for energy. If that goes on for a long period of time we get a malnutrition of amino acids at the cells. And that's why we're promoting this [amino acid supplementation].
We believe that by measuring molecules in the urine we can show this proteolytic response occurring. But that's not new. A proteolytic response occurs if we have trauma. So, if an individual is involved in an accident their body goes into this defence reaction, if we have a chronic infection, if we have burns, etc. We think it is because the body is trying to generate new defence proteins from amino acids.
Amino acids are the building blocks. A protein is basically a "string of pearls" where the amino acids are the individual "pearls". And we have to break this bond, in order to get amino acids from the proteins we take into our body through food.
If we haven't got enough of them [amino acids] and the defence system wants to "get going", it then attacks our muscle proteins and our own [body's] proteins [intracellular proteins], breaks them down into individual "pearls" and uses them.
That is the sort of thing you see if you get a chronic infection - you wake up a day later and you've lost a kilogram of weight. Basically your muscles have "wasted" because you've used them for something else. We believe, in CFS, this process has been going on for a long period of time.
The other thing we do, in the testing we do, is that we look at a whole range of molecules. And, using complex statistics, we've been able to show that there are clusters of profiles of amino acids. We believe that these are going to be the way forward in working out the best sort of supplementation, and we'll probably find that they are a fingerprint of the organism causing the problem.
Some of you may have had a Bioscreen test done on the urine. What we've ended up with is this complex sheet of information that we believe is very useful to doctors who can interpret it -- and now the job of half the people up there [in the CPRU team at the University of Newcastle] is to try to get that message across.
But basically, in a nutshell, we're able to identify anomalies in the excretion of amino acids and organic acids. This can tell us if there is muscle catabolism going on. It can tell us if there is an underlying infection. And it can also tell us whether a particular amino acid supplementation may be useful.
We can also measure unusual markers in the urine, and from those we're looking to identify the organisms involved.
Let me talk about these "unknown metabolites". We've given them names like Urine Metabolite [or UM] 15, 13, 27 and 28. We find that we can grow bacteria in culture that produce these same molecules, in culture, as people have in their urine. Our aim is to match those, to see if we can find what organism we should be looking for as an infective organism in those individuals.
These molecules are associated with symptoms. For instance, one of these (UM15) is associated very closely with depression. And we have some bacteria that will produce UM15 in culture. So this is the kind of research approach that we're following.
At the end of the day, what may be "take home" useful is to look at what is causing this underlying proteolysis. And so we've come up with these [symptom] index reports. If there is a value greater than five we say that is significant. These two [non-fibrillar and fibrillar response] are indicative of proteolysis, and we would say that, if you've got high levels here, then ask your doctor to go away and look for an infection. In this case, if this one's high [Pain/Fatigue Type 2] it relates very strongly to dysfunction of the gut (and I'll be talking about the gut a little more as we go).
Whether you have a urine test done or not, if you have CFS it's highly likely that you're going to have specific amino acid deficits and it's highly likely that amino acid support would be useful. There are some people who use just [amino acid] mixes from the health food shop (eg. Aminocarb) and find that it works very well. We believe that eventually specific amino acid formulations will be useful.
Already there's a company in the United States (that was founded by Bralley and Lord ) called MetaMetrix that is doing this across the United States. There's a psychiatrist in California, Dennis Gersten, who's also using amino acid supplementation for treating a whole lot of psychiatric problems as well as other fatigue problems. And again, without articulating an underlying infection, he's found that the amino acid supplementation is very useful. So it's something that is worth following on . . . .
There are other people who have shown this amino acid problem. Indeed, there was one clinical trial that Bralley and Lord did based on blood amino acid deficiency where supplementation with amino acids gave good results in a trial on CFS patients.
There's another problem in the urine that we have seen. If you have high levels of ornithine, it's likely that you may have a problem with excessive ammonia. And often the symptoms of CFS are due to ammonia toxicity. Ammonia is liberated when we metabolise proteins. So we're breaking down amino acids for energy, which gives off ammonia. If you have too much ammonia then there's a problem. Treatment with alpha-keto-gluterate, which is available through Dr Vera's Formulations from Henry Osiecki in Queensland, proves to be very useful here.
We believe, if there are high levels of citric acid excreted, then there is likely to be taken out from the body the divalent cations of zinc, calcium, selenium and magnesium. So supplementation with minerals is really very important.
If we see there is evidence of catabolism, then we should check for underlying infections. The ones we suggest are:
- the toxin producing staphylococci
- the intracellular infections of mycoplasma & rickettsia - the chlamydiae.
Rickettsia is the group of organisms that cause Typhus, and if any of you have been to Flinders Island you may well have an undetected Flinders Island Typhus, because the symptoms are very, very similar [to CFS]. So if your doctor hasn't done that test or picked it up you may be saying, "I have Chronic Fatigue Syndrome," when indeed, it may well be that you have the infection of a rickettsia obtained during a visit to Flinders Island.
And there are many others of these organisms that we still haven't come across. The other major member [of the underlying infections group] that we need to look at is the group of Chlamydiae. Chlamydiae are probably going to be found to be the cause of heart disease. Heart disease that you associate with high cholesterol and stress, most likely is only an indication that you have an underlying Chlamydia infection. And I think we'll find, in another ten years, that the bulk of heart disease will be shown to be due to infection with this family of organisms.
So these are the hidden (occult) infections. The way to detect them is very difficult because we're still in the Dark Ages here in our medical system for detecting these. The best way to detect them is PCR testing.
You can have that done in the United States in Garth Nicholson's laboratory . You can also have it done in Melbourne Forensic Diagnostic Services with Bill Paspaliaris [or] the Australian Rickettsial Reference Laboratory in Geelong ... [Webmaster's note, January 2002: Dr Bill Paspialaris is now working from the Glenferrie Medical Centre in Hawthorne, Victoria.]
[There are tests for] antibodies against known rickettsia organisms, but the PCR reaction picks up the unknown ones, and my hypothesis is that there are a whole lot of unknown organisms that are causing problems.
If you've got "Pain/Fatigue Type 2" on our system, then we say to look at the faeces, perhaps do a faecal test, and look at ability to digest. The bulk of people with CFS have Irritable Bowel Syndrome (IBS). The bulk of people with Autism have IBS. The bulk of people with Fibromyalgia have IBS.
There is a disturbance to the gut and there is an inability to digest proteins and other foods. Often you will benefit from digestive enzymes.
Often you will benefit from the use of Betaine(?) hydrochloride to increase the hydrochloric acid from the stomach to help you to break down foods.
If we find high levels of Lysine, we say to check for Neurally Mediated Hypotension (NMH). NMH is low blood pressure. When you're standing at attention you'll feel very, very uncomfortable. You'll feel better lying down or sitting down. You go to the doctor and the doctor says, "Oh, your blood pressure is good! It's a little bit low, but it's good." But in fact low blood pressure that decreases on standing is a hallmark of NMH, or Orthostatic Intolerance, and needs to be treated. You treat it with high salt, such as five to nine grams of salt a day, and associated with that (because the problem comes from the adrenal glands) your doctor treats it with fludrocortisone (Florinef), or sometimes even liquorice root extract to stimulate the release of the mineral corticoids from the adrenal glands.
The Newcastle Research Team and Collaborative Pain Research Unit
The CPRU has ceased operating as a single unit. Assoc Prof Tim Roberts and Assoc Prof Hugh Dunstan are still researching pain and fatigue conditions at the University of Newcastle. Meanwhile, the other founder members of the CPRU - Dr Neil McGregor, Dr Henry Butt and Prof Iven Klineberg - and the Bioscreen company moved to Melbourne to continue research and pathology testing - but have recently (2005) ceased operations.
Bioscreen Pty Ltd
www.bioscreenmedical.com
Bio21 Molecular Science and Biotechnology Institute
Building 404, Room G6,
2 Park Drive, University of Melbourne,
Parkville, Victoria 3010,
Australia
MetaMetrix
J. Alexander Bralley, Ph.D, Chief Executive Officer
Richard S. Lord, Ph.D, Director, Technical Services
5000 Peachtree Ind. Blvd.
Norcross, GA 30071
PH 800-221-4640
FAX 770-441-2237
E-MAIL nutrition@metametrix.com
http://www.metametrix.com/
Dennis J. Gersten, M.D.
The Gersten Institute for Integrative Medicine
Website: http://www.aminoacidpower.com/
Alpha-keto-gluterate (AKG) is sold in Australia as a
product called
"Athletic Performance" [capsules containing 500 mg AKG and 10mg HCI
Pyridoxine], from:
Dr Vera's Formulations
PO Box 1472, Eagle Farm, BC, Qld, 4009
Phone: (07) 3868 8622
Fax: (07) 3868 0633
Product Line: 1800 625 934
Bio Concepts (Henry Osiecki )
PO Box 1492, Eagle Farm, BC, Qld, 4009
Ph: 07 3868 0699 Fax: 3868 0600
Practitioner Hotline: 1800 077 113
Email: info@bioconcepts.com.au
"Polymerase Chain Reaction (PCR) is a technique
which amplifies selected parts of DNA making it much easier to detect."
(Melbourne Forensic Diagnostic Services)
"Sensitive Method for the
Quantitative Detection of Mycoplasma Infections" by Aristo Vojdani, Ph.D. and
Paul C. Choppa, C.L.S.
Garth Nicholson
Institute for Molecular Medicine,
Huntington Beach, CA (USA)
http://www.immed.org
Dr Bill Paspaliaris (formerly
of Melbourne Forensic Diagnostic Services)
Glenferrie Medical Centre
738 Glenferrie Road, Hawthorne Victoria
See also www.kurlama.com for information on
Dr Paspialaris' work on adjuvant vaccine technologies.
Australian Rickettsial Reference Laboratory
(Director: Dr Stephen R. Graves)
The Geelong Hospital,
PO Box 281, Geelong, Victoria 3220, Australia.
Phone (03) 5226 7552; fax: (03) 5226 7940;
www.barwonhealth.org.au/arrl
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